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Use of a particulate respirator is recommended during aerosol-generating procedures when the aerosol is likely to contain M. tuberculosis, SARS-CoV, or avian or pandemic influenza viruses. # II.G. Patient Placement II.G.1.Hospitals and long-term care settings.Options for patient placement include single patient rooms, two patient rooms, and multi-bed wards.Of these, single patient rooms are prefered when there is a concern about transmission of an infectious agent.Although some studies have failed to demonstrate the efficacy of single patient rooms to prevent HAIs 791 , other published studies, including one commissioned by the American Institute of Architects and the Facility Guidelines Institute, have documented a beneficial relationship between private rooms and reduction in infectious and noninfectious adverse patient outcomes 792,793 .The AIA notes that private rooms are the trend in hospital planning and design.However, most hospitals and long-term care facilities have multi-bed rooms and must consider many competing priorities when determining the appropriate room placement for patients (e.g., reason for admission; patient characteristics, such as age, gender, mental status; staffing needs; family requests; psychosocial factors; reimbursement concerns).In the absence of obvious infectious diseases that require specified airborne infection isolation rooms (e.g., tuberculosis, SARS, chickenpox), the risk of transmission of infectious agents is not always considered when making placement decisions. When there are only a limited number of single-patient rooms, it is prudent to prioritize them for those patients who have conditions that facilitate transmission of infectious material to other patients (e.g., draining wounds, stool incontinence, uncontained secretions) and for those who are at increased risk of acquisition and adverse outcomes resulting from HAI (e.g., immunosuppression, open wounds, indwelling catheters, anticipated prolonged length of stay, total dependence on HCWs for activities of daily living) 15,24,43,430,794,795 . Single-patient rooms are always indicated for patients placed on Airborne Precautions and in a Protective Environment and are preferred for patients who require Contact or Droplet Precautions 23,24,410,435,796,797 .During a suspected or proven outbreak caused by a pathogen whose reservoir is the gastrointestinal tract, use of single patient rooms with private bathrooms limits opportunities for transmission, especially when the colonized or infected patient has poor personal hygiene habits, fecal incontinence, or cannot be expected to assist in maintaining procedures that prevent transmission of microorganisms (e.g., infants, children, and patients with altered mental status or developmental delay).In the absence of continued transmission, it is not necessary to provide a private bathroom for patients colonized or infected with enteric pathogens as long as personal hygiene practices and Standard Precautions, especially hand hygiene and appropriate environmental cleaning, are maintained.Assignment of a dedicated commode to a patient,and cleaning and disinfecting fixtures and equipment that may have fecal contamination (e.g., bathrooms, commodes 798 , scales used for weighing diapers) and the adjacent surfaces with appropriate agents may be especially important when a single-patient room can not be used since environmental contamination with intestinal tract pathogens is likely from both continent and incontinent patients 54,799 .Results of several studies to determine the benefit of a single-patient room to prevent transmission of Clostridium difficile are inconclusive 167, .Some studies have shown that being in the same room with a colonized or infected patient is not necessarily a risk factor for transmission 791, .However, for children, the risk of healthcare-associated diarrhea is increased with the increased number of patients per room 806 .Thus, patient factors are important determinants of infection transmission risks, and the need for a single-patient room and/or private bathroom for any patient is best determined on a case-by-case basis. Cohorting is the practice of grouping together patients who are colonized or infected with the same organism to confine their care to one area and prevent contact with other patients.Cohorts are created based on clinical diagnosis, microbiologic confirmation when available, epidemiology, and mode of transmission of the infectious agent.It is generally preferred not to place severely immunosuppressed patients in rooms with other patients.Cohorting has been used extensively for managing outbreaks of MDROs including MRSA 22,807 , VRE 638,808,809 , MDR-ESBLs 810 ; Pseudomonas aeruginosa 29 ; methicillin-susceptible Staphylococcus aureus 811 ; RSV 812,813 ; adenovirus keratoconjunctivitis 814 ; rotavirus 815 ; and SARS 816 .Modeling studies provide additional support for cohorting patients to control outbreaks Talon .However, cohorting often is implemented only after routine infection control measures have failed to control an outbreak. Assigning or cohorting healthcare personnel to care only for patients infected or colonized with a single target pathogen limits further transmission of the target pathogen to uninfected patients 740,819 but is difficult to achieve in the face of current staffing shortages in hospitals 583 and residential healthcare sites .However, when continued transmission is occurring after implementing routine infection control measures and creating patient cohorts, cohorting of healthcare personnel may be beneficial. During the seasons when RSV, human metapneumovirus 823 , parainfluenza, influenza, other respiratory viruses 824 , and rotavirus are circulating in the community, cohorting based on the presenting clinical syndrome is often a priority in facilities that care for infants and young children 825 .For example, during the respiratory virus season, infants may be cohorted based soley on the clinical diagnosis of bronchiolitis due to the logistical difficulties and costs associated with requiring microbiologic confirmation prior to room placement, and the predominance of RSV during most of the season.However, when available, single patient rooms are always preferred since a common clinical presentation (e.g., bronchiolitis), can be caused by more than one infectious agent 823,824,826 .Furthermore, the inability of infants and children to contain body fluids, and the close physical contact that occurs during their care, increases infection transmission risks for patients and personnel in this setting 24,795 . # II.G.2.Ambulatory settings. Patients actively infected with or incubating transmissible infectious diseases are seen frequently in ambulatory settings (e.g., outpatient clinics, physicians' offices, emergency departments) and potentially expose healthcare personnel and other patients, family members and visitors 21,34,127,135,142,827 .In response to the global outbreak of SARS in 2003 and in preparation for pandemic influenza, healthcare providers working in outpatient settings are urged to implement source containment measures (e.g., asking couging patients to wear a surgical mask or cover their coughs with tissues) to prevent transmission of respiratory infections, beginning at the point of initial patient encounter 9, 262, 828 as described below in section III.A.1.a.Signs can be posted at the entrance to facilities or at the reception or registration desk requesting that the patient or individuals accompanying the patient promptly inform the receptionist if there are symptoms of a respiratory infection (e.g., cough, flu-like illness, increased production of respiratory secretions).The presence of diarrhea, skin rash, or known or suspected exposure to a transmissible disease (e.g., measles, pertussis, chickenpox, tuberculosis) also could be added.Placement of potentially infectious patients without delay in an examination room limits the number of exposed individuals, e.g., in the common waiting area. In waiting areas, maintaining a distance between symptomatic and non-symptomatic patients (e.g., >3 feet), in addition to source control measures, may limit exposures.However, infections transmitted via the airborne route (e.g., M tuberculosis, measles, chickenpox) require additional precautions 12,125,829 .Patients suspected of having such an infection can wear a surgical mask for source containment, if tolerated, and should be placed in an examination room, preferably an AIIR, as soon as possible.If this is not possible, having the patient wear a mask and segregate him/herself from other patients in the waiting area will reduce opportunities to expose others.Since the person(s) accompanying the patient also may be infectious, application of the same infection control precautions may need to be extended to these persons if they are symptomatic 21,252,830 .For example, family members accompanying children admitted with suspected M. tuberculosis have been found to have unsuspected pulmonary tuberculosis with cavitary lesions, even when asymptomatic 42,831 . Patients with underlying conditions that increase their susceptibility to infection (e.g., those who are immunocompromised 43,44 or have cystic fibrosis 20 ) require special efforts to protect them from exposures to infected patients in common waiting areas.By informing the receptionist of their infection risk upon arrival, appropriate steps may be taken to further protect them from infection.In some cystic fibrosis clinics, in order to avoid exposure to other patients who could be colonized with B. cepacia, patients have been given beepers upon registration so that they may leave the area and receive notification to return when an examination room becomes available 832 . # II.G.3.Home care. In home care, the patient placement concerns focus on protecting others in the home from exposure to an infectious household member.For individuals who are especially vulnerable to adverse outcomes associated with certain infections, it may be beneficial to either remove them from the home or segregate them within the home.Persons who are not part of the household may need to be prohibited from visiting during the period of infectivity.For example, if a patient with pulmonary tuberculosis is contagious and being cared for at home, very young children (<4 years of age) 833 and immunocompromised persons who have not yet been infected should be removed or excluded from the household.During the SARS outbreak of 2003, segregation of infected persons during the communicable phase of the illness was beneficial in preventing household transmission 249,834 . # II.H. Transport of Patients Several principles are used to guide transport of patients requiring Transmission-Based Precautions.In the inpatient and residential settings these include 1.limiting transport of such patients to essential purposes, such as diagnostic and therapeutic procedures that cannot be performed in the patient's room; 2.when transport is necessary, using appropriate barriers on the patient (e.g., mask, gown, wrapping in sheets or use of impervious dressings to cover the affected area(s) when infectious skin lesions or drainage are present, consistent with the route and risk of transmission; 3.notifying healthcare personnel in the receiving area of the impending arrival of the patient and of the precautions necessary to prevent transmission; and 4.for patients being transported outside the facility, informing the receiving facility and the medi-van or emergency vehicle personnel in advance about the type of Transmission-Based Precautions being used. For tuberculosis, additional precautions may be needed in a small shared air space such as in an ambulance 12 . # II.I. Environmental Measures Cleaning and disinfecting non-critical surfaces in patient-care areas are part of Standard Precautions.In general, these procedures do not need to be changed for patients on Transmission-Based Precautions.The cleaning and disinfection of all patient-care areas is important for frequently touched surfaces, especially those closest to the patient, that are most likely to be contaminated (e.g., bedrails, bedside tables, commodes, doorknobs, sinks, surfaces and equipment in close proximity to the patient) 11,72,73,835 . The frequency or intensity of cleaning may need to change based on the patient's level of hygiene and the degree of environmental contamination and for certain for infectious agents whose reservoir is the intestinal tract 54 .This may be especially true in LTCFs and pediatric facilities where patients with stool and urine incontinence are encountered more frequently.Also, increased frequency of cleaning may be needed in a Protective Environment to minimize dust accumulation 11 .Special recommendations for cleaning and disinfecting environmental surfaces in dialysis centers have been published 18 .In all healthcare settings, administrative, staffing and scheduling activities should prioritize the proper cleaning and disinfection of surfaces that could be implicated in transmission. During a suspected or proven outbreak where an environmental reservoir is suspected, routine cleaning procedures should be reviewed, and the need for additional trained cleaning staff should be assessed.Adherence should be monitored and reinforced to promote consistent and correct cleaning is performed. EPA-registered disinfectants or detergents/disinfectants that best meet the overall needs of the healthcare facility for routine cleaning and disinfection should be selected 11,836 .In general, use of the existing facility detergent/disinfectant according to the manufacturer's recommendations for amount, dilution, and contact time is sufficient to remove pathogens from surfaces of rooms where colonized or infected individuals were housed.This includes those pathogens that are resistant to multiple classes of antimicrobial agents (e.g., C. difficile, VRE, MRSA, MDR-GNB 11,24,88,435,746,796,837 ).Most often, environmental reservoirs of pathogens during outbreaks are related to a failure to follow recommended procedures for cleaning and disinfection rather than the specific cleaning and disinfectant agents used . Certain pathogens (e.g., rotavirus, noroviruses, C. difficile) may be resistant to some routinely used hospital disinfectants 275,292, .The role of specific disinfectants in limiting transmission of rotavirus has been demonstrated experimentally 842 .Also, since C. difficile may display increased levels of spore production when exposed to nonchlorine-based cleaning agents, and the spores are more resistant than vegetative cells to commonly used surface disinfectants, some investigators have recommended the use of a 1:10 dilution of 5.25% sodium hypochlorite (household bleach) and water for routine environmental disinfection of rooms of patients with C. difficile when there is continued transmission 844,848 .In one study, the use of a hypochlorite solution was associated with a decrease in rates of C. difficile infections 847 .The need to change disinfectants based on the presence of these organisms can be determined in consultation with the infection control committee 11,847,848 . Detailed recommendations for disinfection and sterilization of surfaces and medical equipment that have been in contact with prion-containing tissue or high risk body fluids, and for cleaning of blood and body substance spills, are available in the Guidelines for Environmental Infection Control in Health-Care Facilities 11 and in the Guideline for Disinfection and Sterilization 848 . # II.J. Patient Care Equipment and Instruments/Devices Medical equipment and instruments/devices must be cleaned and maintained according to the manufacturers' instructions to prevent patient-to-patient transmission of infectious agents 86,87,325,849 .Cleaning to remove organic material must always precede high level disinfection and sterilization of critical and semi-critical instruments and devices because residual proteinacous material reduces the effectiveness of the disinfection and sterilization processes 836,848 .Noncritical equipment, such as commodes, intravenous pumps, and ventilators, must be thoroughly cleaned and disinfected before use on another patient.All such equipment and devices should be handled in a manner that will prevent HCW and environmental contact with potentially infectious material.It is important to include computers and personal digital assistants (PDAs) used in patient care in policies for cleaning and disinfection of non-critical items.The literature on contamination of computers with pathogens has been summarized 850 and two reports have linked computer contamination to colonization and infections in patients 851,852 . Although keyboard covers and washable keyboards that can be easily disinfected are in use, the infection control benefit of those items and optimal management have not been determined. In all healthcare settings, providing patients who are on Transmission-Based Precautions with dedicated noncritical medical equipment (e.g., stethoscope, blood pressure cuff, electronic thermometer) has been beneficial for preventing transmission 74,89,740,853,854 .When this is not possible, disinfection after use is recommended.Consult other guidelines for detailed guidance in developing specific protocols for cleaning and reprocessing medical equipment and patient care items in both routine and special circumstances 11,14,18,20,740,836,848 . In home care, it is preferable to remove visible blood or body fluids from durable medical equipment before it leaves the home.Equipment can be cleaned on-site using a detergent/disinfectant and, when possible, should be placed in a single plastic bag for transport to the reprocessing location 20,739 . # II.K. Textiles and Laundry Soiled textiles, including bedding, towels, and patient or resident clothing may be contaminated with pathogenic microorganisms.However, the risk of disease transmission is negligible if they are handled, transported, and laundered in a safe manner 11,855,856 .Key principles for handling soiled laundry are 1.not shaking the items or handling them in any way that may aerosolize infectious agents; 2.avoiding contact of one's body and personal clothing with the soiled items being handled; and 3.containing soiled items in a laundry bag or designated bin.When laundry chutes are used, they must be maintained to minimize dispersion of aerosols from contaminated items 11 . The methods for handling, transporting, and laundering soiled textiles are determined by organizational policy and any applicable regulations 739 ; guidance is provided in the Guidelines for Environmental Infection Control 11 .Rather than rigid rules and regulations, hygienic and common sense storage and processing of clean textiles is recommended 11,857 .When laundering occurs outside of a healthcare facility, the clean items must be packaged or completely covered and placed in an enclosed space during transport to prevent contamination with outside air or construction dust that could contain infectious fungal spores that are a risk for immunocompromised patients 11 . Institutions are required to launder garments used as personal protective equipment and uniforms visibly soiled with blood or infective material 739 .There are few data to determine the safety of home laundering of HCW uniforms, but no increase in infection rates was observed in the one published study 858 and no pathogens were recovered from home-or hospital-laundered scrubs in another study 859 .In the home, textiles and laundry from patients with potentially transmissible infectious pathogens do not require special handling or separate laundering, and may be washed with warm water and detergent 11,858,859 . # II.L. Solid Waste The management of solid waste emanating from the healthcare environment is subject to federal and state regulations for medical and non-medical waste 860,861 .No additional precautions are needed for non-medical solid waste that is being removed from rooms of patients on Transmission-Based Precautions.Solid waste may be contained in a single bag (as compared to using two bags) of sufficient strength 862 . # II.M. Dishware and Eating Utensils The combination of hot water and detergents used in dishwashers is sufficient to decontaminate dishware and eating utensils.Therefore, no special precautions are needed for dishware (e.g., dishes, glasses, cups) or eating utensils; reusable dishware and utensils may be used for patients requiring Transmission-Based Precautions.

In the home and other communal settings, eating utensils and drinking vessels that are being used should not be shared, consistent with principles of good personal hygiene and for the purpose of preventing transmission of respiratory viruses, Herpes simplex virus, and infectious agents that infect the gastrointestinal tract and are transmitted by the fecal/oral route (e.g., hepatitis A virus, noroviruses).If adequate resources for cleaning utensils and dishes are not available, disposable products may be used. # II.N. Adjunctive Measures Important adjunctive measures that are not considered primary components of programs to prevent transmission of infectious agents, but improve the effectiveness of such programs, include 1.antimicrobial management programs; 2.postexposure chemoprophylaxis with antiviral or antibacterial agents; 3.vaccines used both for pre and postexposure prevention; and 4.screening and restricting visitors with signs of transmissible infections. # II.N.1.Chemoprophylaxis. Antimicrobial agents and topical antiseptics may be used to prevent infection and potential outbreaks of selected agents.Infections for which postexposure chemoprophylaxis is recommended under defined conditions include B. pertussis 17,863 , N. meningitidi 864 , B. anthracis after environmental exposure to aeosolizable material 865 , influenza virus 611 , HIV 866 , and group A streptococcus 160 .Orally administered antimicrobials may also be used under defined circumstances for MRSA decolonization of patients or healthcare personnel 867 . Another form of chemoprophylaxis is the use of topical antiseptic agents.For example, triple dye is used routinely on the umbilical cords of term newborns to reduce the risk of colonization, skin infections, and omphalitis caused by S. aureus, including MRSA, and group A streptococcus 868,869 .Extension of the use of triple dye to low birth weight infants in the NICU was one component of a program that controlled one longstanding MRSA outbreak 22 .Topical antiseptics are also used for decolonization of healthcare personnel or selected patients colonized with MRSA, using mupirocin as discussed in the MDRO guideline 870 867, 871-873 . # II.N.2.Immunoprophylaxis. Certain immunizations recommended for susceptible healthcare personnel have decreased the risk of infection and the potential for transmission in healthcare facilities 17,874 .The OSHA mandate that requires employers to offer hepatitis B vaccination to HCWs played a substantial role in the sharp decline in incidence of occupational HBV infection 778,875 .The use of varicella vaccine in healthcare personnel has decreased the need to place susceptible HCWs on administrative leave following exposure to patients with varicella 775 .Also, reports of healthcare-associated transmission of rubella in obstetrical clinics 33,876 and measles in acute care settings 34 demonstrate the importance of immunization of susceptible healthcare personnel against childhood diseases.Many states have requirements for HCW vaccination for measles and rubella in the absence of evidence of immunity. Annual influenza vaccine campaigns targeted to patients and healthcare personnel in LTCFs and acute-care settings have been instrumental in preventing or limiting institutional outbreaks and increasing attention is being directed toward improving influenza vaccination rates in healthcare personnel 35,611,690,877,878,879 . Transmission of B. pertussis in healthcare facilities has been associated with large and costly outbreaks that include both healthcare personnel and patients 17, 36, 41, 100, 683, 827, 880, 881 .HCWs who have close contact with infants with pertussis are at particularly high risk because of waning immunity and, until 2005, the absence of a vaccine that could be used in adults.However, two acellular pertussis vaccines were licensed in the United States in 2005, one for use in individuals aged 11-18 and one for use in ages 10-64 years 882 .Provisional ACIP recommendations at the time of publication of this document include adolescents and adults, especially those with contact with infants < 12 months of age and healthcare personnel with direct patient contact 883 884 . Immunization of children and adults will help prevent the introduction of vaccinepreventable diseases into healthcare settings.The recommended immunization schedule for children is published annually in the January issues of the Morbidity Mortality Weekly Report with interim updates as needed 885,886 .An adult immunization schedule also is available for healthy adults and those with special immunization needs due to high risk medical conditions 887 . Some vaccines are also used for postexposure prophylaxis of susceptible individuals, including varicella 888 , influenza 611 , hepatitis B 778 , and smallpox 225 vaccines 17,874 .In the future, administration of a newly developed S. aureus conjugate vaccine (still under investigation) to selected patients may provide a novel method of preventing healthcareassociated S. aureus, including MRSA, infections in high-risk groups (e.g., hemodialysis patients and candidates for selected surgical procedures) 889,890 . Immune globulin preparations also are used for postexposure prophylaxis of certain infectious agents under specified circumstances (e.g., varicella-zoster virus , hepatitis B virus , rabies , measles and hepatitis A virus 17,833,874 ).The RSV monoclonal antibody preparation, Palivizumab, may have contributed to controlling a nosocomial outbreak of RSV in one NICU , but there is insufficient evidence to support a routine recommendation for its use in this setting 891 . # II.N. 3.Management of visitors. # II.N.3.a.Visitors as sources of infection. Visitors have been identified as the source of several types of HAIs (e.g., pertussis 40,41 , M. tuberculosis 42,892 , influenza, and other respiratory viruses 24,43,44,373 and SARS 21, ).However, effective methods for visitor screening in healthcare settings have not been studied.Visitor screening is especially important during community outbreaks of infectious diseases and for high risk patient units.Sibling visits are often encouraged in birthing centers, post partum rooms and in pediatric inpatient units, ICUs, and in residential settings for children; in hospital settings, a child visitor should visit only his or her own sibling.Screening of visiting siblings and other children before they are allowed into clinical areas is necessary to prevent the introduction of childhood illnesses and common respiratory infections.Screening may be passive through the use of signs to alert family members and visitors with signs and symptoms of communicable diseases not to enter clinical areas.More active screening may include the completion of a screening tool or questionnaire which elicits information related to recent exposures or current symptoms.That information is reviewed by the facility staff and the visitor is either permitted to visit or is excluded 833 . Family and household members visiting pediatric patients with pertussis and tuberculosis may need to be screened for a history of exposure as well as signs and symptoms of current infection.Potentially infectious visitors are excluded until they receive appropriate medical screening, diagnosis, or treatment.If exclusion is not considered to be in the best interest of the patient or family (i.e., primary family members of critically or terminally ill patients), then the symptomatic visitor must wear a mask while in the healthcare facility and remain in the patient's room, avoiding exposure to others, especially in public waiting areas and the cafeteria. Visitor screening is used consistently on HSCT units 15,43 .However, considering the experience during the 2003 SARS outbreaks and the potential for pandemic influenza, developing effective visitor screening systems will be beneficial 9 .Education concerning Respiratory Hygiene/Cough Etiquette is a useful adjunct to visitor screening. # II.N.3.b.Use of barrier precautions by visitors. The use of gowns, gloves, or masks by visitors in healthcare settings has not been addressed specifically in the scientific literature.Some studies included the use of gowns and gloves by visitors in the control of MDRO's, but did not perform a separate analysis to determine whether their use by visitors had a measurable impact .Family members or visitors who are providing care or having very close patient contact (e.g., feeding, holding) may have contact with other patients and could contribute to transmission if barrier precautions are not used correctly.Specific recommendations may vary by facility or by unit and should be determined by the level of interaction. # Part III: Precautions to Prevent Transmission of Infectious Agents There are two tiers of HICPAC/CDC precautions to prevent transmission of infectious agents, Standard Precautions and Transmission-Based Precautions.Standard Precautions are intended to be applied to the care of all patients in all healthcare settings, regardless of the suspected or confirmed presence of an infectious agent.Implementation of Standard Precautions constitutes the primary strategy for the prevention of healthcare-associated transmission of infectious agents among patients and healthcare personnel.Transmission-Based Precautions are for patients who are known or suspected to be infected or colonized with infectious agents, including certain epidemiologically important pathogens, which require additional control measures to effectively prevent transmission.Since the infecting agent often is not known at the time of admission to a healthcare facility, Transmission-Based Precautions are used empirically, according to the clinical syndrome and the likely etiologic agents at the time, and then modified when the pathogen is identified or a transmissible infectious etiology is ruled out.Examples of this syndromic approach are presented in Table 2. The HICPAC/CDC Guidelines also include recommendations for creating a Protective Environment for allogeneic HSCT patients. 4 and 5 for summaries of the key elements of these sets of precautions. # III.A. Standard Precautions Standard Precautions combine the major features of Universal Precautions (UP) 780,896 and Body Substance Isolation (BSI) 640 and are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents.Standard Precautions include a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which healthcare is delivered (Table 4).These include: hand hygiene; use of gloves, gown, mask, eye protection, or face shield, depending on the anticipated exposure; and safe injection practices.Also, equipment or items in the patient environment likely to have been contaminated with infectious body fluids must be handled in a manner to prevent transmission of infectious agents (e.g., wear gloves for direct contact, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). The application of Standard Precautions during patient care is determined by the nature of the HCW-patient interaction and the extent of anticipated blood, body fluid, or pathogen exposure.For some interactions (e.g., performing venipuncture), only gloves may be needed; during other interactions (e.g., intubation), use of gloves, gown, and face shield or mask and goggles is necessary.Education and training on the principles and rationale for recommended practices are critical elements of Standard Precautions because they facilitate appropriate decision-making and promote adherence when HCWs are faced with new circumstances 655, .An example of the importance of the use of Standard Precautions is intubation, especially under emergency circumstances when infectious agents may not be suspected, but later are identified (e.g., SARS-CoV, N. meningitides).The application of Standard Precautions is described below and summarized in Table 4.Guidance on donning and removing gloves, gowns and other PPE is presented in the Figure. Standard Precautions are also intended to protect patients by ensuring that healthcare personnel do not carry infectious agents to patients on their hands or via equipment used during patient care. 21,254,897 .The strategy proposed has been termed Respiratory Hygiene/Cough Etiquette 9,828 and is intended to be incorporated into infection control practices as a new component of Standard Precautions.The strategy is targeted at patients and accompanying family members and friends with undiagnosed transmissible respiratory infections, and applies to any person with signs of illness including cough, congestion, rhinorrhea, or increased production of respiratory secretions when entering a healthcare facility 40,41,43 .The term cough etiquette is derived from recommended source control measures for M. tuberculosis 12,126 . # III. The elements of Respiratory Hygiene/Cough Etiquette include 1.education of healthcare facility staff, patients, and visitors; 2.posted signs, in language(s) appropriate to the population served, with instructions to patients and accompanying family members or friends; 3.source control measures (e.g., covering the mouth/nose with a tissue when coughing and prompt disposal of used tissues, using surgical masks on the coughing person when tolerated and appropriate); 4.hand hygiene after contact with respiratory secretions; and 5.spatial separation, ideally >3 feet, of persons with respiratory infections in common waiting areas when possible. Covering sneezes and coughs and placing masks on coughing patients are proven means of source containment that prevent infected persons from dispersing respiratory secretions into the air 107,145,898,899 .Masking may be difficult in some settings, (e.g., pediatrics, in which case, the emphasis by necessity may be on cough etiquette 900 .Physical proximity of <3 feet has been associated with an increased risk for transmission of infections via the droplet route (e.g., N. meningitidis 103 and group A streptococcus 114 and therefore supports the practice of distancing infected persons from others who are not infected.The effectiveness of good hygiene practices, especially hand hygiene, in preventing transmission of viruses and reducing the incidence of respiratory infections both within and outside healthcare settings is summarized in several reviews 559,717,904 . These measures should be effective in decreasing the risk of transmission of pathogens contained in large respiratory droplets (e.g., influenza virus 23 , adenovirus 111 , B. pertussis 827 and Mycoplasma pneumoniae 112 .Although fever will be present in many respiratory infections, patients with pertussis and mild upper respiratory tract infections are often afebrile.Therefore, the absence of fever does not always exclude a respiratory infection.Patients who have asthma, allergic rhinitis, or chronic obstructive lung disease also may be coughing and sneezing.While these patients often are not infectious, cough etiquette measures are prudent. Healthcare personnel are advised to observe Droplet Precautions (i.e., wear a mask) and hand hygiene when examining and caring for patients with signs and symptoms of a respiratory infection.Healthcare personnel who have a respiratory infection are advised to avoid direct patient contact, especially with high risk patients.If this is not possible, then a mask should be worn while providing patient care. # III.A.1.b.Safe injection practices. The investigation of four large outbreaks of HBV and HCV among patients in ambulatory care facilities in the United States identified a need to define and reinforce safe injection practices 453 .The four outbreaks occurred in a private medical practice, a pain clinic, an endoscopy clinic, and a hematology/oncology clinic.The primary breaches in infection control practice that contributed to these outbreaks were 1.reinsertion of used needles into a multiple-dose vial or solution container (e.g., saline bag) and 2.use of a single needle/syringe to administer intravenous medication to multiple patients. In one of these outbreaks, preparation of medications in the same workspace where used needle/syringes were dismantled also may have been a contributing factor.These and other outbreaks of viral hepatitis could have been prevented by adherence to basic principles of aseptic technique for the preparation and administration of parenteral medications 453,454 .These include the use of a sterile, single-use, disposable needle and syringe for each injection given and prevention of contamination of injection equipment and medication.Whenever possible, use of single-dose vials is preferred over multiple-dose vials, especially when medications will be administered to multiple patients. Outbreaks related to unsafe injection practices indicate that some healthcare personnel are unaware of, do not understand, or do not adhere to basic principles of infection control and aseptic technique.A survey of US healthcare workers who provide medication through injection found that 1% to 3% reused the same needle and/or syringe on multiple patients 905 .Among the deficiencies identified in recent outbreaks were a lack of oversight of personnel and failure to follow-up on reported breaches in infection control practices in ambulatory settings.Therefore, to ensure that all healthcare workers understand and adhere to recommended practices, principles of infection control and aseptic technique need to be reinforced in training programs and incorporated into institutional polices that are monitored for adherence 454 .Equipment and products used during these procedures (e.g., contrast media) were excluded as probable sources of contamination.Procedural details available for seven cases determined that antiseptic skin preparations and sterile gloves had been used.However, none of the clinicians wore a face mask, giving rise to the speculation that droplet transmission of oralpharyngeal flora was the most likely explanation for these infections.Bacterial meningitis following myelogram and other spinal procedures (e.g., lumbar puncture, spinal and epidural anesthesia, intrathecal chemotherapy) has been reported previously .As a result, the question of whether face masks should be worn to prevent droplet spread of oral flora during spinal procedures (e.g., myelogram, lumbar puncture, spinal anesthesia) has been debated 916,917 .Face masks are effective in limiting the dispersal of oropharyngeal droplets 918 and are recommended for the placement of central venous catheters 919 .In October 2005, the Healthcare Infection Control Practices Advisory Committee (HICPAC) reviewed the evidence and concluded that there is sufficient experience to warrant the additional protection of a face mask for the individual placing a catheter or injecting material into the spinal or epidural space. # III.A.1.c.Infection Control Practices for Special # III.B. Transmission-Based Precautions There are three categories of Transmission-Based Precautions: Contact Precautions, Droplet Precautions, and Airborne Precautions.Transmission-Based Precautions are used when the route(s) of transmission is (are) not completely interrupted using Standard Precautions alone.For some diseases that have multiple routes of transmission (e.g., SARS), more than one Transmission-Based Precautions category may be used.When used either singly or in combination, they are always used in addition to Standard Precautions.See Appendix A for recommended precautions for specific infections.When Transmission-Based Precautions are indicated, efforts must be made to counteract possible adverse effects on patients (i.e., anxiety, depression and other mood disturbances , perceptions of stigma 923 , reduced contact with clinical staff , and increases in preventable adverse events 565 in order to improve acceptance by the patients and adherence by HCWs. 12,13 .Some states require the availability of such rooms in hospitals, emergency departments, and nursing homes that care for patients with M. tuberculosis.

A respiratory protection program that includes education about use of respirators, fit-testing, and user seal checks is required in any facility with AIIRs.In settings where Airborne Precautions cannot be implemented due to limited engineering resources (e.g., physician offices), masking the patient, placing the patient in a private room (e.g., office examination room) with the door closed, and providing N95 or higher level respirators or masks if respirators are not available for healthcare personnel will reduce the likelihood of airborne transmission until the patient is either transferred to a facility with an AIIR or returned to the home environment, as deemed medically appropriate.Healthcare personnel caring for patients on Airborne Precautions wear a mask or respirator, depending on the disease-specific recommendations (Respiratory Protection II.E.4, Table 2, and Appendix A), that is donned prior to room entry.Whenever possible, non-immune HCWs should not care for patients with vaccine-preventable airborne diseases (e.g., measles, chickenpox, and smallpox). # III.B.1.Contact precautions.Contact # III.C. Syndromic and Empiric Applications of Transmission-Based Precautions Diagnosis of many infections requires laboratory confirmation.Since laboratory tests, especially those that depend on culture techniques, often require two or more days for completion, Transmission-Based Precautions must be implemented while test results are pending based on the clinical presentation and likely pathogens.Use of appropriate Transmission-Based Precautions at the time a patient develops symptoms or signs of transmissible infection, or arrives at a healthcare facility for care, reduces transmission opportunities.While it is not possible to identify prospectively all patients needing Transmission-Based Precautions, certain clinical syndromes and conditions carry a sufficiently high risk to warrant their use empirically while confirmatory tests are pending (Table 2).Infection control professionals are encouraged to modify or adapt this table according to local conditions. # III.D. Discontinuation of Transmission-Based Precautions Transmission-Based Precautions remain in effect for limited periods of time (i.e., while the risk for transmission of the infectious agent persists or for the duration of the illness (Appendix A).For most infectious diseases, this duration reflects known patterns of persistence and shedding of infectious agents associated with the natural history of the infectious process and its treatment.For some diseases (e.g., pharyngeal or cutaneous diphtheria, RSV), Transmission-Based Precautions remain in effect until culture or antigen-detection test results document eradication of the pathogen and, for RSV, symptomatic disease is resolved.For other diseases, (e.g., M. tuberculosis) state laws and regulations, and healthcare facility policies, may dictate the duration of precautions 12 ).In immunocompromised patients, viral shedding can persist for prolonged periods of time (many weeks to months) and transmission to others may occur during that time; therefore, the duration of contact and/or droplet precautions may be prolonged for many weeks 500, . The duration of Contact Precautions for patients who are colonized or infected with MDROs remains undefined.MRSA is the only MDRO for which effective decolonization regimens are available 867 .However, carriers of MRSA who have negative nasal cultures after a course of systemic or topical therapy may resume shedding MRSA in the weeks that follow therapy 934,935 .Although early guidelines for VRE suggested discontinuation of Contact Precautions after three stool cultures obtained at weekly intervals proved negative 740 , subsequent experiences have indicated that such screening may fail to detect colonization that can persist for >1 year 27, .Likewise, available data indicate that colonization with VRE, MRSA 939 , and possibly MDR-GNB, can persist for many months, especially in the presence of severe underlying disease, invasive devices, and recurrent courses of antimicrobial agents. It may be prudent to assume that MDRO carriers are colonized permanently and manage them accordingly.Alternatively, an interval free of hospitalizations, antimicrobial therapy, and invasive devices (e.g., 6 or 12 months) before reculturing patients to document clearance of carriage may be used.Determination of the best strategy awaits the results of additional studies.See the 2006 HICPAC/CDC MDRO guideline 927 for discussion of possible criteria to discontinue Contact Precautions for patients colonized or infected with MDROs. # III.E. Application of Transmission-Based Precautions in Ambulatory and Home Care Settings Although Transmission-Based Precautions generally apply in all healthcare settings, exceptions exist.For example, in home care, AIIRs are not available.Furthermore, family members already exposed to diseases such as varicella and tuberculosis would not use masks or respiratory protection, but visiting HCWs would need to use such protection.Similarly, management of patients colonized or infected with MDROs may necessitate Contact Precautions in acute care hospitals and in some LTCFs when there is continued transmission, but the risk of transmission in ambulatory care and home care, has not been defined.Consistent use of Standard Precautions may suffice in these settings, but more information is needed. # III.F. Protective Environment A Protective Environment is designed for allogeneic HSCT patients to minimize fungal spore counts in the air and reduce the risk of invasive environmental fungal infections (see Table 5 for specifications) 11, .The need for such controls has been demonstrated in studies of aspergillus outbreaks associated with construction 11,14,15,157,158 .As defined by the American Insitute of Architecture 13 and presented in detail in the Guideline for Environmental Infection Control 2003 11,861 , air quality for HSCT patients is improved through a combination of environmental controls that include 1.HEPA filtration of incoming air; 2.directed room air flow; 3.positive room air pressure relative to the corridor; 4.well-sealed rooms (including sealed walls, floors, ceilings, windows, electrical outlets) to prevent flow of air from the outside; 5.ventilation to provide >12 air changes per hour; 6.strategies to minimize dust (e.g., scrubbable surfaces rather than upholstery 940 and carpet 941 , and routinely cleaning crevices and sprinkler heads); and 7.prohibiting dried and fresh flowers and potted plants in the rooms of HSCT patients. The latter is based on molecular typing studies that have found indistinguishable strains of Aspergillus terreus in patients with hematologic malignancies and in potted plants in the vicinity of the patients .The desired quality of air may be achieved without incurring the inconvenience or expense of laminar airflow 15,157 .To prevent inhalation of fungal spores during periods when construction, renovation, or other dust-generating activities that may be ongoing in and around the health-care facility, it has been advised that severely immunocompromised patients wear a high-efficiency respiratory-protection device (e.g., an N95 respirator) when they leave the Protective Environment 11,14,945 ).The use of masks or respirators by HSCT patients when they are outside of the Protective Environment for prevention of environmental fungal infections in the absence of construction has not been evaluated.A Protective Environment does not include the use of barrier precautions beyond those indicated for Standard and Transmission-Based Precautions.No published reports support the benefit of placing solid organ transplants or other immunocompromised patients in a Protective Environment. # Part IV: Recommendations These recommendations are designed to prevent transmission of infectious agents among patients and healthcare personnel in all settings where healthcare is delivered.As in other CDC/HICPAC guidelines, each recommendation is categorized on the basis of existing scientific data, theoretical rationale, applicability, and when possible, economic impact.The CDC/HICPAC system for categorizing recommendations is as follows: Category IA Strongly recommended for implementation and strongly supported by welldesigned experimental, clinical, or epidemiologic studies. Category IB Strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale. Category IC Required for implementation, as mandated by federal and/or state regulation or standard. Category II Suggested for implementation and supported by suggestive clinical or epidemiologic studies or a theoretical rationale. No recommendation; unresolved issue.Practices for which insufficient evidence or no consensus regarding efficacy exists. # I. Administrative Responsibilities Healthcare organization administrators should ensure the implementation of recommendations in this section. # I.A. Incorporate preventing transmission of infectious agents into the objectives of the organization's patient and occupational safety programs 543-546, 561, 620, 626, 946 . 739 12, 17, 879-881, 955, 134, 690 .Category IB/IC I.B.8.In all areas where healthcare is delivered, provide supplies and equipment necessary for the consistent observance of Standard Precautions, including hand hygiene products and personal protective equipment (e.g., gloves, gowns, face and eye protection) 739,559,946 .Category IB/IC I.B.9.Develop and implement policies and procedures to ensure that reusable patient care equipment is cleaned and reprocessed appropriately before use on another patient 11,956,957,958,959,836,87,11,960,961 .Category IA/IC I.C. Develop and implement processes to ensure oversight of infection control activities appropriate to the healthcare setting and assign responsibility for oversight of infection control activities to an individual or group within the healthcare organization that is knowledgeable about infection control 434,549,566 . Category # Category II # I.D. Develop and implement systems for early detection and management (e.g., use of appropriate infection control measures, including isolation precautions, PPE) of potentially infectious persons at initial points of patient encounter in outpatient settings (e.g., triage areas, emergency departments, outpatient clinics, physician offices) and at the time of admission to hospitals and long-term care facilities (LTCF) 9,122,134,253,827 .Category IB I.E. Develop and implement policies and procedures to limit patient visitation by persons with signs or symptoms of a communicable infection.Screen visitors to high-risk patient care areas (e.g., oncology units, hematopoietic stem cell transplant units, intensive care units, other severely immunocompromised patients) for possible infection 43 24, 41, 962, 963 566 247 687 .Category IB III.E. Review periodically information on community or regional trends in the incidence and prevalence of epidemiologically-important organisms (e.g., influenza, RSV, pertussis, invasive group A streptococcal disease, MRSA, VRE) (including in other healthcare facilities) that may impact transmission of organisms within the facility 398, 687, 972, 973 974 .Category II # IV.Standard Precautions Assume that every person is potentially infected or colonized with an organism that could be transmitted in the healthcare setting and apply the following infection control practices during the delivery of health care. 956 IV.E.1.Establish policies and procedures for containing, transporting, and handling patient-care equipment and instruments/devices that may be contaminated with blood or body fluids 18,739,975 .Category IB/IC # IV.A. Hand Hygiene IV.E.2.Remove organic material from critical and semi-critical instrument/devices, using recommended cleaning agents before high level disinfection and sterilization to enable effective disinfection and sterilization processes 836 991, 992 .Category IA IV.E.3.Wear PPE (e.g., gloves, gown), according to the level of anticipated contamination, when handling patient-care equipment and instruments/devices that is visibly soiled or may have been in contact with blood or body fluids 18,739,975 .Category IB/IC # IV.F. Care of the Environment 11 Edit : An - indicates recommendations that were renumbered for clarity.The renumbering does not constitute change to the intent of the recommendations. IV.F.1.Establish policies and procedures for routine and targeted cleaning of environmental surfaces as indicated by the level of patient contact and degree of soiling 11 .Category II IV.F.2.Clean and disinfect surfaces that are likely to be contaminated with pathogens, including those that are in close proximity to the patient (e.g., bed rails, over bed tables) and frequently-touched surfaces in the patient care environment (e.g., door knobs, surfaces in and surrounding toilets in patients' rooms) on a more frequent schedule compared to that for other surfaces (e.g., horizontal surfaces in waiting rooms) 11 73, 740, 746, 993, 994 72, 800, 835 995 .Category IB IV.F.3.Use EPA-registered disinfectants that have microbiocidal (i.e., killing) activity against the pathogens most likely to contaminate the patient-care environment.Use in accordance with manufacturer's instructions 842-844, 956, 996 .Category IB/IC IV.F.3.a.Review the efficacy of in-use disinfectants when evidence of continuing transmission of an infectious agent (e.g., rotavirus, C. difficile, norovirus) may indicate resistance to the in-use product and change to a more effective disinfectant as indicated 275,842,847 . Category II # Edit : An - indicates recommendations that were renumbered for clarity.The renumbering does not constitute change to the intent of the recommendations. IV.F.4.In facilities that provide health care to pediatric patients or have waiting areas with child play toys (e.g., obstetric/gynecology offices and clinics), establish policies and procedures for cleaning and disinfecting toys at regular intervals 379,80 .Category IB IV.F.4.a. -Use the following principles in developing this policy and procedures: Category II h Select play toys that can be easily cleaned and disinfected h Do not permit use of stuffed furry toys if they will be shared h Clean and disinfect large stationary toys (e.g., climbing quipment) at least weekly and whenever visibly soiled h If toys are likely to be mouthed, rinse with water after disinfection; alternatively wash in a dishwasher h When a toy requires cleaning and disinfection, do so immediately or store in a designated labeled container separate from toys that are clean and ready for use IV.F.5.Include multi-use electronic equipment in policies and procedures for preventing contamination and for cleaning and disinfection, especially those items that are used by patients, those used during delivery of patient care, and mobile devices that are moved in and out of patient rooms frequently (e.g., daily) 850 851, 852, 997 .Category IB IV.F.5.a.No recommendation for use of removable protective covers or washable keyboards.Unresolved issue # IV.G. Textiles and Laundry IV.G.1.Handle used textiles and fabrics with minimum agitation to avoid contamination of air, surfaces and persons 739,998,999 .Category IB/IC IV.G.2.If laundry chutes are used, ensure that they are properly designed, maintained, and used in a manner to minimize dispersion of aerosols from contaminated laundry 11,13,1000,1001 .Category IB/IC # IV.H. Safe Injection Practices The following recommendations apply to the use of needles, cannulas that replace needles, and, where applicable, intravenous delivery systems 454 IV.H.1.Use aseptic technique to avoid contamination of sterile injection equipment 1002,1003 .Category IA IV.H.2.Do not administer medications from a syringe to multiple patients, even if the needle or cannula on the syringe is changed.Needles, cannulae and syringes are sterile, single-use items; they should not be reused for another patient nor to access a medication or solution that might be used for a subsequent patient 453,919,1004,1005 .Category IA IV.H.3.Use fluid infusion and administration sets (i.e., intravenous bags, tubing and connectors) for one patient only and dispose appropriately after use.Consider a syringe or needle/cannula contaminated once it has been used to enter or connect to a patient's intravenous infusion bag or administration set 453 .Category IB IV.H.4.Use single-dose vials for parenteral medications whenever possible 453 . # Category IA IV.H.5.Do not administer medications from single-dose vials or ampules to multiple patients or combine leftover contents for later use 369 453, 1005 .Category IA IV.H.6.If multidose vials must be used, both the needle or cannula and syringe used to access the multidose vial must be sterile 453,1002 .Category IA IV.H.7.Do not keep multidose vials in the immediate patient treatment area and store in accordance with the manufacturer's recommendations; discard if sterility is compromised or questionable 453,1003 .Category IA IV.H.8.Do not use bags or bottles of intravenous solution as a common source of supply for multiple patients 453,1006 .Category IB IV.I. Infection control practices for special lumbar puncture procedures Wear a surgical mask when placing a catheter or injecting material into the spinal canal or subdural space (i.e., during myelograms, lumbar puncture and spinal or epidural anesthesia).906 V.D.2.a.ii.Direct exhaust of air to the outside.If it is not possible to exhaust air from an AIIR directly to the outside, the air may be returned to the air-handling system or adjacent spaces if all air is directed through HEPA filters.V.D.2.a.iii.Whenever an AIIR is in use for a patient on Airborne Precautions, monitor air pressure daily with visual indicators (e.g., smoke tubes, flutter strips), regardless of the presence of differential pressure sensing devices (e.g., manometers) 11,12,1023,1024 . V.D.2.a.iv.Keep the AIIR door closed when not required for entry and exit.V.D.2.b.When an AIIR is not available, transfer the patient to a facility that has an available AIIR 12 .Category II V.D.2.c.In the event of an outbreak or exposure involving large numbers of patients who require Airborne Precautions:  Consult infection control professionals before patient placement to determine the safety of alternative room that do not meet engineering requirements for an AIIR. Place together (cohort) patients who are presumed to have the same infection( based on clinical presentation and diagnosis when known) in areas of the facility that are away from other patients, especially patients who are at increased risk for infection (e.g., immunocompromised patients). Use temporary portable solutions (e.g., exhaust fan) to create a negative pressure environment in the converted area of the facility.Discharge air directly to the outside,away from people and air intakes, or direct all the air through HEPA filters before it is introduced to other air spaces 12 Category II V.D.2.d.In ambulatory settings: V.D.2.d.i.Develop systems (e.g., triage, signage) to identify patients with known or suspected infections that require Airborne Precautions upon entry into ambulatory settings 9,12,34,127,134 .Category IA V.D.2.d.ii.Place the patient in an AIIR as soon as possible.If an AIIR is not available, place a surgical mask on the patient and place him/her in an examination room.Once the patient leaves, the room should remain vacant for the appropriate time, generally one hour, to allow for a full exchange of air 11,12,122 .Category IB/IC V.D.2.d.iii.Instruct patients with a known or suspected airborne infection to wear a surgical mask and observe Respiratory Hygiene/Cough Etiquette.Once in an AIIR, the mask may be removed; the mask should remain on if the patient is not in an AIIR 12,107,145,899 .Category IB/IC V.D.3.Personnel restrictions Restrict susceptible healthcare personnel from entering the rooms of patients known or suspected to have measles (rubeola), varicella (chickenpox), disseminated zoster, or smallpox if other immune healthcare personnel are available 17,775 .Category IB V.D.4.a.

Wear a fit-tested NIOSH-approved N95 or higher level respirator for respiratory protection when entering the room or home of a patient when the following diseases are suspected or confirmed:  - V.D.4.a.i.Infectious pulmonary or laryngeal tuberculosis or when infectious tuberculosis skin lesions are present and procedures that would aerosolize viable organisms (e.g., irrigation, incision and drainage, whirlpool treatments) are performed 12,1025,1026 .Category IB  - V.D.4.a.ii.Smallpox (vaccinated and unvaccinated). Respiratory protection is recommended for all healthcare personnel, including those with a documented "take" after smallpox vaccination due to the risk of a genetically engineered virus against which the vaccine may not provide protection, or of exposure to a very large viral load (e.g., from high-risk aerosol-generating procedures, immunocompromised patients, hemorrhagic or flat smallpox 108,129 .Category II V.D.4.b. §Suspected measles, chickenpox or disseminated zoster.No recommendation is made regarding the use of PPE by healthcare personnel who are presumed to be immune to measles (rubeola) or varicella-zoster based on history of disease, vaccine, or serologic testing when caring for an individual with known or suspected measles, chickenpox or disseminated zoster, due to difficulties in establishing definite immunity 1027,1028 .Unresolved issue V.D.4.c. §Suspected measles, chickenpox or disseminated zoster.No recommendation is made regarding the type of personal protective equipment (i.e., surgical mask or respiratory protection with a N95 or higher respirator) to be worn by susceptible healthcare personnel who must have contact with patients with known or suspected measles, chickenpox or disseminated herpes zoster.Unresolved issue V.D. 11 for additional guidance on environment strategies for preventing transmission of tuberculosis in healthcare settings.The environmental recommendations in these guidelines may be applied to patients with other infections that require Airborne Precautions. 13 .Category IB VI.C.2.Lower dust levels by using smooth, nonporous surfaces and finishes that can be scrubbed, rather than textured material (e.g., upholstery).Wet dust horizontal surfaces whenever dust detected and routinely clean crevices and sprinkler heads where dust may accumulate 940,941 .Category II VI.C.3.Avoid carpeting in hallways and patient rooms in areas 941 .Category IB VI.C.4.Prohibit dried and fresh flowers and potted plants .Category II VI.D. Minimize the length of time that patients who require a Protective Environment are outside their rooms for diagnostic procedures and other activities 11,158,945 . # VI.Protective Environment ( # Category IB VI.E. During periods of construction, to prevent inhalation of respirable particles that could contain infectious spores, provide respiratory protection (e.g., N95 respirator) to patients who are medically fit to tolerate a respirator when they are required to leave the Protective Environment 945,158 13 .Category IB VI.F.4.b.Use an anteroom to further support the appropriate air-balance relative to the corridor and the Protective Environment; provide independent exhaust of contaminated air to the outside or place a HEPA filter in the exhaust duct if the return air must be recirculated 13,1041 .Category IB VI.F.4.c.If an anteroom is not available, place the patient in an AIIR and use portable, industrial-grade HEPA filters in the room to enhance filtration of spores 1042 .Category II Available from: / Preamble The mode(s) and risk of transmission for each specific disease agent included in Appendix A were reviewed.Principle sources consulted for the development of disease-specific recommendations for Appendix A included infectious disease manuals and textbooks .The published literature was searched for evidence of person-to-person transmission in healthcare and non-healthcare settings with a focus on reported outbreaks that would assist in developing recommendations for all settings where healthcare is delivered.Criteria used to assign Transmission-Based Precautions categories follow: - A Transmission-Based Precautions category was assigned if there was strong evidence for person-to-person transmission via droplet, contact, or airborne routes in healthcare or nonhealthcare settings and/or if patient factors (e.g., diapered infants, diarrhea, draining wounds) increased the risk of transmission - Transmission-Based Precautions category assignments reflect the predominant mode(s) of transmission - If there was no evidence for person-to-person transmission by droplet, contact or airborne routes, Standard Precautions were assigned - If there was a low risk for person-to-person transmission and no evidence of healthcareassociated transmission, Standard Precautions were assigned - Standard Precautions were assigned for bloodborne pathogens (e.g., hepatitis B and C viruses, human immunodeficiency virus) as per CDC recommendations for Universal Precautions issued in 1988 .Subsequent experience has confirmed the efficacy of Standard Precautions to prevent exposure to infected blood and body fluid . Additional information relevant to use of precautions was added in the comments column to assist the caregiver in decision-making.Citations were added as needed to support a change in or provide additional evidence for recommendations for a specific disease and for new infectious agents (e.g., SARS-CoV, avian influenza) that have been added to Appendix A. # Clostridium perfringens Gas gangrene Standard n/a Transmission from person to person rare; 1 outbreak in a surgical setting reported .Use Contact Precautions if wound drainage is extensive. # Infection/Condition # Type of Precaution # Duration of Precaution Precautions/Comments Coccidioidomycosis (valley fever) Draining lesions Standard n/a Not transmitted from person to person except under extraordinary circumstances, because the infectious arthroconidial form of Coccidioides immitis is not produced in humans . # Coccidioidomycosis (valley fever) Pneumonia Standard n/a Not transmitted from person to person except under extraordinary circumstances, (e.g., inhalation of aerosolized tissue phase endospores during necropsy, transplantation of infected lung) because the infectious arthroconidial form of Coccidioides immitis is not produced in humans . Colorado # Gastroenteritis # Giardia lamblia Standard n/a Use Contact Precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. # Infection/Condition # Type of Precaution # Duration of Precaution Precautions/Comments Gastroenteritis Noroviruses Standard n/a Use Contact Precautions for a minimum of 48 hours after the resolution of symptoms or to control institutional outbreaks. Persons who clean areas heavily contaminated with feces or vomitus may benefit from wearing masks since virus can be aerosolized from these body substances ; ensure consistent environmental cleaning and disinfection with focus on restrooms even when apparently unsoiled .Hypochlorite solutions may be required when there is continued transmission .Alcohol is less active, but there is no evidence that alcohol antiseptic handrubs are not effective for hand decontamination .Susceptible HCWs should not enter room if immune care providers are available; no recommendation for face protection for immune HCW; no recommendation for type of face protection for susceptible HCWs, i.e., mask or respirator .For exposed susceptibles, postexposure vaccine within 72 hours or immune globulin within 6 days when available The below note has been superseded by the above recommendation update Note: (Recent assessment of outbreaks in healthy 18-24 year olds has indicated that salivary viral shedding occurred early in the course of illness and that 5 days of isolation after onset of parotitis may be appropriate in community settings; however the implications for healthcare personnel and highrisk patient populations remain to be clarified.) # Infection/Condition # Type of Precaution # Table 3C. Ebola Hemorrhagic Fever # Characteristics Additional Information Site(s) of Infection; Transmission Mode As a rule infection develops after exposure of mucous membranes or respiratory tract, or through broken skin or percutaneous injury.Incubation Period 2-19 days, usually 5-10 days # Clinical Features Febrile illnesses with malaise, myalgias, headache, vomiting and diarrhea that are rapidly complicated by hypotension, shock, and hemorrhagic features.Massive hemorrhage in < 50% pts. # Diagnosis Etiologic diagnosis can be made using respiratory tract-polymerase chain reaction, serologic detection of antibody and antigen, pathologic assessment with immunohistochemistry and viral culture with EM confirmation of morphology, # Infectivity Person-to-person transmission primarily occurs through unprotected contact with blood and body fluids; percutaneous injuries (e.g., needlestick) associated with a high rate of transmission; transmission in healthcare settings has been reported but is prevented by use of barrier precautions. # Characteristics Additional Information Recommended Precautions Hemorrhagic fever specific barrier precautions: If disease is believed to be related to intentional release of a bioweapon, epidemiology of transmission is unpredictable pending observation of disease transmission.Until the nature of the pathogen is understood and its transmission pattern confirmed, Standard, Contact and Airborne Precautions should be used.Once the pathogen is characterized, if the epidemiology of transmission is consistent with natural disease, Droplet Precautions can be substituted for Airborne Precautions. Emphasize: 1.use of sharps safety devices and safe work practices, 2.hand hygiene; 3.barrier protection against blood and body fluids upon entry into room (single gloves and fluid-resistant or impermeable gown, face/eye protection with masks, goggles or face shields); and 4.appropriate waste handling. Use N95 or higher respirators when performing aerosol-generating procedures.In settings where AIIRs are unavailable or the large numbers of patients cannot be accommodated by existing AIIRs, observe Droplet Precautions (plus Standard Precautions and Contact Precautions) and segregate patients from those not suspected of VHF infection.Limit blooddraws to those essential to care.See text for discussion and Appendix A for recommendations for naturally occurring VHFs. # Plague Pneumonic plague is not as contagious as is often thought.Historical accounts and contemporary evidence indicate that persons with plague usually transmit the infection only when the disease is in the end stage.These persons cough copious amounts of bloody sputum that contains many plague bacteria.Patients in the early stage of primary pneumonic plague (approximately the first 20-24 h) apparently pose little risk .Antibiotic medication rapidly clears the sputum of plague bacilli, so that a patient generally is not infective within hours after initiation of effective antibiotic treatment .This means that in modern times many patients will never reach a stage where they pose a significant risk to others.Even in the end stage of disease, transmission only occurs after close contact.Simple protective measures, such as wearing masks, good hygiene, and avoiding close contact, have been effective to interrupt transmission during many pneumonic plague outbreaks .In the United States, the last known cases of person to person transmission of pneumonic plague occurred in 1925 . # Table 3D. Plague # Characteristics Additional Information Site(s) of Infection; Transmission Mode Respiratory Tract: Inhalation of respiratory droplets.Comment: Pneumonic plague most likely to occur if used as a biological weapon, but some cases of bubonic and primary septicemia may also occur.Infective dose 100 to 500 bacteria Incubation Period 1 to 6, usually 2 to 3 days.Fever, malaise, backache, headache, and often vomiting for 2-3 days; then generalized papular or maculopapular rash (more on face and extremities), which becomes vesicular (on day 4 or 5) and then pustular; lesions all in same stage. Clinical # Diagnosis Electron microscopy of vesicular fluid or culture of vesicular fluid by WHO approved laboratory (CDC); detection by polymerase chain reaction available only in select LRN labs, CDC and USAMRID Infectivity Secondary attack rates up to 50% in unvaccinated persons; infected persons may transmit disease from time rash appears until all lesions have crusted over (about 3 weeks); greatest infectivity during first 10 days of rash.Recommended Precautions Combined use of Standard, Contact, and Airborne Precautions until all scabs have separated (3-4 weeks).Transmission by the airborne route is a rare event; Airborne Precautions is recommended when possible, but in the event of mass exposures, barrier precautions and containment within a designated area are most important.204,212 Only immune HCWs to care for pts; Postexposure vaccine within 4 days. Vaccinia: HCWs cover vaccination site with gauze and semi-permeable dressing until scab separates (≥21 days).Observe hand hygiene. Adverse events with virus-containing lesions: Standard plus Contact Precautions until all lesions crusted.Vaccinia adverse events with lesions containing infectious virus include inadvertent autoinoculation, ocular lesions (blepharitis, conjunctivitis), generalized vaccinia, progressive vaccinia, eczema vaccinatum; bacterial superinfection also requires addition of contact precautions if exudates cannot be contained.216,217 # Table 3F. Tularemia # Characteristics Additional Information Site(s) of Infection; Transmission Mode Respiratory Tract: Inhalation of aerosolized bacteria.Gastrointestinal Tract: Ingestion of food or drink contaminated with aerosolized bacteria.Comment: Pneumonic or typhoidal disease likely to occur after bioterrorist event using aerosol delivery.Infective dose 10-50 bacteria Incubation Period 2 to 10 days, usually 3 to 5 days # Clinical Features Pneumonic: malaise, cough, sputum production, dyspnea; Typhoidal: fever, prostration, weight loss and frequently an associated pneumonia. # Diagnosis Diagnosis usually made with serology on acute and convalescent serum specimens; bacterium can be detected by polymerase chain reaction (LRN) or isolated from blood and other body fluids on cysteine-enriched media or mouse inoculation. # Infectivity Person-to-person spread is rare.Laboratory workers who encounter/handle cultures of this organism are at high risk for disease if exposed. # Recommended Precautions Standard Precautions # I. Patients: allogeneic hematopoeitic stem cell transplant (HSCT) only - Maintain in PE room except for required diagnostic or therapeutic procedures that cannot be performed in the room, e.g., radiology, operating room - Respiratory protection e.g., N95 respirator, for the patient when leaving PE during periods of construction # II.Standard and Expanded Precautions - Hand hygiene observed before and after patient contact - Gown, gloves, mask NOT required for HCWs or visitors for routine entry into the room flutter strips, smoke tubes) or a hand held pressure gauge - Self-closing door on all room exits - Maintain back-up ventilation equipment (e.g., portable units for fans or filters) for emergency provision of ventilation requirements for PE areas and take immediate steps to restore the fixed ventilation system - For patients who require both a PE and Airborne Infection Isolation, use an anteroom to ensure proper air balance relationships and provide independent exhaust of contaminated air to the outside or place a HEPA filter in the exhaust duct.If an anteroom is not available, place patient in an AIIR and use portable ventilation units, industrial-grade HEPA filters to enhance filtration of spores. # IV.Surfaces - Daily wet-dusting of horizontal surfaces using cloths moistened with EPA-registered hospital disinfectant/detergent - Avoid dusting methods that disperse dust During outbreaks, healthcare personnel may be assigned to a cohort of patients to further limit opportunities for transmission (cohorting staff). Colonization.Proliferation of microorganisms on or within body sites without detectable host immune response, cellular damage, or clinical expression.The presence of a microorganism within a host may occur with varying duration, but may become a source of potential transmission.In many instances, colonization and carriage are synonymous.Droplet nuclei.Microscopic particles < 5 µm in size that are the residue of evaporated droplets and are produced when a person coughs, sneezes, shouts, or sings.These particles can remain suspended in the air for prolonged periods of time and can be carried on normal air currents in a room or beyond, to adjacent spaces or areas receiving exhaust air. # Hand hygiene. A general term that applies to any one of the following: 1.handwashing with plain (nonantimicrobial) soap and water); 2.antiseptic handwash (soap containing antiseptic agents and water); 3.antiseptic handrub (waterless antiseptic product, most often alcohol-based, rubbed on all surfaces of hands); or 4.surgical hand antisepsis (antiseptic handwash or antiseptic handrub performed preoperatively by surgical personnel to eliminate transient hand flora and reduce resident hand flora) 559 . # Healthcare-associated infection (HAI). An infection that develops in a patient who is cared for in any setting where healthcare is delivered (e.g., acute care hospital, chronic care facility, ambulatory clinic, dialysis center, surgicenter, home) and is related to receiving health care (i.e., was not incubating or present at the time healthcare was provided).In ambulatory and home settings, HAI would apply to any infection that is associated with a medical or surgical intervention.Since the geographic location of infection acquisition is often uncertain, the preferred term is considered to be healthcare-associated rather than healthcare-acquired. Healthcare epidemiologist.A person whose primary training is medical (M.D., D.O.) and/or masters or doctorate-level epidemiology who has received advanced training in healthcare epidemiology.Typically these professionals direct or provide consultation to an infection control program in a hospital, long term care facility (LTCF), or healthcare delivery system (also see infection control professional). Healthcare personnel, healthcare worker (HCW).All paid and unpaid persons who work in a healthcare setting (e.g., any person who has professional or technical training in a healthcare-related field and provides patient care in a healthcare setting or any person who provides services that support the delivery of healthcare such as dietary, housekeeping, engineering, maintenance personnel). # Hematopoietic stem cell transplantation (HSCT). Any transplantation of blood-or bone marrow-derived hematopoietic stem cells, regardless of donor type (e.g., allogeneic or autologous) or cell source (e.g., bone marrow, peripheral blood, or placental/umbilical cord blood); associated with periods of severe immunosuppression that vary with the source of the cells, the intensity of chemotherapy required, and the presence of graft versus host disease (MMWR 2000; 49: RR-10). High-efficiency particulate air (HEPA) filter.An air filter that removes >99.97% of particles ≥ 0.3µm (the most penetrating particle size) at a specified flow rate of air.HEPA filters may be integrated into the central air handling systems, installed at the point of use above the ceiling of a room, or used as portable units (MMWR 2003; 52: RR-10). Home care.A wide-range of medical, nursing, rehabilitation, hospice and social services delivered to patients in their place of residence (e.g., private residence, senior living center, assisted living facility).Home health-care services include care provided by home health aides and skilled nurses, respiratory therapists, dieticians, physicians, chaplains, and volunteers; provision of durable medical equipment; home infusion therapy; and physical, speech, and occupational therapy. # Immunocompromised patients. Those patients whose immune mechanisms are deficient because of congenital or acquired immunologic disorders (e.g., human immunodeficiency virus infection, congenital immune deficiency syndromes), chronic diseases such as diabetes mellitus, cancer, emphysema, or cardiac failure, ICU care, malnutrition, and immunosuppressive therapy of another disease process ).The type of infections for which an immunocompromised patient has increased susceptibility is determined by the severity of immunosuppression and the specific component(s) of the immune system that is affected.Patients undergoing allogeneic HSCT and those with chronic graft versus host disease are considered the most vulnerable to HAIs.

Immunocompromised states also make it more difficult to diagnose certain infections (e.g., tuberculosis) and are associated with more severe clinical disease states than persons with the same infection and a normal immune system. Infection.The transmission of microorganisms into a host after evading or overcoming defense mechanisms, resulting in the organism's proliferation and invasion within host tissue(s).Host responses to infection may include clinical symptoms or may be subclinical, with manifestations of disease mediated by direct organisms pathogenesis and/or a function of cell-mediated or antibody responses that result in the destruction of host tissues. # Infection control and prevention professional (ICP). A person whose primary training is in either nursing, medical technology, microbiology, or epidemiology and who has acquired specialized training in infection control.Responsibilities may include collection, analysis, and feedback of infection data and trends to healthcare providers; consultation on infection risk assessment, prevention and control strategies; performance of education and training activities; implementation of evidence-based infection control practices or those mandated by regulatory and licensing agencies; application of epidemiologic principles to improve patient outcomes; participation in planning renovation and construction projects (e.g., to ensure appropriate containment of construction dust); evaluation of new products or procedures on patient outcomes; oversight of employee health services related to infection prevention; implementation of preparedness plans; communication within the healthcare setting, with local and state health departments, and with the community at large concerning infection control issues; and participation in research.Certification in infection control (CIC) is available through the Certification Board of Infection Control and Epidemiology. # Infection control and prevention program. A multidisciplinary program that includes a group of activities to ensure that recommended practices for the prevention of healthcare-associated infections are implemented and followed by HCWs, making the healthcare setting safe from infection for patients and healthcare personnel.The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires the following five components of an infection control program for accreditation: 1.surveillance: monitoring patients and healthcare personnel for acquisition of infection and/or colonization; 2.investigation: identification and analysis of infection problems or undesirable trends; 3.prevention: implementation of measures to prevent transmission of infectious agents and to reduce risks for device-and procedure-related infections; 4) control: evaluation and management of outbreaks; and 4.reporting: provision of information to external agencies as required by state and federal law and regulation (The Joint Commission (/ accessed May 2016) ). The infection control program staff has the ultimate authority to determine infection control policies for a healthcare organization with the approval of the organization's governing body. Long-term care facilities (LTCFs).An array of residential and outpatient facilities designed to meet the bio-psychosocial needs of persons with sustained self-care deficits.These include skilled nursing facilities, chronic disease hospitals, nursing homes, foster and group homes, institutions for the developmentally disabled, residential care facilities, assisted living facilities, retirement homes, adult day health care facilities, rehabilitation centers, and long-term psychiatric hospitals. # Mask. A term that applies collectively to items used to cover the nose and mouth and includes both procedure masks and surgical masks ([This link is no longer active: www.fda.gov/cdrh/ode/guidance/094.html#4.Similar information may be found at FDA: Masks and N95 Respirators ( evicesandSupplies/PersonalProtectiveEquipment/ucm055977.htm accessed May 2016)]). # Multidrug-resistant organisms (MDROs). In general, bacteria (excluding M. tuberculosis) that are resistant to one or more classes of antimicrobial agents and usually are resistant to all but one or two commercially available antimicrobial agents (e.g., MRSA, VRE, extended spectrum beta-lactamase -producing or intrinsically resistant gram-negative bacilli) 176 . # Nosocomial infection.Derived from two Greek words "nosos" (disease) and "komeion" (to take care of).Refers to any infection that develops during or as a result of an admission to an acute care facility (hospital) and was not incubating at the time of admission. # Personal protective equipment (PPE). A variety of barriers used alone or in combination to protect mucous membranes, skin, and clothing from contact with infectious agents.PPE includes gloves, masks, respirators, goggles, face shields, and gowns. Procedure Mask.A covering for the nose and mouth that is intended for use in general patient care situations.These masks generally attach to the face with ear loops rather than ties or elastic.Unlike surgical masks, procedure masks are not regulated by the Food and Drug Administration. Protective Environment.A specialized patient-care area, usually in a hospital, with a positive air flow relative to the corridor (i.e., air flows from the room to the outside adjacent space).The combination of high-efficiency particulate air (HEPA) filtration, high numbers (≥12) of air changes per hour (ACH), and minimal leakage of air into the room creates an environment that can safely accommodate patients with a severely compromised immune system (e.g., those who have received allogeneic hemopoietic stem-cell transplant ) and decrease the risk of exposure to spores produced by environmental fungi.Other components include use of scrubbable surfaces instead of materials such as upholstery or carpeting, cleaning to prevent dust accumulation, and prohibition of fresh flowers or potted plants. Quasi-experimental studies.Studies to evaluate interventions but do not use randomization as part of the study design.These studies are also referred to as nonrandomized, pre-post-intervention study designs.These studies aim to demonstrate causality between an intervention and an outcome but cannot achieve the level of confidence concerning attributable benefit obtained through a randomized, controlled trial.In hospitals and public health settings, randomized control trials often cannot be implemented due to ethical, practical and urgency reasons; therefore, quasiexperimental design studies are used commonly.However, even if an intervention appears to be effective statistically, the question can be raised as to the possibility of alternative explanations for the result.Such study design is used when it is not logistically feasible or ethically possible to conduct a randomized, controlled trial, (e.g., during outbreaks).Within the classification of quasi-experimental study designs, there is 1.senior management support for safety programs; 2.absence of workplace barriers to safe work practices; 3.cleanliness and orderliness of the worksite; 4.minimal conflict and good communication among staff members; 5.frequent safety-related feedback/training by supervisors; and 6.availability of PPE and engineering controls 620 . Source Control.The process of containing an infectious agent either at the portal of exit from the body or within a confined space.The term is applied most frequently to containment of infectious agents transmitted by the respiratory route but could apply to other routes of transmission, (e.g., a draining wound, vesicular or bullous skin lesions). Respiratory Hygiene/Cough Etiquette that encourages individuals to "cover your cough" and/or wear a mask is a source control measure.The use of enclosing devices for local exhaust ventilation (e.g., booths for sputum induction or administration of aerosolized medication) is another example of source control. Standard Precautions.A group of infection prevention practices that apply to all patients, regardless of suspected or confirmed diagnosis or presumed infection status.Standard Precautions is a combination and expansion of Universal Precautions 780 and Body Substance Isolation 1102 .Standard Precautions is based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents.Standard Precautions includes hand hygiene, and depending on the anticipated exposure, use of gloves, gown, mask, eye protection, or face shield.Also, equipment or items in the patient environment likely to have been contaminated with infectious fluids must be handled in a manner to prevent transmission of infectious agents, (e.g., wear gloves for handling, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). # Surgical mask. A device worn over the mouth and nose by operating room personnel during surgical procedures to protect both surgical patients and operating room personnel from transfer of microorganisms and body fluids.Surgical masks also are used to protect healthcare personnel from contact with large infectious droplets (>5 μm in size).According to draft guidance issued by the Food and Drug Administration on May 15, 2003, surgical masks are evaluated using standardized testing procedures for fluid resistance, bacterial filtration efficiency, differential pressure (air exchange), and flammability in order to mitigate the risks to health associated with the use of surgical masks.These specifications apply to any masks that are labeled surgical, laser, isolation, or dental or medical procedure ().Surgical masks do not protect against inhalation of small particles or droplet nuclei and should not be confused with particulate respirators that are recommended for protection against selected airborne infectious agents, (e.g., Mycobacterium tuberculosis). # Glossary Airborne infection isolation room (AIIR).Formerly, negative pressure isolation room, an AIIR is a single-occupancy patient-care room used to isolate persons with a suspected or confirmed airborne infectious disease.Environmental factors are controlled in AIIRs to minimize the transmission of infectious agents that are usually transmitted from person to person by droplet nuclei associated with coughing or aerosolization of contaminated fluids.AIIRs should provide negative pressure in the room (so that air flows under the door gap into the room); and an air flow rate of 6-12 ACH (6 ACH for existing structures, 12 ACH for new construction or renovation); and direct exhaust of air from the room to the outside of the building or recirculation of air through a HEPA filter before retruning to circulation (MMWR 2003; 52 ; MMWR 1994; 43 ).Bioaerosols.An airborne dispersion of particles containing whole or parts of biological entities, such as bacteria, viruses, dust mites, fungal hyphae, or fungal spores.Such aerosols usually consist of a mixture of mono-dispersed and aggregate cells, spores or viruses, carried by other materials, such as respiratory secretions and/or inert particles.Infectious bioaerosols (i.e., those that contain biological agents capable of causing an infectious disease) can be generated from human sources (e.g., expulsion from the respiratory tract during coughing, sneezing, talking or singing; during suctioning or wound irrigation), wet environmental sources (e.g., HVAC and cooling tower water with Legionella) or dry sources (e.g., construction dust with spores produced by Aspergillus spp.).Bioaerosols include large respiratory droplets and small droplet nuclei (Cole EC.AJIC 1998;26: 453-64). # American Institute of Architects (AIA). Caregivers.All persons who are not employees of an organization, are not paid, and provide or assist in providing healthcare to a patient (e.g., family member, friend) and acquire technical training as needed based on the tasks that must be performed. # Cohorting. In the context of this guideline, this term applies to the practice of grouping patients infected or colonized with the same infectious agent together to confine their care to one area and prevent contact with susceptible patients (cohorting patients).a hierarchy of design features that may contribute to validity of results (Harris et al.CID 2004:38: 1586). # Residential care setting. A facility in which people live, minimal medical care is delivered, and the psychosocial needs of the residents are provided for. # Respirator. A personal protective device worn by healthcare personnel over the nose and mouth to protect them from acquiring airborne infectious diseases due to inhalation of infectious airborne particles that are < 5 μm in size.These include infectious droplet nuclei from patients with M. tuberculosis, variola virus , SARS-CoV), and dust particles that contain infectious particles, such as spores of environmental fungi (e.g., Aspergillus sp. # Respiratory Hygiene/ Cough Etiquette. A combination of measures designed to minimize the transmission of respiratory pathogens via droplet or airborne routes in healthcare settings.The components of respiratory hygiene/cough etiquette are 1.covering the mouth and nose during coughing and sneezing, 2.using tissues to contain respiratory secretions with prompt disposal into a no-touch receptacle, 3.offering a surgical mask to persons who are coughing to decrease contamination of the surrounding environment, and 4.turning the head away from others and maintaining spatial separation, ideally >3 feet, when coughing. These measures are targeted to all patients with symptoms of respiratory infection and their accompanying family members or friends beginning at the point of initial encounter with a healthcare setting (e.g., reception/triage in emergency departments, ambulatory clinics, healthcare provider offices) 126

These recommendations were developed by the Advisory Committee for Elimination of Tuberculosis, CDC staff, and public health consultants.They describe tuberculosis control activities appropriate for nursing homes and other facilities providing long-term care for elderly persons.Such facilities include long-term-care wings or units in hospitals, adult foster-care homes, board and care homes, and other congregate settings for the elderly (referred to hereafter as "facilities").The recommendations are intended for use by staff and administrators of these facilities, consultants to these facilities, and regulatory and licensing bodies.This document is not intended for use as a primer on tuberculosis.More general information about tuberculosis is available in the American Thoracic Society (ATS)/CDC statements referenced in this document.State and local health departments are encouraged to continue the search for new, innovative, and more effective approaches for controlling and preventing tuberculosis in facilities providing long-term care for the elderly.BACKGROUND# Persons greater than or equal to 65 years of age constitute a large repository of Mycobacterium tuberculosis infection in the United States.Tuberculosis case rates are higher for this age group than for any other.In 1987, the 6,150 tuberculosis cases reported for persons greater than or equal to 65 years of age accounted for 27% of the total U.S. tuberculosis morbidity, even though this age group represents only 12% of the U.S. population (1).The control and prevention of tuberculosis among the elderly must be addressed aggressively to achieve the goal of eliminating tuberculosis in the United States by the year 2010 (2). CDC surveillance data indicate that, as with younger age groups, most elderly tuberculosis patients (84%) have pulmonary disease; because more than half of these patients have sputum smears positive for acid-fast bacilli, they are potentially capable of transmitting the infection to other persons (CDC, unpublished data). In the United States, more elderly persons live in nursing homes than in any other type of residential institution; based on data from CDC's National Center for Health Statistics, approximately 5% of all elderly persons live in a nursing home (3).However, elderly persons represent 88% of the nation's approximately 1.7 million nursing home residents (3).Such concentrations of elderly persons, many of whom are infected with tubercle bacilli and some of whom are immunosuppressed, create high-risk situations for tuberculosis transmission. Elderly nursing home residents are at greater risk for tuberculosis than elderly persons living in the community.In 1984In -1985, a CDC-sponsored study of 15,379 routinely reported tuberculosis cases from 29 states indicated that the incidence of tuberculosis among nursing home residents was 39.2 cases per 100,000 population; in comparison, the incidence of tuberculosis among elderly persons living in the community was 21.5 cases per 100,000 population (CDC, unpublished data). Nursing home employees are also at increased risk for tuberculosis when compared with other employed adults.In the CDC study, the observed case rate among nursing home employees was three times higher than the rate expected for employed adults of similar age, race, and sex (CDC, unpublished data). Investigators have reported outbreaks in nursing homes in which transmission of tuberculosis was documented among residents and staff (4)(5)(6)(7)(8).The person having the source case has usually been a resident but may be a member of the staff.In such situations, isoniazid preventive therapy has effectively reduced the risk of tuberculosis among contacts of newly infected elderly persons (9,10). The following recommendations for addressing the problem of tuberculosis in facilities providing long-term care to the elderly have been developed in response to requests from state and local tuberculosis control officials, representatives of nursing homes and other long-term-care facilities, physicians in academic and clinical practice, and representatives of regulatory and resource-providing agencies.GENERAL GUIDELINES Each facility should assure that appropriate tuberculosis prevention and control measures are undertaken to protect residents and staff.In large facilities, an infection control committee will usually be responsible for operating the tuberculosis prevention and control program.In a system that has more than one facility providing long-term care to the elderly, a qualified person should oversee the control activities at all of the facilities.Responsibility for surveillance, containment, assessment, and education should be specified in this person's job description.--Surveillance refers to identifying and reporting all cases of tuberculosis in the facility and identifying all infected residents and staff.When an infectious case is identified, additional cases and new infections (as indicated by skin-test conversion) should be identified with the help of the state or local health department, and appropriate therapy should be instituted.--Containment refers to ensuring that transmission of tuberculous infection is stopped promptly.Persons for whom treatment of disease or preventive treatment is indicated should complete the appropriate course of treatment under direct supervision (i.e., the actual ingestion of medication is observed by a staff member).In addition, appropriate ventilation control measures should be applied.--Assessment refers to monitoring and evaluating the surveillance and containment activities throughout each facility.--Education refers to providing information and imparting skills to patients, families, visitors, and employees so that they understand and cooperate with surveillance, containment, and assessment activities.SURVEILLANCE Diagnosis The intracutaneous administration of 5 units of purified protein derivative tuberculin (PPD-T) (Mantoux test) should be used to identify persons infected with tubercle bacilli.Multiple-puncture devices are not recommended.False-negative reactions to the tuberculin test may occur for up to 30% of persons with tuberculosis but without acquired immunodeficiency syndrome (AIDS); in comparison, false-negative reactions may occur for up to 60% of persons with tuberculosis and AIDS (11; CDC, unpublished data).Therefore, a negative skin test does not exclude the diagnosis of tuberculosis.Chest radiography and bacteriologic examinations are indicated for all residents and staff with symptoms compatible with tuberculosis, regardless of the size of the skin-test reaction. Skin tests should be administered to all new residents and employees as soon as their residency or employment begins unless they have documentation of a previous positive reaction.A two-step procedure is advisable for the initial testing of residents and employees in order to establish a reliable baseline (11-13).Appendix I explains this procedure and the rationale for using it.Each skin test should be administered and read by appropriately trained personnel and recorded (in mm induration) in the person's medical record.A record of all reactions of greater than or equal to 10 mm should be placed in a prominent location in order to facilitate the consideration of tuberculosis if the person develops signs or symptoms of tuberculosis, such as a cough of greater than 3 weeks' duration, unexplained weight loss, or unexplained fever.All persons with a reaction of greater than or equal to 10 mm should receive a chest radiograph to identify current or past disease. Skin-test-negative employees and volunteers having contact (of greater than or equal to 10 hours per week) with elderly residents should periodically have repeat skin tests; the recommended frequency of repeat testing depends upon the risk of tuberculosis infection in that facility (13).Each tuberculin-positive resident should be evaluated annually, and a record should be kept that documents the presence or absence of symptoms of tuberculosis (e.g., weight loss, cough, fever).Repeat skin tests should be provided for tuberculin-negative residents and employees after any suspected exposure to a documented case of active tuberculosis.A skin-test conversion is defined as an increase of greater than or equal to 10 mm for a person less than 35 years of age or an increase of greater than or equal to 15 mm for a person greater than or equal to 35 years of age*. Each skin-test converter should have a chest radiograph; if the radiograph is negative for tuberculosis, the individual should be treated preventively.If the source of infection is not known and/or if additional conversions occur, periodic retesting of residents and a careful search for the source case should be continued. Persons with reactions greater than or equal to 10 mm and persons with symptoms suggesting tuberculosis (e.g., cough, anorexia, weight loss, fever), regardless of the size of the skin-test reaction, should have a chest radiograph within 72 hours.Persons with abnormal chest radiographs and/or symptoms compatible with tuberculosis should also have sputum smear and culture examinations.In addition, sputum should be submitted for smear and culture for acid-fast bacilli for persons with a chronic cough, pneumonia, or bronchitis who do not respond promptly and completely to antibiotic treatment.At least three sputum specimens should be submitted.In the absence of spontaneous production of sputum, suction of laryngeal or pharyngeal mucus is satisfactory if sterile water is used in clearing the catheter.Usually, the early detection of tuberculosis by such means either prevents or greatly diminishes the spread of infection. Staff members who are considered to have infectious tuberculosis should be relieved of work responsibilities until the diagnosis is excluded or until they become noninfectious as a result of effective chemotherapy.Case Reporting Whenever tuberculosis is suspected or confirmed among residents or staff, this information should be recorded and kept on file (in the medical record, personnel record, or other appropriate place).A prototype tuberculosis record is shown in Appendix II.The local or state health department should also be notified, as required by state and local laws or regulations.Tuberculosis and Human Immunodeficiency Virus Infection Staff members and residents with tuberculosis or tuberculous infection should be assessed for human immunodeficiency virus (HIV) infection because the medical management of tuberculosis and tuberculous infection must be altered in the presence of HIV infection.Factors that are associated with an increased risk or prevalence of HIV infection should be routinely sought.If HIV infection is considered a possibility, counseling and HIV-antibody testing should be strongly encouraged.Previously published guidelines provide additional information about this topic (14).CONTAINMENT Isolation Persons with suspected or confirmed tuberculosis can remain in their usual environment, provided 1) chemotherapy is promptly instituted at the time the diagnosis is suspected or confirmed, 2) recent and current contacts are evaluated and placed on appropriate therapy, and 3) new contacts can be prevented for a 1-to 2-week period.If these conditions cannot be met, the person with suspected or confirmed tuberculosis should be placed under appropriate isolation precautions to prevent the spread of infection (15).The local health department should be contacted regarding the need for isolation and the methods used for achieving it.Treatment ATS/CDC recommendations should be followed in treating and managing persons with confirmed or suspected tuberculosis (14,16).For newly diagnosed, previously untreated patients, the treatment regimen should contain both isoniazid and rifampin.If the patient has been treated for tuberculosis in the past, other or additional drugs may be needed. Antituberculosis medication should be given along with other medication administered by nursing home staff.Each dose of medication should be dispensed by a staff person who watches the patient swallow the pills and who is trained to monitor for evidence of drug toxicity.Persons with positive sputum smears or cultures at the beginning of therapy should be monitored by repeat sputum examinations for treatment response until smears become negative.Failure to achieve negative smears and cultures is usually due to the patient's noncompliance with therapy but may be due to the presence of drug-resistant organisms or other complications.Patients should also be monitored by trained personnel for signs and symptoms of adverse drug reactions during therapy (14,16).Expert medical consultation should be sought when treating patients with complications (e.g., drug resistance, adverse reactions, nonpulmonary tuberculosis).Such consultation is usually available through the local or state health department.Investigation for Contacts Because tuberculosis is transmitted by the airborne route, persons who sleep, live, work, or who are otherwise in contact with an infectious person through a common ventilation system for a prolonged time are "close contacts" at risk of acquiring infection.These persons may include other residents, staff, and visitors.When a person with confirmed tuberculosis appears to be infectious (e.g., has pulmonary involvement as seen by chest radiograph and a cough and/or positive sputum smear), contacts who were previously tuberculin-negative should be retested (13).If the case occurs in a known tuberculin converter, a search for the person who has the source case (referred to hereafter as the "source patient") should be undertaken by performing chest radiographs for all persons known to be tuberculin reactors and by submitting sputum specimens for smear and culture for all patients with a cough. General guidelines for conducting a contact investigation in a nursing home or other facility are given in Appendix III, but health department personnel should be consulted to help determine which contacts should be examined.Preventive Therapy Contacts who have documented skin-test conversions and whose chest radiographs do not reveal tuberculosis should be given at least 6 months' preventive therapy unless it is medically contraindicated.Other residents and staff with positive tuberculin reactions should be given preventive therapy and monitored according to previously published guidelines (17). Preventive therapy for residents should be incorporated into the facility's routine for delivering medications (e.g., blister pack, cardex file) and should be dispensed by a staff person trained to monitor for signs and symptoms of drug toxicity (16).If such signs or symptoms appear, medication should be withheld pending evaluation by a physician. If tuberculosis preventive therapy is recommended, but individuals refuse or are unable to complete the recommended course, they should be advised to seek prompt medical attention if they develop signs or symptoms compatible with tuberculosis (e.g., persistent cough, anorexia, weight loss, night sweats).Routine periodic chest radiographs are not useful for detecting disease in the absence of symptoms; however, chest radiographs should be obtained promptly for persons with a cough that persists for more than 3 weeks and/or with a prolonged and unexplained fever.ASSESSMENT A record-keeping system, such as that shown in Appendix II, is essential for tracking and assessing the status of persons with tuberculosis and tuberculous infection in nursing homes/facilities that provide long-term care for elderly persons.This system should also provide data needed to assess the overall effectiveness of tuberculosis control efforts.The following information should be reviewed annually with health department staff and should be compared with previous data and data from State and local health departments should assist in developing and updating policies, procedures, and record systems for tuberculosis control in nursing homes and other facilities that provide residential care for elderly persons.The health department should also provide access to expert tuberculosis medical consultation.A health department representative should be designated to provide epidemiologic and management assistance to such facilities, and this responsibility should be an element in that person's job performance plan.At a minimum, he or she should be required to complete an initial on-site consultation, to be available for telephone consultation, and to conduct an annual evaluation of individual facilities. State health departments should assist local units in developing programs to train facility staff to administer, read, and record tuberculin skin tests; to identify signs and symptoms of tuberculosis; to initiate and observe therapy; to monitor for side effects; to collect diagnostic specimens; and to maintain record systems. Health departments should also provide consultation for contact investigations within facilities, and they should assure appropriate examinations of nonresident contacts of persons with tuberculosis diagnosed in these facilities. State health departments have a responsibility to maintain a tuberculosis registry with updated medical information on all persons who currently have tuberculosis within their jurisdiction, including persons in nursing homes and other facilities providing residential care for elderly persons.Records should be assessed annually, and necessary revisions in policies or procedures should be recommended.In addition, state health departments should periodically assess the impact of tuberculosis acquired in a residential facility and the impact of tuberculous infection on the community as a whole. The Committee chose a larger increase in reaction size to define a skin-test conversion among persons greater than or equal to 35 years of age because of the increased risk of isoniazid-associated hepatotoxicity in this age group.With the use of this criterion, the benefits of using isoniazid preventive therapy should clearly outweigh its risks. On the basis of seroprevalence studies, factors that place a person at risk for HIV infection include intravenous (IV)-drug use and homosexual/bisexual contact.Other factors that increase the risk for HIV infection among adults include having received blood or clotting-factor concentrate between 1978 and 1985 and having had sexual relations at any time since 1978 with 1) a person known to be infected with HIV or to have AIDS, 2) a man who has had homosexual/bisexual contact, 3) prostitutes, 4) IV-drug users, or (5) persons born in countries where most transmission of HIV is thought to occur through heterosexual sexual contact.Appendix I Detection of Newly Infected Persons (Skin-Test Converters) The tuberculin test can be especially valuable when it is repeated periodically in the surveillance of tuberculin-negative persons likely to be exposed to tuberculosis.However, special problems exist in identifying newly infected persons. First, some errors may occur in even the most carefully performed tests.For this reason, small increases in reaction size are usually not meaningful.Only persons whose tuberculin reactions show marked increases in size (i.e., greater than or equal to 10 mm among persons less than 35 years of age and greater than or equal to 15 mm among those greater than or equal to 35 years) within a 2-year period should be considered newly infected. A second problem in identifying newly infected persons is the "booster phenomenon."Repeated testing of uninfected persons does not sensitize them to tuberculin.However, delayed hypersensitivity to tuberculin, once it has been established by infection with any species of mycobacteria or by Bacillus of Calmette and Guerin (BCG) vaccination, may gradually wane over the years.When tested at this point, these persons may have negative reactions.The stimulus of this test may then boost or increase the size of the reaction to a subsequent test, sometimes causing an apparent conversion or development of sensitivity.Although the booster phenomenon may occur at any age, its importance increases with age.

When tuberculin skin testing of adults is to be repeated periodically, the use of two-step testing initially can reduce the likelihood that a boosted reaction will be interpreted as representing recent infection.If the reaction to the first test is negative, a second test should be given a week later.If the second test result remains below the cutting point for a positive test, the reaction is considered to be negative.If the reaction to the second test is positive, it probably represents a boosted reaction and not a new infection. Multiple-puncture devices should not be used in tuberculin-testing surveillance programs designed to detect newly infected persons (such as in periodic testing programs for employees of hospitals and other institutions or in the evaluation of contacts).Appendix II Tuberculosis Summary Record The Prototype Tuberculosis Summary Record is designed to update the tuberculosis status of each resident and employee in a facility.This record may be kept in a central location (e.g., in the infection control office) or may be kept in individual patient or staff medical records.The form should not replace the tuberculosis diagnostic and treatment information found in the medical records of persons with tuberculosis symptoms or of those persons receiving antituberculosis medications. The form can also be used to prepare statistical reports and to track residents and employees requiring periodic skin testing.This information is important for assessing the overall effectiveness of tuberculosis control efforts in a facility.If kept current, the data on the forms can be summarized periodically and compared with previous data in order to determine: --The number of staff and residents having positive tuberculin skin tests --The number of persons whose tuberculin tests have shown conversions from negative to positive --The number of persons in the home receiving tuberculosis therapy and supervision --The number and percentage of persons recommended for therapy who complete the prescribed course (goal is greater than or equal to 95%) When tuberculosis is diagnosed, the form contains the necessary information for reporting the case to the state or local health department.The form also reflects 1) if the case was reported, 2) if a contact investigation was completed, or 3) if HIV testing was performed.Summary information regarding the use of chemotherapy for infection or disease can also be recorded. Many items on the form require only a check in the appropriate box.The format follows events in the order they are likely to occur in the diagnosis of tuberculosis infection and disease. The first section can be completed at the time of admission or employment; it documents personal information, as well as baseline skin-testing results.Space is provided for recording the results of a second initial skin test when the two-step procedure is used. If baseline skin testing is negative, the results of retesting can be recorded on the second section of the form. The final section of the form can be used to document x-ray and bacteriologic results, diagnosis, chemotherapy, and other information.This part of the form is generally used only for those residents or employees who have tuberculous infection or disease, those who have tuberculosis symptoms, or those who require follow-up after exposure to tuberculosis.Appendix III Investigation for Contacts Contacts of persons with newly diagnosed tuberculosis are at risk of infection and disease.The risk to contacts is related to various factors pertaining to the person who has the source case (the "source patient"), the contact, and the environment that they share.Many factors interact to influence the transmission of infectious particles (droplet nuclei) from the source patient to the contact. As soon as the diagnosis is reasonably established on laboratory and/or clinical bases, investigation of contacts should begin.Health-care personnel should not wait for positive cultures if history, sputum smears, and chest radiographs are suggestive of tuberculosis.A. Development of Transmission Probability Data When a source patient has been identified, the appropriate procedure in contact investigation entails the development of a data base and an evaluation of each of the factors noted below.These data are usually gathered by interviewing the source patient and by reviewing related historic and laboratory records.A visit to the source patient's home or place of employment will usually be necessary to assemble a satisfactory initial data base.Source-patient characteristics.Any person who is generating aerosolized particles containing tubercle bacilli is a potential transmitter of infection.Factors that indicate the probability of spreading tuberculous infection are: --If the source patient is not receiving adequate antituberculosis chemotherapy, the probability of his or her producing infectious particles is enhanced. --The presence of acid-fast bacilli in the appropriately examined sputum smear is indicative of a greater potential for infection.--The ability to culture Mycobacterium tuberculosis from secretions of the source patient is less important quantitatively as an indicator than is the positive sputum smear.--The presence of tuberculous laryngitis increases infectiousness.--The presence of cough increases the probability of aerosol generation.--The volume and viscosity of respiratory secretions influence the production of infectious particles; high volume and watery sputum are regarded as risk factors.--Forceful exhalation (e.g., singing or shouting) may increase the potential for producing infectious particles.--Prolonged duration of respiratory symptoms may augument the likelihood that infection will be transmitted.Environmental air factors.Air is the vehicle by which the infectious particle or droplet nucleus is transported from the source patient to susceptible persons.The greater the concentration of these droplet nuclei in air shared by the source patient and his or her associates, the greater the risk to these contacts.The following factors alter the concentration of infectious particles in the air: --The volume of air common to the source patient and contact is critical.If low, the concentration of infectious particles is increased (e.g., as in sharing a small room).The estimated probability of transmission, based on information obtained by following the steps described above, should influence the priority, rapidity, and thoroughness with which a contact investigation is conducted.By using this systematic approach, appropriate and productive public health programs can be implemented.Classification of contacts.For each source patient, the contact investigation should proceed in an orderly manner, starting with persons who are most likely to have been infected.Members of the immediate family or others who have shared accommodations with the source patient in the recent past usually are labeled household contacts.Contacts in working, leisure, or other settings are designated by other terms such as "close," "intimate," or "casual."The most important consideration in a contact investigation is the probability of infection among contacts; therefore, the first step is to allocate contacts into higher-and lower-risk contacts. A higher-risk contact is defined as any person who shared the environment air with a source patient for a relatively longer time and who has other risk factors relatively higher than those of other known contacts.Nursing home/facility residents sharing the same wing or ventilation circuit should usually be considered close contacts.C. Establishing Limits for Contact Investigations By initially evaluating the higher-risk contacts for evidence of tuberculous infection and/or disease, the actual infectiousness of the source patient can be inferred.The following are guidelines for limiting the extent of a contact investigation: --Initiate investigation with higher-risk contacts; if there is no evidence of recent transmission of infection in this group, extending the investigation is not appropriate.--If data indicate recent infection in the higher-risk group, extend the limits of investigation to progressively lower-risk contacts until the levels of infection detected approximate the levels of infection in the local community.--At each stage of the investigation, establish the number and identity of contacts to be examined.Establishing such a denominator helps to assure that no contact who should be examined is missed. 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# Foreword Since its inception in 1970 the National Institute for Occupational Safety and Health (NIOSH) has extensively investigated and assessed coal miner morbidity and m or tality.This history of research encompasses epidemiology; medical surveillance; laboratory-based toxicology, biochemistry, physiology, and pathology; exposure assessment; disease prevention approaches; and methods development.The experi ence gained in those activities, together with knowledge from external publications and reports, was brought together in 1995 in a major NIOSH review and report of recommendations, entitled Criteria for a Recommended Standard-Occupational Exposure to Respirable Coal Mine Dust.This document had the following major recommendations: 1.Exposures to respirable coal mine dust should be limited to 1 mg/m3 as a time-weighted average concentration for up to a 10 hour day during a 40 hour work week; 2.Exposures to respirable crystalline silica should be limited to 0.05 mg/m3 as a time-weighted average concentration for up to a 10 hour day during a 40 hour work week; 3.The periodic medical examination for coal miners should include spirometry; 4.Periodic medical examinations should include a standardized respiratory symptom questionnaire; 5.Surface coal miners should be added to and included in the periodic medical monitoring.This Current Intelligence Bulletin (CIB) updates the information on coal mine dust exposures and associated health effects from 1995 to the present.A principal intent is to determine whether the 1995 recommendations remain valid in the light of the new findings, and whether they need to be updated or supplemented.The report does not deal with issues of sampling and analytical feasibility nor technical feasibil ity in achieving compliance. # Executive Summary Information relating to occupational pulmonary disease morbidity and mortality of coal miners available up to 1995 was reviewed in the NIOSH publication: Criteria for a Recommended Standard-Occupational Exposure to Respirable Coal Mine Dust, or Coal Criteria Document (CCD).This led to the following principal conclusions concerning health effects associated with coal mining: 1.Exposure to coal mine dust causes various pulmonary diseases, including coal workers' pneumoconiosis (CWP) and chronic obstructive pulmonary disease (COPD).2.Coal miners are also exposed to crystalline silica dust, which causes silicosis, COPD, and other diseases.3.These lung diseases can bring about impairment, disability and premature death.This Current Intelligence Bulletin updates the previously published review with re spect to findings relevant to the health of U.S. coal miners published since 1995.The main conclusions are: 1.After a long period of declining CWP prevalence, recent surveillance data indicate that the prevalence is rising.2.Coal miners are developing severe CWP at relatively young ages (<50 years).3.There is some indication that early development of CWP is being manifested as premature mortality.4.The above individuals would have been employed all of their working lives in environmental conditions mandated by the 1969 Coal Mine Health and Safety Act.5.The increase in CWP occurrence appears to be concentrated in hot spots of disease mostly concentrated in the central Appalachian region of southern West Virginia, eastern Kentucky, and western Virginia.6.The cause of this resurgence in disease is likely multifactorial.Possible expla nations include excessive exposure due to increases in coal mine dust levels and duration of exposure (longer working hours), and increases in crystalline silica exposure (see below).As indicated by data on disease prevalence and severity, workers in smaller mines may be at special risk.7.Given that the more productive seams of coal are being mined out, a transi tion by the industry to mining thinner coal seams and those with more rock 1968-87.Figure 3.Probability that an individual starting with no pneumoconiosis (cate gory 0/0) will be classified as 2/1 or greater after 35 years of exposure to various concentrations of coal mine dust.Figure 4.Predicted prevalence of PMF among British coal miners after a 35-year working lifetime by mean concentration of respirable coal mine dust.Figure 5.Prevalence of simple CWP category 1 or greater among U.S. coal miners by estimated cumulative dust exposure and coal rank.Figure 6.Prercentage of evaluated miners with rapidly progressive coal workers' pneumoconiosis by county.Figure 7.Percentage of miners in the NIOSH Coal Workers' X-ray Surveillance Program with coal workers' pneumoconiosis (category 1 or greater) from 1970-2009, by tenure in coal mining.Figure 8.Percentage of miners examined in the NIOSH Coal Workers' X-ray Sur veillance Program with progressive massive fibrosis (PMF) from 1970 2009, by tenure in mining.Figure 9.Observed and predicted prevalences (%) of CWP category 1 or greater by age group and MSHA District.Figure 10 # List of Figures # List of Tables # Aerodynamic diameter: The diameter of a sphere with a density of 1 g/cm3 and with the same stopping time as the particle.Particles of a given aerodynamic diameter move within the air spaces of the respiratory system identically, regardless of density or shape. # Chronic obstructive pulmonary disease (COPD): Includes chronic bronchitis (in flammation of the lung airways associated with cough and phlegm production), impaired lung function, and emphysema (destruction of the air spaces where gas transfer occurs).COPD is characterized by irreversible (although sometimes vari able) obstruction of lung airways, and should be considered in any patient who has dyspnea, chronic cough or sputum, and/or a history of exposure to risk factors for COPD.The diagnosis should be confirmed by spirometry. Coal rank: A classification of coal based on fixed carbon, volatile matter, and heat ing value of the coal.Coal rank indicates the progressive geological alteration (coalification) from lignite to anthracite. # Coal workers' pneumoconiosis (CWP): A chronic dust disease of the lung arising from employment in a coal mine.In workers who are or have been exposed to coal mine dust, diagnosis is based on the radiographic classification of the size, shape, profusion, and extent of parenchymal opacities. Crystalline silica: Silicon dioxide (SiO2). "Crystalline" refers to the orientation of SiO2 molecules in a fixed pattern as opposed to a nonperiodic, random molecular arrangement defined as amorphous.The three most common crystalline forms of free silica encountered in general industry are quartz, tridymite, and cristobalite.The predominant form is quartz. Excess (exposure-attributable) prevalence: The prevalence (cases/population at risk) attributable to workplace dust exposure (in the case of CWP, the prevalence adjusted for radiographic appearances associated with lung aging). International Labour Office (ILO) classification system: A standardized method for assessing abnormalities related to the pneumoconioses based substantially on compari son of test with reference radiographs.In the system there are 4 categories of simple pneumoconiosis (categories 0, 1, 2, and 3), with 0 implying no definite abnormality. Progressive massive fibrosis: Coal workers' complicated pneumoconiosis.Diagno sis is based on determination of the presence of large opacities (1 cm or larger) using radiography or the finding of specific lung pathology on biopsy or autopsy. # Glossary x ii Quartz: Crystalline silicon dioxide (SiO2) not chemically combined with other sub stances and having a distinctive physical structure. Respirable coal mine dust: That portion of airborne dust in coal mines that is ca pable of entering the gas-exchange regions of the lungs if inhaled: by convention, a particle-size-selective fraction of the total airborne dust; includes particles with aerodynamic diameters less than approximately 10 ^m. # D ivision o f R e sp irato ry Disease Studies (DRDS) Janet Hale, Eva Suarthana, Mei Lin Wang # H e a lth Effects L a b o ra to ry D ivision (HELD) Vincent Castranova, Kimberly Clough Thomas This Current Intelligence Bulletin has undergone substantial internal and external scientific peer review with subsequent revision.A draft version of the document was published on the NIOSH website for public comment for 60 days, with notification of its availability via the Federal Register.All input, both internal and external, has been considered, addressed, and responded to in preparation of this final version. # Introduction The publication of the NIOSH Criteria for a Rec ommended Standard-Occupational Exposure to Respirable Coal Mine Dust or Coal Criteria Document (CCD) in 1995 (1) followed a long period of extensive research activity focused on exposure to coal mine dust and its health effects in coal miners.From this research, substantial information had emerged about the extent and severity of respiratory disease caused by coal mine dust, its quantitative rela tionship with dust exposure, its pathology and toxicology, environmental patterns of relevant exposures, and methodologies for assessing these variables.In particular, the findings dem onstrated that not only was there a consider able burden of coal workers' pneumoconiosis (CWP) in the U.S. and other countries, but that underground coal miners were vulnerable to other lung diseases, notably chronic obstruc tive pulmonary disease (COPD).The evidence came from extensive and well-planned epide miologic and laboratory-based investigations undertaken primarily in the U.S., the United Kingdom, and (West) Germany, with support ing information coming from studies in other European countries and Australia. The available information was thoroughly sum marized in the CCD.It showed that, in 1995, CWP was in decline in the U.S., with downward trends in prevalence in all tenure groups (Figure 4-2 of the CCD (1), included here as Figure 1).This decline was consistent with reductions in coal mine dust exposure mandated by the 1969 Coal Mine Health and Safety Act (1969 Coal Mine Act) (CCD Figure 4-1 (1); Figure 2).De spite this decline in disease levels, NIOSH con cluded from review of the surveillance data and quantitative risk estimates based on the epide miologic studies that the current dust exposure regulations for U.S. coal mines were not suffi ciently protective.Consequently, it proposed lower dust limits for coal mines, enhanced med ical surveillance, and other requirements. 1967 1969 1971 1973 1975 1977 1979 1981 1983 1985 1987 Y ear F ig u re 2.Trend in reported dust concentrations for continuous miner operators, 1968-87. (Source: Attfield and Wagner ( 2)). 3 Q o H- i- i- i- i- i- i- i- i- i- i-i- i-i- i- i- i- i- i- i- i The CCD noted that the current U.S. federal dust limit for underground coal mines dated back to the 1969 Coal Mine Act, which m an dated a compliance permissible exposure limit of 2 milligrams per cubic meter (mg/m3) of respirable coal mine dust.This limit was derived from British research, which provided the only quantitative exposure-response relationship available at that time.This exposure-response curve (CCD Figure 7-2 (1); Figure 3) predicted that no cases of CWP as severe as category 2 on the International Labour Office (ILO) classifi cation system (3) would develop among m in ers who worked 35 years at 2 mg/m 3.Similarly at that time, the current information indicated that the disabling form of CWP, progressive massive fibrosis (PMF), was very unlikely to develop from less severe ILO categories (e.g., category 1 CWP).Therefore, adoption of the 2 mg/m3 limit was believed, at that time, to be protective against the risk of disability and pre mature mortality that accompanies PMF. Subsequent scientific findings, emerging be tween 1969 and 1995, disproved some of the assumptions inherent in the adoption of the 2 mg/m3 standard.Firstly, the assumption that miners with CWP less severe than category 2 were at minimal risk of PMF was found to be incorrect.Moreover, additional findings from the British data (CCD Figure 7-6 and Table 4-6 (1); Figure 4 and Table 1), together with new results on U.S. underground coal miners from research undertaken by NIOSH (CCD Figure 7-4 and Table 4-6 (1); Figure 5 and Table 1) showed that there was no threshold at 2 mg/m3 as had been indicated by the original British study (CCD Figure 7-2 (1); Figure 3).Furthermore, the CCD reviewed findings on other lung diseases and their relationship with coal mine dust exposure.It concluded that coal miners were at additional risk of developing ventilatory function deficits, respiratory symp toms, and emphysema in addition to CWP (CCD Table 4-7 (1); Table 2). (Note that the results provided here are selected to illustrate the main CCD conclusions.For a full under standing of the complete body of knowledge, please see the CCD (1).) . /0.1- < i i i i i i i i i i i i i i i i i 1 On the basis of the updated body of evidence on the adverse health effects and an evalua tion of the technological feasibility of reduc ing dust exposures, NIOSH recommended that the federal coal mine dust limit be re duced to 1 m g/m 3.Critical to this decision were computed excess (exposure-attributable) prevalences of CWP derived from two stud ies of U.S. coal miners undertaken by NIOSH (CCD Table 7-2 (1); Table 3).Predictions were derived from each study for a working lifetime (i.e., 45 years) exposure at 2 mg/m3 and 1 mg/ m 3.Another source of information critical to the recommendations was information on pre dicted excess lung function decrements for a lifetime's exposure to 1 mg/m 3 and 2 mg/m3 respectively (CCD Table 7-3 (1); Table 4).De tails of the rationale for, and development of, the risk analyses employed in the CCD were subsequently published separately (8).NIOSH also evaluated information from other epide miologic studies in coming to its recommen dations in the CCD.However, because no oth er studies had quantitative exposure-response information, apart from strengthening the case for more stringent regulation, these ad ditional study results did not provide any nu merical basis for standard setting.For simplic ity, NIOSH recommended one exposure limit for the nation rather than different limits by coal rank, based on technological feasibility of reducing exposures, even though CWP preva lence has been shown to vary according to the rank of the coal in studies of miners in the U.S. and other countries. In addition to recommending a reduction in the exposure limit for coal mine dust, NIOSH also recommended a change in the exposure limit for crystalline silica dust and the method by which it is enforced.Currently, silica levels are intended to be controlled by a reduction in the level of coal mine dust commensurate with the proportion of the dust that is silica.NIOSH proposed a separate limit for respirable crystal line silica in order to more effectively monitor (19)(20)(21). To gain a better understanding of the extent of the problem, NIOSH undertook a systematic analysis of rapidly progressive CWP (22).Sta tistics were derived based on each miner' s ra diographic steps of progression of CWP using the standard ILO categorical scores standard ized to a five-year interval.These data were summarized by county and then plotted to reveal 'hot spots' of rapid disease progression (Figure 6; from Antao et al, 2005 (22)).These tended to be located on the eastern edge of the on the NIOSH internet site (24).These results showed that the prevalence of CWP appeared to have stopped declining around 1995-1999, and has risen since then.The trend reversal appears most apparent in the longer-tenured miners.Virtually that entire group had spent their whole working life in dust conditions mandated by the 1969 Coal Mine Act.An up dated (unpublished) version of this graphic, taking the data up to 2009, shows the increased CWP prevalence observed over the past de cade (Figure 7). The upward trend visible in Figure 7 for all pneumoconiosis cases (category 1+) is even more evident for PMF (Figure 8).O f particular concern are the prevalence values for the last three five-year periods (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009) for m in ers with <25 years tenure, which are well above those observed in the early 1990s.In 2005-2009 alone, 69 coal miners examined in the CWXSP were determined to have PMF.Of these, 11 had less than 25 years total tenure in coal mining, and the majority (56, or 81%) were working in the central Appalachian region. Since the data from 2005 in Figures 7 and 8 were derived, in part, from the special NIOSH surveys targeted at hot spot areas, there could be the concern that the recent CWXSP find ings may be upwardly biased, with the implica tion that the apparent rise in prevalence may be an artifact.However, overall prevalences for 2005-2009 for the Enhanced and regular programs, derived from state-specific preva lences weighted by the participation rates for the whole program from the different states gives rise to figures of 3.2% prevalence for data from the targeted surveys (Enhanced pro gram) compared to 3.1% for data from the reg ular program.There is therefore no indication whatsoever of any major bias.Moreover, it is A number of reports of surveillance informa tion from other countries have emerged since 1995 (26)(27)(28)(29)(30)(31).Although mining conditions differ in these other countries, these studies are supportive of the findings in U.S. coal miners. # Epidem iology The CWXSP finding of increased prevalence of CWP has prompted a series of analyses by NIOSH aimed at identifying factors that might be causing the increase.In an analysis under taken as part of this series (32), predicted risk of CWP was derived for each individual who participated in the CWXSP from 2005-2009 using published exposure-response models (7).The models were coal-rank specific, and used both age and cumulative coal mine dust exposure as predictors.The resulting indi vidual risks (lying between 0 and 1) were then summed over subsets of the data and com pared with the observed prevalences. (Further models, published later, were also available, but the early relationships were preferred because they were based on greater numbers of ob servations and had more specific adjustment for coal rank.The later predicted prevalences were somewhat higher than those presented here.)The results tabulated by MSHA region and age are shown here in Figure 9.It is clear that CWP prevalence is less than expected in some regions (observed predicted).That is, in the north ern Appalachian region and the mid-west and western coal fields the observed prevalences are generally below those predicted in all age groups.

However, in the southern WV, eastern and central KY, Tennessee, and VA MSHA re gions the observed prevalences are 2-4 times greater than predicted from cumulative coal mine dust exposure and age.Clearly, some fac tor or factors must be acting differently across the regions to cause this regional pattern. At least three environmental factors impact the central Appalachian region in this respect.These are: thin seams, small mines, and, for VA, high coal rank.The mining of thin coal seams, which often involves the deliberate cut ting and extraction of substantial amounts of (often siliceous) rock overlying or underlying the coal seam, is particularly prevalent in Ap palachia (33).NIOSH has been investigating the health implications of possible excessive crystalline silica exposure arising from the cutting of the rock adjacent to the coal seams (34).This analysis used the presence of r-type pneumoconiotic opacities on the chest X-ray as an indicator of crystalline silica exposure.This type of opacity is a radiographic manifes tation of nodules in the lung having a typology often associated with excessive exposure to sil ica dust.An increase in the prevalence of such opacities could then well indicate that miners are more frequently being exposed to crystal line silica dust, or are experiencing exposure to higher levels of silica dust.Increased exposure to crystalline silica dust may well be arising from industry trends, whereby there is greater focus on mining thinner seams of coal as the more productive thicker seams are mined out. The findings from this study indicated that the proportion of radiographs showing r-type opacities increased during the 1990s, and particularly after 1999, in KY, VA, and WV, compared to the 1980s.They could potentially be explained by an increase in the frequency and/or intensity of silica exposure among un derground coal miners.This hypothesis was confirmed by evidence from dust sampling in mines in that region indicating that excessive silica exposures are occurring (35).In the CCD, NIOSH not only recommended that compli ance procedures for crystalline silica be made more effective, but that the exposure limit be reduced.In the light of these epidemiological findings (34), therefore, this recommendation remains appropriate and even more urgent.A report on British coal miners also associated an increase in CWP prevalence with rock cut ting (36). In another NIOSH analysis (19) trends in CWP prevalence were examined by mine size (i.e., employment).The hypothesis investigated was that smaller mines lack resources in many ar eas for the full protection of workers, including dust suppression and up-to-date knowledge of means to prevent disease development. (It may also be that smaller mines tend to be those m in ing the thinner coal seams.)The results show that CWP prevalence is increasing in mines of all sizes, but the trend is much more obvious and much greater among miners employed in smaller coal mines.a contributory causative factor for CWP, work ing longer hours leads to the inhalation of more dust into the lungs.For example, working 12 hours leads to 50% more dust entering the lung compared to a regular 8-hour shift, assuming all other factors are equal (e.g., exposure con centration and breathing rates).Additionally, working longer workshifts reduces the time available between workshifts for the process of clearing the dust deposited in the lungs.Unfor tunately, the available information on working hours in U.S. coal miners is not miner-specific but rather by coal mine, substantially reducing the validity of a formal analysis of this hypoth esis.A report on British miners concluded that longer working hours were a factor in causing an increase in CWP prevalence at two mines (36).In the CCD, NIOSH recommended re ducing dust exposures below the 1 mg/m 3 REL for work shifts exceeding 40 hr/week (using the method of Brief and Scala (37)).This ap proach has also been recommended for British coal mines (38). Finally, productivity per hour worked also increased from 1978-2000, although it has since declined (Figure 11).Of course, these increases in productivity (and, presumably, in creased potential for dust generation) should have been met by commensurate increases in dust prevention measures (e.g., ventilation and water sprays) in order to maintain compliance with the permissible exposure limit.Superfi cially, the current data appear to confirm this, in that airborne dust levels have apparently not risen during that period (Figure 12).However, the veracity of coal mine dust data has been challenged in the past (39).Moreover, the dis covery of abnormal white centers in the dust sampling filters prompted a special inspection (42).Not only has the YPLL been increasing in younger CWP decedents (<65 years old), but the YPLL per CWP dece dent has also been increasing over those same years (Figure 15; Figure 2 from CDC (42)).This may be related to the observed increase in CWP prevalence observed in recent years as noted earlier. I i i i i i i i i i 1- The post-1995 period saw the publication of a number of mortality analyses that augmented the earlier mortality findings on coal miners. program (40) that showed that dust levels from operator samples consistently were lower than those from MSHA inspector samples, and that these differences were greater the smaller the mine (Figure 13).As with hours worked, there is a lack of reliable productivity data linkable with the health outcome data in order to inves tigate this issue further. # M o rta lity A report on temporal patterns in pneumoconio sis mortality in the U.S. showed a substantial de cline in numbers of deaths from CWP between 1968 and 2000 (41).This decline is consistent with the reductions in dust level mandated by the 1969 Coal Mine Act.A major additional factor contributing to the declining number of CWP deaths is the diminishing coal mining Most of those studies outside of the United States and United Kingdom did not have quantitative measurements of dust exposure.However, they do support previous findings concerning the overall increased mortality of coal miners and the additional risk imposed by the development of CWP (43)(44)(45).Studies using quantitative exposures showed that m or tality from CWP increased with increasing cumulative exposure to coal mine dust (46).The British study (47) included exposure esti mates for respirable quartz; cumulative expo sure to respirable coal mine dust and respirable quartz were each highly significant predictors of pneumoconiosis mortality, although the relationship was stronger with coal dust than quartz.Respirable quartz exposure was asso ciated with a small but statistically significant relative risk for lung cancer mortality (47). # Toxicology Although coal mine dust and crystalline sili ca dust remain the two exposures of primary concern for environmental control, the post-1995 period has seen the publication of results from analyses aimed at eliciting information on what constituents of coal mine dust predict CWP development.These include: 1) free radi cals, in which particles from freshly-fractured siliceous rock have been found to be more fibrogenic than aged particles (48); 2) particle occlusion, in which clay present in the rock strata can surround the silica particles and render them less toxic (49); and 3) bioavailable iron, which has been found to predict coal mine dust toxicity (50,51). McCunney et al. (52), favored the third expla nation (bioavailable iron) and downplayed the role of quartz in the etiology of coal workers' pneumoconiosis.However, in an analysis of lung inflammatory cell counts from bronchoalveolar lavage in coal miners and non-miners, Kuempel et al. (53) showed that quartz dust (as ei ther cumulative exposure or estimated lung burden) was a significant predictor of pulmo nary inflammation and radiographic category of simple CWP.Cumulative coal dust exposure did not significantly add to those predictions, which may have been due to the high correla tion between the coal and quartz cumulative exposures, such that separate effects for these two dusts could not be clearly demonstrated. Against this, epidemiologic research has not demonstrated a strong effect of crystalline sil ica on CWP development in situations where silica levels are low.Rather, the level of coal mine dust, per se, has been the strongest pre dictor of CWP.However, the work of Laney et al. (34), as noted above, showed clear evidence of an increase in r-type radiographic opacities (typically associated with silicosis) and rapid progression of pneumoconiosis among U.S. coal miners in Kentucky, Virginia, and West Virginia, suggesting that they were exposed to excessive levels of respirable crystalline silica, and were thus at risk of silicosis.As noted pre viously, dust sampling results support this hy pothesis (23).There is, therefore, the clear need to minimize exposure to silica dust, especial ly for those jobs involving drilling or cutting sandstone and other siliceous rock.Moreover, as noted above, this is particularly pertinent because changing mining conditions might be leading to an increase in the potential for expo sure to silica dust. Page and Organiscak (54) linked the issue of coal rank, a known risk factor for CWP devel opment in the U.S., Britain, and Germany, with the potential for higher levels of free radicals to be encountered where such coals are mined, and noted above by Dalal (48) and others to have greater levels of cytotoxicity. # Risk Analysis Kuempel et al. (13) describe in more detail the risk analyses provided in the NIOSH CCD, in cluding the excess (exposure-attributable) prev alence of CWP and PMF in underground coal miners exposed to various levels of coal mine dust for a working lifetime (as shown in the CCD and also presented here in Table 1).More recent risk estimates have been provided from research on British coal miners (Figure 16, from Figure 1 of Soutar et al. (55)).The latter apply to coal composed of 86.2% carbon (coal rank) and to underground coal miners who work 40 years at the designated coal mine dust level.Risks of PMF range from 0.8% at 1.5 mg/m3 to about 5% at 6 mg/m3, while risks of category 2 or greater CWP range from about 1.5% at 1.5 mg/m3 to about 9% at 6 mg/m3.Note that due to the different ways in which the risk estimates are derived, these are not directly comparable with those from U.S. studies shown in Table 1.How ever, the findings are consistent with those from U.S. studies in indicating that even at the lower coal mine dust levels recommended by NIOSH, and as noted in the CCD, some incidence of CWP would still be expected, especially among miners of higher rank coal.Soutar et al. (55) also provide information on the risk of silicosis in underground coal miners. Their findings were developed from observa tions at one mine in which unusually high con centrations of crystalline silica dust occurred periodically (56).In their analysis, the authors chose to divide the analysis between exposures 2 mg/m 3.This dichotomy, in the authors' presentation, was associated with more rapid development of silicosis in the > 2 mg/m3 exposure range compared to chronic sil icosis development at exposures < 2 mg/m3.The findings indicate that short excursions to high silica dust intensities are considerably more hazardous than the same level of cumulative exposure at a lower intensity.They therefore demonstrate that mining situations involving the cutting of rock should be avoided if at all possible, or if necessary, that all precautions should be taken to minimize dust exposures. The findings for <2 mg/m3 (which apply to most coal mining environments that do not involve direct rock cutting) are given in Figure 17 (Figure 3 3 Other Respiratory Disease Outcomes Coggon and Taylor (57), in an extensive re view, concluded that the "...balance of evi dence points overwhelmingly to an impair ment of lung function from exposure to coal mine dust, and this is consistent with the in creased mortality from COPD that has been observed in coal miners."Findings on COPD and related outcomes in coal miners since 1995 (58)(59)(60)(61)(62)(63)(64) have continued to support their con clusion (which was largely based on pre-1995 information).The findings have also identified other risk factors in coal mining for pulmo nary disease development.These include work in roof bolting, exposure to explosive blasting fumes, and exposure to dust control spray wa ter previously stored in holding tanks (65). The post-1995 findings have also elucidated patterns of lung function decline in coal m in ers, indicating that new miners tend to suffer more severe declines on starting work, after which the declines attenuate somewhat.This finding, derived initially from the analysis by Seixas et al. (66), was explored further by Hen neberger and Attfield (58), who confirmed that the temporal pattern of lung function decline was different in newly-hired coal miners as compared to experienced miners.A possible reason for this could be a healthy worker sur vival effect.A study to explore this issue fur ther, undertaken on new Chinese coal miners, confirmed that starting work in coal mining led to large initial drops in lung function, after which lung function declined at a lesser rate (67).In a follow-up analysis, the researchers reported that the development of respiratory symptoms consistent with bronchitis contrib uted to the early declines in lung function (68). A recently published mortality study from the United States ( 46) comprised a longer followup of a study on the same cohort of under ground coal miners published in 1995 (69). It showed that mortality from chronic airway obstruction (CAO) was elevated.Smoking, pneumoconiosis, coal rank region, and cumu lative coal mine dust exposure were all predic tors of mortality from CAO.Dust exposure ef fects were observed within the never-smoker subset of the cohort.The observed dust-related relative risks for CAO were similar to those for pneumoconiosis.The findings showed dustrelated effects for chronic bronchitis and em physema as well as CAO.A recent British study re-affirmed that mortality from COPD was re lated to coal mine dust exposure (47).Finally, the implications of COPD (due to coal mine dust exposure as well as smoking) in causing increased mortality was explored by examin ing mortality risk in relation to rates of ventila tory function decline in coal miners (70).Rates of ventilatory decline 2-3 times the normal age-related decline were associated with dis tinct increases in subsequent mortality. Past pathologic studies have shown that em physema severity in coal miners is related to dust exposure.Recent studies on South African and U.S. coal miners confirmed these findings (71,72).Important additional information on this topic, using quantitative estimates of both coal mine dust exposure and smoking amount, has been recently published by Kuempel et al. (73).These authors found a highly significant relationship between cumulative exposure to respirable coal mine dust and emphysema severity at autopsy, controlling for effects of smoking, age, and other variables.The effect of dust exposure was similar in magnitude to that of smoking, and was seen in the never-smok ing subgroup.In a further analysis, Kuempel et al.established that exposure to coal mine dust can produce clinically important levels of em physema in coal miners (74). The above findings support the CCD's recom mendation to reduce the permissible coal mine dust exposure limit in underground coal mines to prevent the development of COPD, the as sociated severe declines in lung function, and the ensuing premature mortality. There have been several reports of interstitial disease associated with exposure to coal mine dust, perhaps representing a manifestation of CWP, although little systematic research on this topic has been undertaken (75, 76). # Risk Analysis Kuempel et al. (13) describe in more detail the risk analyses summarized in the NIOSH CCD, including the excess (exposure-attributable) prevalence of lung function deficits in under ground coal miners exposed to various levels of coal mine dust for a working lifetime (CCD Table 4-7 (1); Table 2).More recent risk esti mates from research on U.K. coal miners have been published (Figure 15; Figure 1 of Soutar et al. (55)).They apply to coal composed of 86.2% carbon (coal rank) and to underground coal miners who work 35 years at specified coal mine dust levels ranging from 1 to 6 mg/m3.Risks of a deficit of approximately 1 liter in forced expira tory volume in 1 second (FEV1) among never smokers range from 10% at zero dust expo sure to about 19% at 6 mg/m3.The concomi tant risks for smokers range from about 22% to 36%, respectively.Note that due to the differ ent ways in which the risk estimates have been derived, these are not directly comparable with those shown from U.S. studies shown in Table 2.However, they are consistent with findings from U.S. studies in that even at the 1 mg/m3 coal mine dust exposure limit recommended by the CCD, some occupational effect on ven tilatory function is expected. ).Overall, levels of both coal mine dust and crystalline silica dust were re ported to be higher in underground mines than in surface mines. # Dust Exposure Assessment The primary advance since 1995 in the dust as sessment arena has been the development of a continuously-measuring personal dust monitor (PDM) (81).The PDM enables within-shift as sessment of dust exposures, permitting prompt action to intervene and reduce excessive lev els.Conventional practices that rely on the gravimetric assessment of dust collected on air sample filters preclude speedy remediation be cause the delay in obtaining results from the dust laboratory could mean that miners con tinue to be over-exposed before any indication of a problem is available from the laboratory results.The personal dust monitor is now a commercially available product and, as its use is adopted by mines, more timely and targeted interventions to reduce dust exposures will be possible.

In 2010, the Mine Safety and Health Administration published new rules that pro vide for the approval and use of the PDM, in addition to the Coal Mine Dust Personal Sam pler Unit, for determining the concentration of respirable dust in coal mine atmospheres (82). # Com pliance Policy and Procedures The federal policies and procedures for regu lating underground coal mine dust levels have been the subject of criticism from their intro duction in 1969.Since 1995 further critiques have been published (83,84).The first publica tion provided a historical review, the basic ar gument being that the problems were intrinsic to a process in which an industry essentially regulates itself (i.e., through performing the airborne sampling upon which citations are based).The second publication revisited an issue that was addressed in the NIOSH CCD, in which it was recommended that MSHA not apply any upward adjustment of the REL for instrument uncertainty.Information indicat ing that reported dust levels from mine opera tor sampling were systematically lower than those obtained by mine inspectors during un announced visits to mines to measure expo sures has been published by MSHA (40). # Surface Coal Mining Studies published prior to the NIOSH CCD showed that U.S. surface coal miners (particular ly workers on drill crews) were at risk of develop ing CWP (or silicosis).There was also evidence that ventilatory function was reduced in relation to the number of years worked as drill operators or helpers.Since the CCD, a British study has reported evidence of CWP among workers in the dustier jobs and an association with intensity of exposure (85).Dust exposures were generally <1 mg/m3.In the United States, a relationship between tenure in surface coal mining jobs and prevalence of CWP (ILO category 1/0 or greater, and PMF) was reported (16). # Summary A considerable body of literature has been pro duced from studies of coal miners and the coal mining environment since 1995, both in the United States and elsewhere.Many of the new er publications, particularly those from other countries, lack quantitative dust exposure mea surements, prohibiting full and valid examina tion of exposure-response relationships.Never theless, their findings all support early findings on British and U.S. coal miners, reinforcing the generally-accepted understanding that exposure to coal mine dust can give rise to various respira tory diseases, and that those diseases can cause disability and premature mortality.The remain der of the newer publications that do have quan titative exposure data report findings that refine or augment the fundamental exposure-response results summarized in the CCD. Overall, the following conclusions can be made: 1.No new findings have emerged since 1995 that contradict the basic summarization of the respiratory health effects of coal mine dust and their relationship with dust exposures described in the CCD (1).2.No new findings have emerged that sub stantially modify the basic understand ing of coal mine dust exposure and its impact on respiratory health described in the CCD.3.The new findings that have emerged strengthen prior results and also refine or add further knowledge on disease pat terns and etiology described in the CCD.4.Overall, the logical basis for recommen dations concerning prevention of occu pational respiratory disease among coal miners remains essentially unaffected by the newer findings that have emerged since publication of the CCD. New findings of particular note are: 1.After a long period of declining CWP prevalence, recent federal surveillance data indicate that the prevalence is rising.2.Coal miners are developing severe CWP at relatively young ages.3.There is some indication that the m or tality of younger coal miners from CWP is increasing.These workers would have been employed all of their working lives in environmental conditions mandated by the 1969 Coal Mine Act.4.The pattern of CWP occurrence across the nation is not uniform; hot spots of disease appear to be concentrated in the central Appalachian region of southern WV, eastern KY, and western VA.5.The cause of this resurgence in disease is likely multifactorial.Possible explanations include excessive exposure due to increas es in coal mine dust levels and duration of exposure (longer working hours), and in creases in crystalline silica exposure (see below).As indicated by data on disease prevalence and severity, workers in small er mines may be at special risk.6.Given that the more productive seams of coal are being m ined out, a transi tion by the industry to mining thinner coal seams and those with more rock intrusions is taking place and will likely accelerate in the future.Concomitant with this is the likelihood of increased potential for exposure to crystalline sil ica, and associated increased risk of sili cosis, in coal mining. In summary, every effort needs to be made to reduce exposures both to respirable coal mine dust and to respirable crystalline silica.As rec ommended in the CCD, the latter task requires establishing a separate compliance standard in order to effectively limit exposure to silica dust.

# CDC Guideline Development Decision Tool A CDC guideline document contains recommendations for practice that carries the authority of the Agency.To strengthen the process for developing CDC guidelines, the Office of Science (OS), Office of Science Quality (OSQ), Guidelines and Recommendations Team has updated the CDC Guideline Development Decision Tool (GDDT). The GDDT consists of questions in two steps.Step 1 helps you determine whether the proposed guideline is needed. Step 2 helps you determine whether CDC is an appropriate organization to develop the proposed guideline.Information is provided under each question to help you answer those questions.Since guideline development can take many years and consume many resources, we encourage guideline developers to answer each question in their order before developing a guideline, and to justify their answers in the boxes provided.Respondents can attach a document, link, citation, or highlighted section as rationale.For a more informative process, we recommend that more than one guideline developer respond to the questions. Step 1: Answer all four questions under "Step 1."If you have answered all questions without any "reconsider" responses, a strong case exists for developing the proposed guideline.Proceed to step 2. Step 2: Answer all questions under "Step 2."If you have answered all questions without any "reconsider" responses, a strong case exists for CDC to be involved in developing the proposed guideline. We recognize that this tool will be used for multiple and diverse public health guidelines, so not every question will be equally relevant.Although the primary use of the information is to inform decision-making, it may also be useful for providing background information in the guideline manuscript. The Guidelines and Recommendations Team has other resources to assist developers in answering these questions.You may contact the Guidelines and Recommendation Team for a consultation at any stage of the guideline development process.For more information about guideline resources, tools, and training visit the Office of Science, Guidelines and Recommendations.Randy Elder, PhD, rfe3@cdc.gov, 404-498-0953 Vilma Carande-Kulis, PhD, MS vcarande-kulis@cdc.gov, 404-639-4691 Dyann Matson Koffman, DrPH, MPH, CHES dmatsonkoffman@cdc.gov, 404-639-4783 Step 1: Should the guideline be developed at all, regardless of whether CDC or an external party develops it?PUBLIC HEALTH BURDEN OR OTHER JUSTIFICATION: 1.1 Will the guideline address a current or potential public health burden, gap in clinical care or laboratory practices, or other important need? For example, the guideline could address a current or potential public health burden, an emerging public health hazard, important public health methods, best practices, safety guidelines, surveillance reports, lab practices, or meaningfully reduce the gap between current and optimal practice in clinical care. Current or potential burden or hazard can be expressed in various metrics such as prevalence of mortality, morbidity, injury, disability, quality of life years (QALYs), Disability Adjusted Life Year (DALYs). Gaps can be reflected in deficiencies in knowledge, adherence, progress in a particular public health area, preventing, detecting, or treating a condition, reducing health disparities, or meeting health objectives. If "Yes," briefly describe the justification for the guideline. Type description here. If "No," reconsider whether the proposed guideline should be developed. # SIMILAR GUIDELINES 1.2.Are there current, credible, and relevant guidelines that make the proposed guideline entirely duplicative? For example, an existing guideline on the same topic would not be entirely duplicative if the plan was to adapt or update the guideline based on current evidence. If "Yes," reconsider whether the proposed guideline should be developed. If "No," describe differences between existing and proposed guideline. Type description here. # EVIDENCE 1.3.Does an evidence base exist on which to develop the proposed guideline? Potential sources of evidence to consider beyond direct and indirect research findings include epidemiological data, case reports, EHR data, and practice-based evidence from subject matter experts. A preliminary scan of the literature can be helpful to determine whether published evidence is available to support the proposed guidelines. If "Yes," briefly describe available evidence and literature sources. Type description here. If "No," reconsider whether the proposed guideline should be developed. # ASSESSMENT OF STAKEHOLDER INTERESTS: # Has your intended audience or other stakeholders expressed a need for new or updated guideline on the topic? Audience or stakeholder needs can be communicated through different channels, such as conferences, meetings, focus groups, surveys, public hearings, or requests for information. # An assessment of stakeholder and end-user needs can inform decisions on whether to produce a guideline, what questions should be prioritized, and what communication and dissemination strategies may be needed to foster uptake.Consider additional stakeholder engagement if views of key stakeholders are not clear.For example, opinions can be collected from internal and external champions, subject matter experts, and partners interested in collaboration. If "Yes," briefly describe stakeholder feedback. Type description here. If "No," reconsider whether the proposed guideline should be developed. # STEP 1 RESULTS: IF YOU HAVE REACHED THIS POINT WITHOUT ANY "RECONSIDERS" ALONG THE PATH, A STRONG CASE EXISTS FOR DEVELOPING THE GUIDELINE Step 2: Should CDC develop the proposed guideline?If "Yes," briefly describe how the proposed guideline aligns with the CDC Centers, Institutes, and Offices (CIO) mission and goals. Type description here. If "No," reconsider whether CDC should develop the proposed guideline. # PARTNERSHIPS 2.2.Is it appropriate for CDC to partner with another organization to develop the proposed guideline? For example, a partnership could increase support and reach of the proposed CDC guideline, inspire creative ideas, solutions, and greater potential for guideline use, or provide an opportunity to reduce staffing and financial burden.On the contrary, it may not be appropriate to partner with another organization due to anticipated challenges, e.g., lengthening the time, less control over the process, FACA requirements. If "Yes," briefly describe the organization and the proposed approach for collaboration. Type description here. If "No," describe why it is not appropriate or feasible for CDC to partner with another organization to develop the proposed guideline.If "Yes," briefly describe resources and time necessary to carry out these activities. Type description here. If "No," reconsider whether CDC should be involved in developing the proposed guideline. # STEP 2 RESULTS: IF YOU HAVE REACHED THIS POINT WITHOUT ANY "RECONSIDERS" ALONG THE PATH, A STRONG CASE EXISTS FOR CDC TO BE INVOLVED IN DEVELOPING THE PROPOSED GUIDELINE.

Since 1979, when the last Immunization Practices Advisory Committee (ACIP) statement on vaccination with Bacillus of Calmette and Guerin (BCG*) was published, additional data have been published on the epidemiology of tuberculosis (TB) in the United States and on the efficacy of childhood BCG vaccines.As a result, ACIP and the Advisory Committee for Elimination of Tuberculosis have issued the following educational update on BCG vaccines.Immunization with BCG vaccine lowers the risk of serious complications of primary TB in children (1-4).However, BCG vaccination should be considered only for children with negative tuberculin skin tests who fall into the following categories: 1) those who cannot be placed on isoniazid preventive therapy but who have continuous exposure to persons with active disease; 2) those with continuous exposure to patients with organisms resistant to isoniazid and rifampin; or 3) those belonging to groups with exceptionally high annual rates of new infection (i.e., greater than 1% per year).BCG vaccination is no longer recommended for health-care workers or other adults at high risk for acquiring TB infection.In addition, BCG should not be given to persons who are immunocompromised, including those with human immunodeficiency virus (HIV) infection. -Official name: BCG Vaccine. Replaces previous recommendation on BCG vaccines (MMWR 1979;28:241-4).Disclaimer All MMWR HTML documents published before January 1993 are electronic conversions from ASCII text into HTML.This conversion may have resulted in character translation or format errors in the HTML version.Users should not rely on this HTML document, but are referred to the original MMWR paper copy for the official text, figures, and tables.An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800.Contact GPO for current prices.#INTRODUCTION Transmission and Pathogenesis of TB TB is a bacterial disease caused by organisms of the Mycobacterium tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum).It is transmitted primarily by airborne droplets; infection occurs when susceptible persons inhale infectious droplets produced by the exhalations of persons with respiratory tract TB.The risk for infection is directly related to duration and intensity of exposure to air contaminated with these droplets.TB infection usually begins in the lungs and spreads to the hilar lymph nodes, then to the blood stream.Thus, disease can occur in any organ of the body.Most infected persons react to the purified protein derivative (PPD) tuberculin skin test, and 5%-40% will develop clinically apparent TB.Infection is more likely to progress to clinical disease in the presence of certain risk factors, including younger and older ages, male sex, infection within the past 2 years, leanness, and suppression of cell-mediated immunity. TB can be presumptively diagnosed if acid-fast bacilli are found in sputum, body fluids, or tissue or if at least two of three other conditions are met: 1) symptoms are compatible with TB; 2) chest radiograph is abnormal or abnormalities are found on physical examination; or 3) reaction to the tuberculin skin test is positive.Definitive diagnosis requires isolation and identification of organisms of the M. tuberculosis complex from a clinical specimen.Diagnosis of extrapulmonary TB is more difficult because it requires tissue biopsies or body fluids (e.g., spinal fluid) that usually contain only a few organisms. # Epidemiology of TB in the United States TB in the United States has declined approximately 6% per year since nationwide reporting began in 1953.However, in 1986, the morbidity rate for TB increased slightly to 9.4/100,000, a rate 82% lower than that for 1953 but 1.1% higher than the 1985 rate.A total of 22,768 cases were reported (5), and approximately 80% were pulmonary disease. Untreated TB is fatal in up to 50% of cases.However, chemotherapy has helped reduce the case-mortality rate 94% since 1953.In 1984, the most recent year for which final mortality data are available, 1729 deaths were attributed to TB, representing a mortality rate of 0.7/100,000 population. Prevalence of TB infection and disease varies for different segments of the population.Disease rates are twice as high in males as in females and increase sharply with age in both sexes and all races.Groups at high risk for TB include most racial/ethnic minorities, immigrants from countries with a high prevalence of TB, the homeless population, close contacts of persons with pulmonary TB, and persons with HIV infection.In 1986, 62% of all TB cases occurred in racial/ethnic minorities, and over 20% of all cases were in foreign-born persons (5).Although the prevalence of active TB in the homeless population is difficult to assess, surveillance of selected clinics and shelters showed infection rates between 1.6% and 6.8% (6).Based on 1985 data from U.S. health departments, 29% of close contacts of TB patients were infected at the time the patients were diagnosed (7).In addition, the estimated risk for active TB in persons with symptomatic HIV infection is 100-200 times greater than that of persons in the general population (8).Persons with asymptomatic HIV infection and M. tuberculosis infection may have an equally high risk for developing clinical disease. In 1985, the 1261 cases of TB in children <15 years of age accounted for 5.7% of cases in all age groups.Eighty percent of these were among racial/ethnic minorities (9).One fourth (315) of all childhood cases were extrapulmonary; of these, 41 cases were meningeal, and 17 were miliary.Childhood cases of TB meningitis and miliary TB remained stable between 1981 and 1985, averaging 55 cases annually. In the past, TB was regarded as an occupational hazard for health-care workers, who had higher rates of infection and disease than persons of the same age groups in the general population.Although these rates have decreased over time, persons who work with high-risk patients or in high-prevalence communities still may be at risk for new infection, defined as conversion from a negative to a positive tuberculin skin test (10)(11)(12)(13)(14)(15)(16)(17)(18).However, in recent studies, which found increased conversion rates among health-care personnel, rates were highest in health-care workers who did not have patient contact (10,11), suggesting that conversion resulted from community-acquired infection with M. tuberculosis or exposure to nontuberculous mycobacteria rather than from occupational exposure. # Control of TB There are four general strategies for controlling TB: 1.The most important and universally applied strategy is the early identification and treatment of persons with infectious TB.This strategy not only cures the affected person but also renders the patient noncontagious within a few weeks.Thus, case-finding and treatment programs have both clinical and public health benefits (19). 2.Identifying and treating persons with noncontagious TB (such as extrapulmonary disease, primary pulmonary disease in children, bacteriologically unconfirmed pulmonary disease, and tuberculous infection) can prevent infectious cases (20).Therapy to prevent progression of infection to clinical disease is particularly useful in countries, such as the United States, where the risk of new infection is low. # Use of ventilation and ultraviolet lights will decontaminate air containing infectious droplet nuclei. Because sites of potential transmission of tubercle bacilli are numerous and difficult to identify in advance, this strategy is used routinely only where the risk of transmission is known to be exceptionally high.Some of theses areas include mycobacteriology laboratories, sputum induction cubicles, chest clinic waiting areas, and selected shelters for the homeless.To be effective, ventilation systems and ultraviolet lights must be properly maintained. 4.In the United States, BCG vaccination is recommended only for uninfected children who are at unavoidable risk of exposure to TB and for whom other methods of prevention and control have failed or are not feasible. # BCG VACCINES BCG was derived from a strain of M. bovis attenuated through years of serial passage in culture by Calmette and Guerin at the Pasteur Institute in Lille, France.It was first administered to humans in 1921.Many BCG vaccines are available worldwide; all are derived from the original strain but vary in cultural characteristics and in ability to induce sensitization to tuberculin.BCG vaccines vary because of genetic changes in the bacterial strains and because of differences in techniques of production, in methods and routes of vaccine administration, and in characteristics of the populations and environments in which BCG vaccines have been studied. Production standards for BCG vaccines, set by the Food and Drug Administration, specify that they be freeze-dried products containing live bacteria from a documented strain of BCG.The strain must demonstrate various specified characteristics of safety and potency in animals and induce tuberculin sensitivity in guinea pigs and humans.The vaccines currently available in the United States have been evaluated only for their ability to induce a delayed hypersensitivity state. Vaccine Efficacy Studies BCG vaccines vary substantially in efficacy.Different preparations of liquid BCG used in controlled community trials conducted before 1955 gave estimated efficacies ranging from -56% and 80% (21).In 1969, a large controlled trail was begun in Madras (Chingleput) in south India to estimate the efficacy of two strains of freeze-dried BCG vaccine and two different doses.After 15 years of follow-up, the risk of sputum-positive pulmonary TB in persons vaccinated with BCG was not lower than that in persons given placebo (22). Although randomized controlled trials are the most reliable method for assessing vaccine efficacy, less precise estimates can be obtained more quickly and less expensively by observational studies (casecontrol, historical cohort, and cross-sectional studies) in areas where vaccination is performed at birth.Data from such studies show that the incidence of tuberculous meningitis and miliary TB is 52%-100% lower and that the incidence of pulmonary TB is 2%-80% lower in vaccinated children <15 years of age than in unvaccinated controls (1)(2)(3)(4)23,24).However, because vaccination is not allocated randomly in observational studies, disproportionate exposure to TB may distort the estimates of vaccine efficacy. # Side Effects and Adverse Reactions BCG rarely causes serious complications.Side effects vary by vaccine strain; they also vary for the same strain over time.Side effects occur in 1%-10% of vaccinated persons and usually include severe or prolonged ulceration at the vaccination site, lymphadenitis, and lupus vulgaris.The risk of side effects is greater with more potent vaccines.Some vaccine strains have caused osteomyelitis in one case per million doses administered.Disseminated BCG infection and death have occurred in one to 10 cases per 10 million doses administered, although this problem is restricted almost exclusively to persons with impaired immunity. Data on adverse reactions may pertain to the vaccines licensed in the United States.The reported frequency of complications has varied, depending in part on the intensity of the surveillance effort. In persons with tuberculous infections, the response to BCG vaccine is accelerated.This accelerated response is generally characterized by the appearance of induration >5 mm in diameter within 24-48 hours after vaccination, formation of a pustule within 5-7 days, and scab formation and healing in 10-15 days (25).The normal response to BCG vaccine begins 2-3 weeks after vaccination.Scar formation and healing occur within 3 months. # Interpretation of Tuberculin Test Following BCG Vaccination The size of tuberculin skin test reactions caused by BCG vaccination (i.e., postvaccination sensitivity) varies by strain and dose of vaccine, age and nutritional status at vaccination, number of years since vaccination, and frequency of tuberculin testing.Mean size of skin test reactions in BCG-vaccinated children range from 3 mm to 19 mm (26)(27)(28)(29)(30)(31)(32)(33)(34)(35).The presence or size of postvaccination tuberculin skin test reactions does not reliably predict the degree of protection afforded by BCG (36). After BCG vaccination, it is usually not possible to distinguish between a tuberculin skin test reaction caused by virulent mycobacterial infection or by vaccination itself (37).Therefore, TB should be included in the differential diagnosis of any TB-like illness, especially if the person has been recently exposed to a person with infectious TB or received BCG several years before being tuberculin tested (38). General guidelines exist for interpreting tuberculin skin test reactions in BCG vaccine recipients.The probability that a skin test reaction results from exposure to M. tuberculosis increases 1) as the size of the reaction increases, 2) when the patient is a contact of a person with TB, especially if that person has infected others, 3) when there is a family history of TB or when the patient's country of origin has a high TB prevalence, and 4) as the length of time between vaccination and tuberculin testing increases (38).For example, a positive skin test (>10 mm) usually can be attributed to M. tuberculosis infection if the vaccinated person is in a group at high risk for TB or has known exposure to a person with infectious TB.However, in vaccinated persons who do not belong to groups at high risk for infection and have no known exposure, a positive skin test reaction probably does not indicate recent infection with M. tuberculosis. # GENERAL RECOMMENDATIONS In the United States, the general population is at low risk for acquiring tuberculous infection.Furthermore, TB can be controlled successfully in most high-risk groups by modern methods of case detection, chemotherapy, and preventive therapy.In most population groups, prevention of TB is most reliably accomplished by periodic Mantoux testing with PPD tuberculin for high-risk children and adults and with administration of preventive therapy to those whose skin test reactions convert from negative to positive.Preventive chemotherapy should also be given to tuberculin-positive persons who are contacts of persons with infectious TB and to other high-risk tuberculin-positive persons (39).Therefore, a BCG vaccination policy for the entire population is not indicated.However, BCG vaccination may contribute to TB control in selected population groups.For example, it may benefit uninfected children who are a high risk for continuous or repeated exposure to infectious persons who remain undetected or untreated. # Recommended Vaccine Recipients Exposed tuberculin skin-test-negative infants and children.BCG vaccination is strongly recommended for infants and children with negative tuberculin skin tests who 1) are at high risk of intimate and prolonged exposure to persistently untreated or ineffectively treated patients with infectious pulmonary TB, cannot be removed from the source of exposure, and cannot be placed on long-term preventive therapy, or 2) are continuously exposed to persons with TB who have bacilli resistant to isoniazid and rifampin. Groups with an excessive rate of new infections.BCG vaccination is also recommended for tuberculinnegative infants and children in groups in which the rate of new infections exceeds 1% per year (40) and for whom the usual surveillance and treatment programs have been attempted but are not operationally feasible.These groups include persons without regular access to health care, those for whom usual health care is culturally or socially unacceptable, or groups who have demonstrated an inability to effectively use existing accessible care. Discontinued Recommendation for Health-Care Workers In the past, BCG vaccine was recommended for health-care workers, who as a group experienced high rates of new infections.However, BCG is no longer recommended for this group.Instead, health-care workers should be protected by adequate surveillance by periodic tuberculin skin testing (41) and isoniazid preventive therapy for all skin-test-positive health-care workers who are a high risk for developing disease.These persons include recent skin test converters and workers who are close contacts of TB patients or those who have medical conditions such as diabetes, renal failure, or immunosuppression associated with therapy or disease (39).In addition, hospital infection control measures, especially the prompt identification and implementation of precautions for patients with suspected TB, will help reduce the risk of TB transmission to health-care workers (42). # Vaccine Availability Two BCG vaccine strains licensed in the United States are available.The Glaxo strain is available from Quad Pharmaceuticals, Inc., Indianapolis.The Tice strain is available from Bionetics Research, Inc., Chicago, or Antigen Supply House, Northridge, California. Vaccine Dose and Administration BCG should be reserved for persons whose skin test is negative to 5 tuberculin units of PPD tuberculin.The Glaxo strain is administered intradermally and the Tice strain percutaneously.Vaccination should be administered only by the route indicated in the package labeling and only in the suggested dose. Infants <30 days old should receive one half the usual dose.If the indications for vaccination persist, they should receive a full dose at 1 year of age. Freeze-dried vaccine should be reconstituted, protected from exposure to light, refrigerated when not in use, and used within 8 hours. # Contraindications to Use BCG should not be given to persons 1) whose immunologic responses are impaired because of congenital immunodeficiency, HIV infection, leukemia, lymphoma, or generalized malignancy or 2) whose immunologic responses have been suppressed by steroids, alkylating agents, antimetabolites, or radiation. BCG vaccine should be administered with caution to persons in groups at high risk for HIV infection.An AIDS patient was reported to have developed disseminated M. bovis disease after vaccination with BCG (43).Three infants with symptomatic HIV infection were reported to have developed BCG adenitis after vaccination (44); however, disseminated BCG disease has not been reported in persons with asymptomatic HIV infection. Theoretically, persons with asymptomatic HIV infection may be at greater risk for complications from BCG vaccine, but data are inconclusive regarding this elevated risk.The World Health Organization has recommended that in populations where the risk of tuberculosis is high, HIV-infected children who are asymptomatic should receive BCG vaccine at birth or as soon as possible thereafter.BCG vaccine should not be given to children with symptomatic HIV infection (45).In populations where the risk of TB is low, BCG vaccine should be withheld from persons known or suspected to be infected with HIV (45).The latter recommendation would apply to most populations in the United States for whom BCG might be considered. # Use in Pregnancy Although harmful effects of BCG on the fetus have not been observed, women should avoid vaccination during pregnancy. # SURVEILLANCE All suspected adverse reactions to BCG should be reported to the manufacturer and to the Office of Biologics Research, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland.

These reactions occasionally occur > 1 year after vaccination.

depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction Each year, influenza virus infections cause substantial morbidity and mortality in the United States (1).Prevention of influenza relies primarily on vaccination.Until recently, only inactivated influenza vaccine administered by injection was available for use in the United States.Inactivated influenza vaccine is approved for persons aged >6 months, both with and without chronic medical conditions.In 2003, an intranasal, trivalent, cold-adapted, live, attenuated vaccine (LAIV) was newly approved for use among healthy persons aged 5-49 years.LAIV adds an option for vaccinating healthy persons aged 5-49 years who either want to avoid influenza or who have close contact with persons at high risk for experiencing serious complications from influenza infection. # Description and Action Mechanisms of LAIV LAIVs are in use in Russia and have been in development since the 1960s in the United States, where they have been evaluated as mono-, bi-, and trivalent formulations (2)(3)(4)(5)(6).The newly licensed LAIV is produced by MedImmune, Inc., (Gaithersburg, Maryland; ) and marketed under the name FluMist™.It is a live, trivalent, intranasally administered vaccine that is - attenuated, producing mild or no signs or symptoms related to influenza virus infection; - temperature-sensitive, a property that limits the replication of the vaccine viruses at 38 º C-39 º C, and thus restricts LAIV viruses from replicating efficiently in human lower airways; and - cold-adapted, replicating efficiently at 25 º C, a temperature that is permissive for replication of LAIV viruses, but restrictive for replication of different wild-type viruses.In animal studies, LAIV viruses replicate in the mucosa of the nasopharynx, inducing protective immunity against The first step in developing an LAIV was the derivation of two stably attenuated master donor viruses (MDV), one for type A and one for type B influenza viruses.The two MDVs each acquired the cold-adapted, temperature-sensitive, attenuated phenotypes through serial passage in viral culture conducted at progressively lower temperatures.The vaccine viruses in LAIV are reassortant viruses containing genes from these MDVs that confer attenuation, temperature sensitivity, and cold adaptation and genes from the recommended contemporary wild-type influenza viruses, encoding the surface antigens hemagglutinin (HA) and neuraminidase (NA).Thus, MDVs provide the stably attenuated vehicles for presenting influenza HA and NA antigens, to which the protective antibody response is directed, to the immune system.The reassortant vaccine viruses are grown in embryonated hens' eggs.After the vaccine is formulated and inserted into individual sprayers for nasal administration, the vaccine must be stored at -15 º C or colder. The immunogenicity of the approved LAIV has been assessed in multiple studies (7)(8)(9)(10)(11)(12)(13)(14)(15), which included approximately 100 children aged 5-17 years, and approximately 300 adults aged 18-49 years.LAIV virus strains replicate primarily in nasopharyngeal epithelial cells.The protective mechanisms induced by vaccination with LAIV are not completely understood but appear to involve both serum and nasal secretory antibodies.No single laboratory measurement closely correlates with protective immunity induced by LAIV. # Comparison of LAIV with Inactivated Influenza Vaccine Major Similarities LAIV and inactivated influenza vaccine contain strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one A (H1N1) virus, and one B virus.Each year, one or more virus strains might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains.Viruses for both vaccines are grown in eggs.Both vaccines are administered annually to provide optimal pro-tection against influenza infection.This report includes a more detailed comparison of LAIV with inactivated influenza vaccine (Tables 1 and 2). # Major Differences Inactivated influenza vaccine contains killed viruses, whereas LAIV contains attenuated viruses still capable of replication.LAIV is administered intranasally by sprayer, whereas inactivated influenza vaccine is administered intramuscularly by injection.LAIV is more expensive than inactivated influenza vaccine.LAIV is approved for use only among healthy persons aged 5-49 years; inactivated influenza vaccine is approved for use among persons aged >6 months, including those who are healthy and those with chronic medical conditions.This report includes a more detailed comparison of LAIV with inactivated influenza vaccine (Tables 1 and 2). # Efficacy and Effectiveness of LAIV Efficacy Among Healthy Children A randomized, double-blind, placebo-controlled trial among 1,602 healthy children initially aged 15-71 months assessed the efficacy of the trivalent LAIV against culture-confirmed influenza during two seasons- (8,9).This trial included subsets of 238 healthy children (163 vaccinees and 75 placebo recipients) aged 60-71 months who received two doses and 74 children (54 vaccinees and 20 placebo recipients) aged 60-71 months who received a single dose during season one, and a subset of 544 children (375 vaccinees and 169 placebo recipients) aged 60-84 months during season two.Children who continued from season one to season two remained in the same study group.In season one, when vaccine and circulating virus strains were well-matched, efficacy was 93% for all participants, regardless of age, among subjects receiving 2 doses of LAIV.Efficacy was 87% in the 60-71-month subset for those who received 2 doses, and was 91% in the subset for those who received 1 or 2 doses.In season two, when the A (H3N2) component was not well-matched between vaccine and circulating virus strains, efficacy was 86% overall and 87% among those aged 60-84 months.The vaccine was 92% efficacious in preventing culture-confirmed influenza during the two-season study.Other results included a 27% reduction in febrile otitis media and a 28% reduction in otitis media with concomitant antibiotic use.Receipt of LAIV also resulted in decreased fever and otitis media among vaccine recipients who experienced influenza. If not simultaneously administered, can be administered within 4 weeks of an inactivated vaccine Yes Yes - Populations at high risk from complications of influenza infection include persons aged >65 years; residents of nursing homes and other facilities that house persons with chronic medical conditions; adults and children with chronic disorders of the pulmonary or cardiovascular systems; adults and children with chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunnosuppression; children and adolescents receiving long-term aspirin therapy (at risk for developing Reye syndrome after wild-type influenza infection); and women who will be in the second or third trimester of pregnancy during influenza season. †Immunosuppressed persons include, but are not limited to, those persons with human immunodeficiency virus, malignancy, or those receiving immunosuppressive therapies. §No data are available regarding effect on safety or efficacy. ¶Inactivated influenza vaccine coadministration with pneumococcal polysaccharide vaccine has been evaluated systematically only among adults. # Effectiveness and Efficacy Among Healthy Adults A randomized, double-blind, placebo-controlled trial among 4,561 healthy working adults aged 18-64 years assessed multiple endpoints, including reductions in illness, absenteeism, health-care visits, and medication use during peak and total influenza outbreak periods (16).The study was conducted during the 1997-98 influenza season, when the vaccine and circulating A (H3N2) strains were not well-matched.The study did not include laboratory virus testing of cases.Dur-ing peak outbreak periods, no difference was identified between LAIV and placebo recipients experiencing any febrile episodes.However, vaccination was associated with reductions in severe febrile illnesses of 19% and febrile upper respiratory tract illnesses of 24%.Vaccination also was associated with fewer days of illness, fewer days of work lost, fewer days with health-care provider visits, and reduced use of prescription antibiotics and over-thecounter medications. Among the subset of 3,637 healthy adults aged 18-49 years, LAIV recipients (n = 2,411) had 26% fewer febrile upper respiratory illness episodes; 27% fewer lost work days as a result of febrile upper respiratory illness; and 18%-37% fewer days of health-care provider visits caused by febrile illness, compared with placebo recipients (n = 1,226).Days of antibiotic use were reduced by 41%-45% in this age subset.Another randomized, double-blind, placebo-controlled challenge study among 92 healthy adults (LAIV, n = 29; placebo, n = 31; inactivated influenza vaccine, n = 32) aged 18-41 years assessed the efficacy of both LAIV and trivalent inactivated vaccine (15).The overall efficacy of LAIV and inactivated influenza vaccine in preventing laboratory documented influenza from all three influenza strains combined was 85% and 71%, respectively, on the basis of experimental challenge by viruses to which study participants were susceptible before vaccination.The difference between the two vaccines was not statistically significant. # Person-to-Person Transmission of Vaccine Viruses Because LAIV contains live influenza viruses, a potential exists for transmission of these viruses from vaccinees to other persons.Vaccinated immunocompetent children can shed vaccine viruses for 1 virus strain, with a mean of 7.6 days duration (17).One influenza type B isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus.The estimated probability of acquiring vaccine virus after close contact with a single LAIV recipient was 0.58%-2.4%.The type B isolate retained the cold-adapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient in the same children's play group. # Stability of Vaccine Viruses In clinical trials, viruses shed by vaccine recipients have been phenotypically stable.In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt (18).Virus isolates were analyzed by multiple genetic techniques.All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes. # Recommendations for Influenza Vaccination Recommendations for inactivated influenza vaccination have targeted specific groups for annual immunization, including persons aged >6 months who are at high risk for complications from influenza because of age or presence of certain medical conditions, persons who are in close contact with those at † These persons should receive inactivated influenza vaccine.high risk, persons aged 50-64 years, and close contacts of infants aged 0-6 months (1).Vaccination with inactivated influenza vaccine is also encouraged when feasible for children aged 6-23 months and their close contacts and caregivers.In addition, physicians should administer inactivated influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza.Recommendations for use of inactivated influenza vaccine are located at http:// www.cdc.gov/mmwr/PDF/rr/rr5208.pdf. # Recommendations for Using Live, Attenuated Influenza Vaccine LAIV is an option for vaccination of healthy persons aged 5-49 years, including persons in close contact with groups at high risk and those wanting to avoid influenza (Tables 1 and 2).Possible advantages of LAIV include its potential to induce a broad mucosal and systemic immune response, its ease of administration, and the acceptability of an intranasal rather than intramuscular route of administration (1). # Persons Who Should Not Be Vaccinated with LAIV The following populations should not be vaccinated with LAIV: # Close Contacts of Persons at High Risk for Complications from Influenza Close contacts of persons at high risk for complications from influenza should receive influenza vaccine to reduce transmission of wild-type influenza viruses to persons at high risk.No data are available assessing the risk for transmission of LAIV from vaccine recipients to immunosuppressed contacts.In the absence of such data, use of inactivated influenza vaccine is preferred for vaccinating household members, health-care workers, and others who have close contact with immunosuppressed persons because of the theoretical risk that a live, attenuated vaccine virus could be transmitted to the immunosuppressed person and cause disease.Otherwise, no preference is given to either inactivated influenza vaccine or LAIV for vaccination of healthy persons aged 5-49 years in close contact with all other groups at high risk. # Timing of LAIV Administration Administration of LAIV is not subject to tiered timing recommendations because it is not approved for use among populations at high risk.The optimal time to vaccinate is usually in October and November, but providers can begin vaccinating with LAIV as soon as vaccine supplies are available.Children aged 5-8 years who have never received influenza vaccine should receive LAIV for the first time in October or earlier because they need a second dose 6-10 weeks after the initial dose. # Dosage, Administration, and Storage # LAIV Dosage LAIV is intended for intranasal administration only and should not be administered by the intramuscular, intradermal, or intravenous route.LAIV must be stored at -15 º C or colder.LAIV should not be stored in a frost-free freezer (because the temperature might cycle above -15 º C), unless a manufacturer-supplied freezer box is used.LAIV must be thawed before administration.This can be accomplished by holding an individual sprayer in the palm of the hand until thawed, with subsequent immediate administration.Alternatively, the vaccine can be thawed in a refrigerator and stored at 2 º C-8 º C for <24 hours before use.Vaccine should not be refrozen after thawing.LAIV is supplied in a prefilled singleuse sprayer containing 0.5 mL of vaccine.Approximately 0.25 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position.An attached dose-divider clip is removed from the sprayer to administer the second half of the dose into the other nostril.If the vaccine recipient sneezes after administration, the dose should not be repeated. LAIV should be administered annually according to the following schedule: - Children aged 5-8 years previously unvaccinated at any time with either LAIV or inactivated influenza vaccine should receive 2 doses § of LAIV separated by 6-10 weeks. §One dose equals 0.5 mL, divided equally between each nostril. - Children aged 5-8 years previously vaccinated at any time with either LAIV or inactivated influenza vaccine should receive 1 dose of LAIV.They do not require a second dose. -Persons aged 9-49 years should receive 1 dose of LAIV.LAIV can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infection with or without fever).However, if clinical judgment indicates nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness. Whether concurrent administration of LAIV with other vaccines affects the safety or efficacy of either LAIV or the simultaneously administered vaccine is unknown.In the absence of specific data indicating interference, following the ACIP general recommendations for immunization is prudent (19).Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines.An inactivated vaccine can be administered either simultaneously or at any time before or after LAIV.Two live vaccines not administered on the same day should be administered >4 weeks apart when possible. # LAIV Administration and Use of Influenza Antiviral Medications The effect on safety and efficacy of LAIV coadministration with influenza antiviral medications has not been studied.However, because influenza antivirals reduce replication of influenza viruses, LAIV should not be administered until 48 hours after cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for 2 weeks after receipt of LAIV. # LAIV Storage LAIV must be stored at -15 º C or colder.LAIV should not be stored in a frost-free freezer because the temperature might cycle above -15 º C, unless a manufacturer-supplied freezer box or other strategy is used.LAIV may be thawed in a refrigerator and stored at 2 º C-8 º C for <24 hours before use.It should not be refrozen after thawing.Additional information is available at Wyeth Product Quality (1-800-411-0086) or at http:/ /www.FluMist.com. # Side Effects and Adverse Reactions Twenty prelicensure clinical trials assessed the safety of the approved LAIV.In these combined studies, approximately 28,000 doses of the vaccine were administered to >20,000 subjects.A subset of these trials were randomized, placebo-controlled studies in which >4,000 healthy children aged 5-17 years and >2,000 healthy adults aged 18-49 years were vaccinated.The incidence of adverse events possibly complicating influenza (e.g., pneumonia, bronchitis, bronchiolitis, or central nervous system events) was not statistically different among LAIV and placebo recipients aged 5-49 years. # Children Signs and symptoms reported more often among vaccine recipients than placebo recipients included runny nose or nasal congestion (20%-75%), headache (2%-46%), fever (0%-26%), and vomiting (3%-13%), abdominal pain (2%), and myalgias (0%-21%) (7,12,14,(20)(21)(22).These symptoms were associated more often with the first dose and were self-limited.In a subset of healthy children aged 60-71 months from one clinical trial (8,9), certain signs and symptoms were reported more often among LAIV recipients after the first dose (n = 214) than placebo recipients (n = 95) (e.g., runny nose, 48.1% versus 44.2%; headache, 17.8% versus 11.6%; vomiting, 4.7% versus 3.2%; myalgias, 6.1% versus 4.2%), but these differences were not statistically significant.Unpublished data from a study including subjects aged 1-17 years indicated an increase in asthma or reactive airways disease in the subset aged 12-59 months.Because of this, LAIV is not approved for use among children aged <60 months (see Recommendations for Using Live, Attenuated Influenza Vaccine). # Adults Among adults, runny nose or nasal congestion (28%-78%), headache (16%-44%), and sore throat (15%-27%) have been reported more often among vaccine recipients than placebo recipients (16,23,24).In one clinical trial (16), among a subset of healthy adults aged 18-49 years, signs and symptoms reported more frequently among LAIV recipients (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (13.9% versus 10.8%); runny nose (44.5% versus 27.1%); sore throat (27.8% versus 17.1%); chills (8.6% versus 6.0%); and tiredness/weakness (25.7% versus 21.6%). # Safety Among Groups at High Risk from Influenza-Related Morbidity Until additional data are acquired, persons at high risk for experiencing complications from influenza infection (e.g., immunocompromised patients; patients with asthma, cystic fibrosis, or chronic obstructive pulmonary disease; or persons aged >65 years) should not be vaccinated with LAIV.Protection from influenza in these groups should be accomplished Online know what matters.e ncore.

Week after week, MMWR Online plays an important role in helping you stay informed.From the latest CDC guidance to breaking health news, count on MMWR Online to deliver the news you need, when you need it. Log on to cdc.gov/mmwr and enjoy MMWR performance.by using inactivated influenza vaccine (see Recommendations for Using Live, Attenuated Influenza Vaccine). # Serious Adverse Events Serious adverse events among healthy children aged 5-17 years or healthy adults aged 18-

INSIDE: Continuing Education Examination depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Hepatitis B vaccination is the most effective measure to prevent HBV infection and its consequences.Since they were first issued in 1982, recommendations for hepatitis B vaccination have evolved into a comprehensive strategy to eliminate HBV transmission in the United States (2-6) (Box 1).A primary focus of this strategy is universal vaccination of infants to prevent early childhood HBV infection and to eventually protect adolescents and adults from infection.Other components include routine screening of all pregnant women for hepatitis B surface antigen (HBsAg) and postexposure immunoprophylaxis of infants born to HBsAg-positive women, vaccination of children and adolescents who were not previously vaccinated, and vaccination of unvaccinated adults at increased risk for infection. To date, the immunization strategy has been implemented with considerable success.Recent estimates indicate that >95% of pregnant women are tested for HBsAg, and case management has been effective in ensuring high levels of initiation and completion of postexposure immunoprophylaxis among identified infants born to HBsAg-positive women (7).Hepatitis B vaccine has been successfully integrated into the childhood vaccine schedule, and infant vaccine coverage levels are now equivalent to those of other vaccines in the childhood schedule.During 1990-2004, incidence of acute hepatitis B # Strategy to Eliminate Hepatitis B Virus Transmission Hepatitis B virus (HBV) is a bloodborne and sexually transmitted virus.Rates of new infection and acute disease are highest among adults, but chronic infection is more likely to occur in persons infected as infants or young children.Before hepatitis B vaccination programs became routine in the United States, an estimated 30%-40% of chronic infections are believed to have resulted from perinatal or early childhood transmission, even though 92% had been fully vaccinated with 3 doses of hepatitis B vaccine (8).This success can be attributed in part to the established infrastructure for vaccine delivery to children and to federal support for perinatal hepatitis B prevention programs. Vaccine coverage among adolescents has also increased substantially.Preliminary data demonstrate that 50%-60% of adolescents aged 13-15 years have records indicating vaccination (with 3 doses) against hepatitis B (CDC, unpublished data, 2003).As of November 2005, a total of 34 states require vaccination for middle-school entry (9).Certain programs provide hepatitis B vaccine to youth who engage in behaviors that place them at high risk for HBV infection (i.e., injectiondrug use, having more than one sex partner, and male sexual activity with other males), and adolescent hepatitis B vaccination is included as a Health Plan Employer Data Information Set (HEDIS) measure (10). Despite these successes, challenges remain.Even with improvements in the management of pregnant women, only approximately 50% of expected births to HBsAg-positive women are identified (on the basis of application of racial/ ethnic-specific HBsAg prevalence estimates to U.S. natality data) for case management, which maximizes timely delivery of postexposure immunoprophylaxis (11;CDC, unpublished data, 2004).The need for proper management of women without prenatal care, including HBsAg testing at the time of admission for delivery and administration of the first dose of vaccine to infants <12 hours of birth, is underscored by the higher prevalence of HBsAg seropositivity among these women than among women who are screened prenatally (12).Even when maternal HBsAg testing does occur, certain infants of HBsAg-positive mothers do not receive postexposure immuno-prophylaxis because of testing errors and lapses in reporting of test results (13), and infants of women with unknown HBsAg status at the time of delivery often do not receive a birth dose of vaccine (14).Birth dose coverage in 2004 was only 46% (National Immunization Survey, unpublished data, 2004), and coverage has not returned to levels from before July 1999 (54%), when recommendations were made to temporarily suspend administration of hepatitis B vaccines at birth until vaccines that do not contain thimerosal as a preservative became available (15).Among adolescents, efforts to prevent HBV transmission are hampered by the low rate of healthcare visits in this age group compared with that of young children and the frequency of initiation of high-risk behaviors. To address these remaining challenges and accelerate progress toward elimination of HBV transmission in the United States, the ACIP has updated the hepatitis B immunization recommendations for infants, children, and adolescents and supplemented the recommendations with strategies for implementation.The recommendations and implementation strategies address prevention of perinatal and early childhood transmission and routine vaccination of children and adolescents.A main focus is on universal infant vaccination beginning at birth, which provides a "safety net" for prevention of perinatal infection, prevents early childhood infections, facilitates implementation of universal vaccination recommendations, and prevents infections in adolescents and adults.The second part of the ACIP statement, which includes updated recommendations and implementation strategies to increase hepatitis B vaccination among unvaccinated adults, will be published separately (16). # Major Updates to the Recommendations This report provides updated recommendations and approaches to address challenges in implementing the strategy to eliminate HBV transmission in the United States.These include the following measures: - Improve prevention of perinatal and early childhood HBV transmission.Implement delivery hospital policies and procedures, case-management programs, and laws and regulations to improve identification of infants born to HBsAg-positive mothers and to mothers with unknown HBsAg status at the time of delivery, ensure administration of appropriate postexposure immunoprophylaxis to these infants beginning at birth, and administer a birth dose of hepatitis B vaccine to medically stable infants who weigh >2,000 g and who are born to HBsAg-negative mothers. # BOX 1.Immunization strategy to eliminate transmission of hepatitis B virus (HBV) infection in the United States - Universal vaccination of infants beginning at birth - Prevention of perinatal HBV infection through -routine screening of all pregnant women for hepatitis B surface antigen (HBsAg), and -immunoprophylaxis of infants born to HBsAgpositive women and infants born to women with unknown HBsAg status - Routine vaccination of previously unvaccinated children and adolescents - Vaccination of previously unvaccinated adults at increased risk for infection - Improve vaccine coverage of children and adolescents who were not previously vaccinated.Implement immunization record reviews for all children aged 11-12 years and children and adolescents aged <19 years who were born in countries in which HBV endemicity is high or intermediate (Figure 1 and Box 2); adopt hepatitis B vaccine requirements for school entry; and vaccinate all unvaccinated adolescents in settings that provide health-care services to persons in this age group. # Background Clinical Features and Natural History of HBV Infection HBV is a 42-nm DNA virus classified in the Hepadnaviridae family.The liver is the primary site of HBV replication.After a susceptible person is exposed, the virus enters the liver via the bloodstream; no evidence exists indicating that the virus replicates at mucosal surfaces.HBV infection can produce either asymptomatic or symptomatic infection.The average incubation period is 90 days (range: 60-150 days) from exposure to onset of jaundice and 60 days (range: 40-90 days) from exposure to onset of abnormal serum alanine aminotransferase (ALT) levels (17,18). The onset of acute disease is usually insidious.Infants and young children (aged 60 years (21). Although the consequences of acute hepatitis B can be severe, the majority of serious sequelae associated with HBV disease occur in persons who are chronically infected.Persons with chronic infection also serve as the major reservoir for continued HBV transmission.Chronic infection occurs in approximately 90% of infected infants, 30% of infected children aged 5 years, with continuing viral replication in the liver and persistent viremia (19,(22)(23)(24).Primary infections also become chronic more fre- (27)(28)(29). No specific treatment exists for acute hepatitis B. Persons who have chronic HBV infection require medical evaluation and regular monitoring (30,31).Therapeutic agents approved by the Food and Drug Administration (FDA) for treatment of chronic hepatitis B can achieve sustained suppression of HBV replication and remission of liver disease in certain persons (31).Periodic screening with alfa fetoprotein or imaging studies has been demonstrated to enhance early detection of HCC (31).Chronically infected persons with HCC have been reported to have experienced long-term survival after resection or ablation of small HCCs, and persons who were screened had a substantial survival advantage compared with historic controls (31). Reinfection or reactivation of latent HBV infection has been reported among certain groups of immunosuppressed persons, including renal transplant recipients, HIV-infected patients, bone marrow transplant recipients, and patients receiving che-motherapy (32)(33)(34)(35).The frequency with which this phenomenon occurs is unknown. # Interpretation of Serologic Markers of HBV Infection The antigens and antibodies associated with HBV infection include HBsAg and antibody to HBsAg (anti-HBs), hepatitis B core antigen (HBcAg) and antibody to HBcAg (anti-HBc), and hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe).At least one serologic marker is present during the different phases of HBV infection (Table 1) (18,36).Serologic assays are commercially available for all markers except HBcAg because no free HBcAg circulates in blood. The presence of a confirmed HBsAg result is indicative of ongoing HBV infection.All HBsAg-positive persons should be considered infectious.In newly infected persons, HBsAg is the only serologic marker detected during the first 3-5 weeks after infection, and it persists for variable periods at very low levels.The average time from exposure to detection of HBsAg is 30 days (range: 6-60 days) (17,18).Highly sensitive single- (37).Transient HBsAg positivity has been reported for up to 18 days after vaccination and is clinically insignificant (38,39). Anti-HBc appears at the onset of symptoms or liver test abnormalities in acute HBV infection and persists for life.Acute or recently acquired infection can be distinguished by the presence of the IgM class of anti-HBc, which is detected at the onset of acute hepatitis B and persists for up to 6 months if the disease resolves.In patients who develop chronic hepatitis B, IgM anti-HBc can persist at low levels during viral replication and can result in positive tests for IgM anti-HBc (40).In addition, false-positive IgM anti-HBc test results can occur.Because the positive predictive value is low in asymptomatic persons, for diagnosis of acute hepatitis B, testing for IgM anti-HBc should be limited to persons with clinical evidence of acute hepatitis or an epidemiologic link to a case. In persons who recover from HBV infection, HBsAg is eliminated from the blood, usually within 3-4 months, and anti-HBs develops during convalescence.The presence of anti-HBs typically indicates immunity from HBV infection.Infection or immunization with one genotype of HBV confers immunity to all genotypes.In addition, anti-HBs can be detected for several months after hepatitis B immune globulin (HBIG) administration.The majority of persons who recover from natural infection will be positive for both anti-HBs and anti-HBc, whereas persons who respond to hepatitis B vaccine have only anti-HBs.In persons who become chronically infected, HBsAg and anti-HBc persist, typically for life.HBsAg will become undetectable in approximately 0.5%-2% of chronically infected persons yearly, and anti-HBs will occur in the majority of these persons (41)(42)(43)(44). In certain persons, the only HBV serologic marker detected in serum is anti-HBc.Isolated anti-HBc can occur after HBV infection among persons who have recovered but whose anti-HBs levels have waned or among persons in whom anti-HBs failed to occur.Persons in the latter category include those with circulating HBsAg levels not detectable by commercial assays.These persons are unlikely to be infectious except under circumstances in which they are the source for direct percutaneous exposure of susceptible recipients to substantial quantities of virus (e.g., through blood transfusion or following liver transplantation) (45).HBV DNA has been detected in the blood of <5% of persons with isolated anti-HBc (46).Typically, the frequency of isolated anti-HBc relates directly to the prevalence of HBV infection in the population.In populations with a high prevalence of HBV infection, isolated anti-HBc likely indicates previous infection, with loss of anti-HBs.For persons in populations with a low prevalence of HBV infection, an isolated anti-HBc result often represents a falsepositive reaction.The majority of these persons have a primary anti-HBs response after a 3-dose series of hepatitis B vaccine (47,48).Infants who are born to HBsAg-positive mothers and who do not become infected might have detectable anti-HBc for <24 months after birth from passively transferred maternal antibody. HBeAg can be detected in the serum of persons with acute or chronic HBV infection.The presence of HBeAg correlates with viral replication and high levels of virus (i.e., high infectivity) (49,50).Anti-HBe correlates with the loss of replicating virus and with lower levels of virus, although reversion to HBeAg positivity has been observed (44). # Epidemiology of HBV Infection Transmission HBV is transmitted by percutaneous (i.e., puncture through the skin) or mucosal (i.e., direct contact with mucous membranes) exposure to infectious blood or to body fluids that contain blood.All HBsAg-positive persons are infectious, but those who are also HBeAg positive are more infectious because their blood contains high titers of HBV (typically 10 7 -10 9 virions/mL) (49,50).Although HBsAg has been detected in multiple body fluids, only serum, semen, and saliva have been demonstrated to be infectious (51,52).HBV is comparatively stable in the environment and remains viable for >7 days on environmental surfaces at room temperature (53).HBV at concentrations of 10 2-3 virions/mL can be present on environmental surfaces in the absence of any visible blood and still cause transmission (53,54). For infants and children, the two primary sources of HBV infection are perinatal transmission from infected mothers and horizontal transmission from infected household contacts.Adolescents are at risk for HBV infection primarily through high-risk sexual activity (i.e., sex with more than one partner and male sexual activity with other males) and injection-drug use (21).Transmission of HBV via transfusion of blood and plasma-derived products is rare because of donor screening for HBsAg and viral inactivation procedures. For a newborn infant whose mother is positive for both HBsAg and HBeAg, the risk for chronic HBV infection is 70%-90% by age 6 months in the absence of postexposure immunoprophylaxis (55)(56)(57).For infants of women who are HBsAg positive but HBeAg negative, the risk for chronic infection is <10% in the absence of postexposure immunoprophylaxis (58)(59)(60).Rare cases of fulminant hepatitis B among perinatally infected infants also have been reported (61,62).Studies suggest that breastfeeding by an HBsAg-positive mother does not increase the risk for acquisition of HBV infection in the infant (63). Children who are not infected at birth remain at risk from long-term interpersonal contact with their infected mothers.In one study, 38% of infants who were born to HBsAgpositive mothers and who were not infected perinatally became infected by age 4 years (64).In addition, children living with any chronically infected persons are at risk for becoming infected through percutaneous or mucosal exposures to blood or infectious body fluids (e.g., sharing a toothbrush, contact with exudates from dermatologic lesions, contact with HBsAg-contaminated surfaces).HBV transmission rates to susceptible household contacts of chronically infected persons have varied (range: 14%-60%) (65,66).High rates of infection also have been reported among unvaccinated long-term residents of institutions for the mentally handicapped (67,68), and, in rare instances, person-to-person transmission has been reported in child care settings (69,70). # Incidence During 1990-2004, overall incidence of reported acute hepatitis B declined 75%, from 8.5 to 2.1 per 100,000 population.The most dramatic declines occurred in the cohort of children to whom recommendations for routine infant and adolescent vaccination have applied.Incidence among children aged <12 years and adolescents aged 12-19 years declined 94%, from 1.1 to 0.36 and 6.1 to 2.8 per 100,000 population, respectively (Figure 2).Since implementation of routine childhood immunization, an estimated 6,800 perinatal infections and an additional 18,700 infections during the first 10 years of life have been prevented annually in the United States (71). Although infections in infants and children aged <10 years represented <10% of all HBV infections before implementation of childhood immunization programs, childhood infections resulted in an estimated 30%-40% of the chronic HBV infections among persons who acquired their infections in the United States (1).In two population-based studies conducted among Asian/Pacific Islander children who were born in the United States before perinatal hepatitis B prevention programs were widely implemented, 61%-66% of the chronic HBV infections occurred in children born to HBsAg-negative mothers (72,73).A substantial proportion of these chronic infections would not have been prevented by a selective program of identification and immunization of only infants born to HBsAg-positive mothers. In addition to declines in incidence among all age groups, racial disparities in hepatitis B incidence among children have been substantially reduced (Figure 3).The reduction of the disparity between Asian/Pacific Islander and other children is consistent with recent observations noting a decline in seroprevalence of HBV infection after successful implementation of routine hepatitis B vaccination among Asians who have recently immigrated to the United States (74,75).However, as hepatitis B incidence has declined among U.S.-born children, unvaccinated foreign-born children account for a high proportion of infections.During 2001-2002, of 19 children born after 1991 in whom acute hepatitis B had been verified, eight (42%) were foreign born (76). # Prevalence In the U.S. population, the overall age-adjusted prevalence of HBV infection (including persons with chronic infection and those with previous infection) was 4.9% in the third - Per 100,000 population. # Prophylaxis Against HBV Infection Hepatitis B Vaccine HBsAg is the antigen used for hepatitis B vaccination (79,80).Vaccine antigen can be purified from the plasma of persons with chronic HBV infection or produced by recombinant DNA technology.Vaccines available in the United States use recombinant DNA technology to express HBsAg in yeast, which is then purified from the cells by biochemical and biophysical separation techniques (81,82).

Hepatitis B vaccines licensed in the United States are formulated to contain 10-40 µg of HBsAg protein/mL. Since March 2000, hepatitis B vaccines produced for distribution in the United States do not contain thimerosal as a preservative or contain only a trace amount (<1.0 mcg mercury/mL) from the manufacturing process (83,84). Hepatitis B vaccine is available as a single-antigen formulation and also in fixed combination with other vaccines.Two single-antigen vaccines are available in the United States # HBIG HBIG provides passively acquired anti-HBs and temporary protection (i.e., 3-6 months) when administered in standard doses.HBIG is typically used as an adjunct to hepatitis B vaccine for postexposure immunoprophylaxis to prevent HBV infection.HBIG administered alone is the primary means of protection after an HBV exposure for nonresponders to hepatitis B vaccination. HBIG is prepared from the plasma of donors with high concentrations of anti-HBs.The plasma is screened to eliminate donors who are positive for HBsAg, antibodies to HIV and hepatitis C virus (HCV), and HCV RNA.In addition, proper manufacturing techniques for HBIG inactivate viruses (e.g., HBV, HCV, and HIV) from the final product (85,86).No evidence exists that HBV, HCV, or HIV ever has been transmitted by HBIG commercially available in the United States.HBIG that is commercially available in the United States does not contain thimerosal. # Vaccination Schedules and Results of Vaccination Preexposure Vaccination # Infants and Children Primary vaccination consists of >3 intramuscular doses of hepatitis B vaccine (Table 2).Vaccine schedules for infants and children (Tables 3-5) are determined on the basis of immunogenicity data and the need to integrate hepatitis B vaccine into a harmonized childhood vaccination schedule.Although not all possible schedules for each product have been evaluated in clinical trials, available licensed formulations for both single-antigen vaccines produce high (>95%) levels of seroprotection among infants and children when administered in multiple schedules (87)(88)(89)(90)(91). The immunogenicity of the combined hepatitis B-Hib conjugate vaccine (Comvax) and the combined hepatitis B-DTaP-IPV vaccine (Pediarix) is equivalent to that of their individual antigens administered separately.However, these vaccines cannot be administered to infants aged <6 weeks; only singleantigen hepatitis B vaccine may be used for the birth dose.Use of 4-dose hepatitis B vaccine schedules, including schedules with a birth dose, has not increased vaccine reactogenicity (92,93).Anti-HBs responses after a 3-dose series of hepatitis B-containing combination vaccines among infants who were previously vaccinated at birth with single-antigen hepatitis B vaccine are comparable to those observed after a 3-dose series of combination vaccine without a birth dose (93). # Birth Dose Hepatitis B vaccine can be administered soon after birth with only minimal decrease in immunogenicity, compared with administration at older ages, and no decrease in protective efficacy (87).Administration of a birth dose of hepatitis B vaccine is required for effective postexposure immunoprophylaxis to prevent perinatal HBV infection.Although infants who require postexposure immunoprophylaxis should be identified by maternal HBsAg testing, administering a birth dose to infants even without HBIG serves as a "safety net" to prevent perinatal infection among infants born to HBsAgpositive mothers who are not identified because of errors in maternal HBsAg testing or failures in reporting of test results (13).The birth dose also provides early protection to infants at risk for infection after the perinatal period.Administration of a birth dose has been associated with higher rates of on-time completion of the hepatitis B vaccine series (15,94).In certain populations, the birth dose has been associated with improved completion rates for all other infant vaccines (95), although findings have not been consistent (15,94). # Adolescents Recommended vaccination schedules for adolescents balance available immunogenicity data with the need to achieve compliance with vaccination in this age group (Tables 2 and 5).Both licensed single-antigen hepatitis B vaccines administered intramuscularly at 0, 1, and 6 months produce a >95% sero-protection rate in adolescents.Equivalent seroprotection rates are achieved among adolescents vaccinated at 0, 1-2, and 4 months and 0, 12, and 24 months.The adult (10 µg) dose of Recombivax-HB administered in a 2-dose schedule to children and adolescents aged 11-15 years at 0 and 4-6 months produces antibody levels equivalent to those obtained with the 5-µg dose administered on a 3-dose schedule (96,97).However, no data on long-term antibody persistence or protection are available for 2-dose schedules.No combination vaccines containing hepatitis B vaccine antigen are approved for use in adolescents aged 11-17 years. # Nonstandard Vaccine Schedules No apparent effect on immunogenicity has been documented when minimum spacing of doses is not achieved precisely.Increasing the interval between the first 2 doses has little effect on immunogenicity or final antibody concentration (98-100).The third dose confers the maximum level of seroprotection but acts primarily as a booster and appears to provide optimal long-term protection (101).Longer intervals between the last 2 doses result in higher final antibody levels but might increase the risk for acquisition of HBV infection among persons who have a delayed response to vaccination.No differences in immunogenicity have been observed when 1 or 2 doses of hepatitis B vaccine produced by one manufacturer are followed by doses from a different manufacturer (102). † †Adult formulation administered on a 2-dose schedule. § §Higher doses might be more immunogenic, but no specific recommendations have been made. ¶ ¶Dialysis formulation administered on a 3-dose schedule at age 0, 1, and 6 months. *Two 1.0-mL doses administered at one site, on a 4-dose schedule at age 0, 1, 2, and 6 months. # Response to Revaccination A study of infants born to HBsAg-positive mothers who did not respond to a primary vaccine series indicated that all those not infected with HBV responded satisfactorily to a repeat 3-dose revaccination series (103).No data suggest that children who have no detectable antibody after 6 doses of vaccine would benefit from additional doses. # Groups Requiring Different Vaccination Doses or Schedules Preterm infants.Preterm infants weighing <2,000 g at birth have a decreased response to hepatitis B vaccine administered before age 1 month (104)(105)(106).By age 1 month, medically stable preterm infants, regardless of initial birth weight or gestational age, have a response to vaccination that is comparable to that of full-term infants (107)(108)(109)(110). Hemodialysis patients and other immunocompromised persons.Although data concerning the response of pediatric hemodialysis patients to vaccination with standard pediatric doses are lacking, protective levels of antibody occur in 75%-97% of those who receive higher dosages (20-µg) on either the 3-or the 4-dose schedule (111)(112)(113)(114).Humoral response to hepatitis B vaccination is also reduced in other children and adolescents who are immunocompromised (e.g., hematopoietic stem cell transplant recipients, patients undergoing chemotherapy, and HIV-infected persons) (115)(116)(117)(118)(119).Modified dosing regimens, including a doubling of the standard antigen dose or administration of additional doses, might increase response rates (120).However, data on response to these alternative vaccination schedules are limited (121). # Immune Memory Anti-HBs is the only easily measurable correlate of vaccine-induced protection.Immunocompetent persons who achieve anti-HBs concentrations >10 mIU/mL after preexposure vaccination have virtually complete protection against both acute disease and chronic infection even if anti HBs concentrations subsequently decline to <10 mIU/mL (122)(123)(124)(125).Although immunogenicity is lower among immunocompromised persons, those who achieve and maintain a protective antibody response before exposure to HBV have a high level of protection from infection. After primary immunization with hepatitis B vaccine, anti-HBs concentrations decline rapidly within the first after admission for delivery; if the mother is found to be HBsAg positive, the infant should receive HBIG as soon as possible but no later than age 7 days. † †On a case-by-case basis and only in rare circumstances, the first dose may be delayed until after hospital discharge for an infant who weighs >2,000 g and whose mother is HBsAg negative, but only if a physician's order to withhold the birth dose and a copy of the mother's original HBsAg-negative laboratory report are documented in the infant's medical record.year and more slowly thereafter.Among children who respond to a primary vaccine series with antibody levels >10 mIU/mL, 15%-50% have low or undetectable concentrations of anti-HBs (anti-HBs loss) 5-15 years after vaccination (126)(127)(128)(129)(130).The persistence of detectable anti-HBs after vaccination, in the absence of exposure to HBV, depends on the level of postvaccination antibody concentration. Despite declines in anti-HBs to <10 mIU/mL, nearly all vaccinated persons are still protected against HBV infection.The mechanism for continued vaccine-induced protection is thought to be the preservation of immune memory through selective expansion and differentiation of clones of antigenspecific B and T lymphocytes (131).Persistence of vaccineinduced immune memory among persons who responded to a primary childhood vaccine series 13-23 years earlier but then had levels of anti-HBs below 10 mIU/mL has been demonstrated by an anamnestic increase in anti-HBs levels in 67%-76% of these persons 2-4 weeks after administration of an additional vaccine dose (132,133).Although direct measurement of immune memory is not yet possible, these data indicate that a high proportion of vaccine recipients retain immune memory and would develop an anti-HBs response upon exposure to HBV. Studies of cohorts of immunocompetent persons vaccinated as children or infants also indicate that, despite anti-HBs loss years after immunization, nearly all vaccinated persons who respond to a primary series remain protected from HBV infection.No clinical cases of hepatitis B have been observed in follow-up studies conducted 15-20 years after vaccination among immunocompetent vaccinated persons with antibody levels >10 mIU/mL. Certain studies have documented breakthrough infections (detected by the presence of anti-HBc or HBV DNA) in a limited percentage of vaccinated persons (130,131), but these infections are usually transient and asymptomatic; chronic infections have been documented only rarely (134).Breakthrough infections resulting in chronic infection have been observed only among vaccinated infants born to HBsAg-positive women. Limited data are available on the duration of immune memory after hepatitis B vaccination in immunocompromised persons (e.g., HIV-infected patients, dialysis patients, patients undergoing chemotherapy, or hematopoietic stem cell transplant patients).No clinically important HBV infections have been documented among immunocompromised persons who maintain protective levels of anti-HBs.In studies of long-term protection among HIV-infected persons, breakthrough infections occurring after a decline in anti-HBs concentrations to 10 mIU/mL (136). # Postexposure Prophylaxis Both passive-active postexposure prophylaxis (PEP) with HBIG and hepatitis B vaccine and active PEP with hepatitis B vaccine alone have been demonstrated to be highly effective in preventing transmission after exposure to HBV (137)(138)(139)(140).HBIG alone has also been demonstrated to be effective in preventing HBV transmission (141)(142)(143)(144), but with the availability of hepatitis B vaccine, HBIG typically is used as an adjunct to vaccination. The major determinant of the effectiveness of PEP is early administration of the initial dose of vaccine.The effectiveness of PEP diminishes the longer it is initiated after exposure (17,145,146).Studies are limited on the maximum interval after exposure during which PEP is effective, but the interval is unlikely to exceed 7 days for perinatal (147) and needlestick (140)(141)(142) exposures and 14 days for sexual exposures (122,138,139,143,144). No data are available on the efficacy of HBsAg-containing combination vaccines when used to complete the vaccine series for PEP, but the efficacy of combination vaccines is expected to be similar to that of single-antigen vaccines because the HBsAg component induces a comparable anti-HBs response. # Perinatal HBV Exposure Passive-active PEP.PEP with hepatitis B vaccine and HBIG administered 12-24 hours after birth, followed by completion of a 3-dose vaccine series, has been demonstrated to be 85%-95% effective in preventing acute and chronic HBV infection in infants born to women who are positive for both HBsAg and HBeAg (137).Although clinical trials have evaluated the efficacy of passive-active PEP with hepatitis B vaccine and HBIG administered only within 24 hours of birth, studies of passive immunoprophylaxis have demonstrated that HBIG provided protection when administered as late as 72 hours after exposure.The majority of clinical trials have evaluated the efficacy of passive-active PEP when the second vaccine dose was administered at age 1 month (137).Administration of HBIG plus vaccine at birth, 1 month, and 6 months and at birth, 2 months, and 6 months has demonstrated comparable efficacy in prevention of acute and chronic infection among infants born to women who were both HBsAg and HBeAg positive (Cladd E. Stevens, MD, New York Blood Center, personal communication, 1994). Infants born to HBsAg-positive/HBeAg-negative mothers who receive passive-active PEP with HBIG and hepatitis B vaccine should have the same high degree of protection as infants born to women who are HBsAg positive/HBeAg positive.However, the efficacy of this regimen has not been examined in controlled clinical trials because the low infection rate would require an unattainable sample size. Active PEP.Active PEP with hepatitis B vaccine alone (i.e., without HBIG) is frequently used in certain remote areas (e.g., Alaska and the Pacific Islands) where implementation of maternal HBsAg testing is difficult because no access exists to a laboratory.In randomized, placebo-controlled clinical trials, administration of hepatitis B vaccine in a 3-or 4-dose schedule without HBIG beginning <12 hours after birth has been demonstrated to prevent 70%-95% of perinatal HBV infections among infants born to women who are positive for both HBsAg and HBeAg (58,(148)(149)(150)(151)(152).Population-based studies in areas with a high endemicity of HBV infection have demonstrated that active postexposure vaccination is highly effective in preventing infection when the first dose is administered soon after birth, the second at age 1-2 months, and the third at age 6-8 months (153)(154)(155). # Vaccine Safety Hepatitis B vaccines have been demonstrated to be safe when administered to infants, children, adolescents, and adults.Since 1982, an estimated >60 million adolescents and adults and >40 million infants and children have been vaccinated in the United States. # Vaccine Reactogenicity The most frequently reported side effects among persons receiving hepatitis B vaccine are pain at the injection site (3%-29%) and fever >99.9° F (>37.7° C) (1%-6%) (156,157).However, in placebo-controlled studies, these side effects were reported no more frequently among persons receiving hepatitis B vaccine than among persons receiving placebo (87).Administration of hepatitis B vaccine soon after birth has not been associated with an increased rate of elevated temperatures or microbiologic evaluations for possible sepsis in the first 21 days of life (158). # Adverse Events A causal association has been established between receipt of hepatitis B vaccine and anaphylaxis (159).On the basis of data from the Vaccine Safety Datalink (VSD) project, the estimated incidence of anaphylaxis among children and adolescents who received hepatitis B vaccine is one case per 1.1 million vaccine doses distributed (95% confidence interval = 0.1-3.9) (160). Early postlicensure surveillance of adverse events suggested a possible association between Guillain-Barré syndrome and receipt of the first dose of plasma-derived hepatitis B vaccine among U.S. adults (161).However, in a subsequent analysis of Guillain-Barré syndrome cases reported to CDC, FDA, and vaccine manufacturers, among an estimated 2.5 million adults who received >1 dose of recombinant hepatitis B vaccine during 1986-1990, the rate of Guillain-Barré syndrome occurring after hepatitis B vaccination did not exceed the background rate among unvaccinated persons (CDC, unpublished data, 1992).A review by persons with clinical expertise concluded that evidence was insufficient to reject or accept a causal association between Guillain-Barré syndrome and hepatitis B vaccination (159,162). Multiple sclerosis (MS) has not been reported after hepatitis B vaccination among children.However, one retrospective case-control study (163,164) reported an association between hepatitis B vaccine and MS among adults.Multiple other studies (165)(166)(167)(168) have demonstrated no association between hepatitis B vaccine and MS.Reviews of these data by panels of persons with clinical expertise have favored rejection of a causal association between hepatitis B vaccination and MS (169,170). Chronic illnesses that have been reported in rare instances after hepatitis B vaccination include chronic fatigue syndrome (171), neurologic disorders (e.g., leukoencephalitis, optic neu-ritis, and transverse myelitis) (172-174), rheumatoid arthritis (175,176), type 1 diabetes (177), and autoimmune disease (178).No evidence of a causal association between these conditions or other chronic illnesses and hepatitis B vaccine has been demonstrated (159,169,170,(179)(180)(181)(182). Reported episodes of alopecia (hair loss) after rechallenge with hepatitis B vaccine suggest that vaccination might, in rare cases, trigger episodes of alopecia (183).However, a population-based study determined no statistically significant association between alopecia and hepatitis B vaccine (184). No evidence exists of a causal association between hepatitis B vaccination, including administration of the birth dose, and sudden infant death syndrome (SIDS) or other causes of death during the first year of life (185)(186)(187).Infant death rates, including rates of SIDS, declined substantially in the United States during the 1990s, coincident with an increase in infant hepatitis B vaccination coverage from 90% and implementation of efforts to reduce SIDS through infant sleep positioning and separation from other persons in bed (188). The safety of hepatitis B vaccine and other vaccines is assessed continuously through ongoing monitoring of data from VSD, the Vaccine Adverse Events Reporting System (VAERS), and other surveillance systems.Any adverse events after vaccination should be reported to VAERS; report forms and assistance are available from CDC at telephone 1-800-822-7967 or at . # Contraindications and Precautions Hepatitis B vaccination is contraindicated for persons with a history of hypersensitivity to yeast or to any vaccine component (92,(189)(190)(191).Despite a theoretic risk for allergic reaction to vaccination in persons with allergy to Saccharomyces cerevisiae (baker's yeast), no evidence exists that documents adverse reactions after vaccination of persons with a history of yeast allergy. Persons with a history of serious adverse events (e.g., anaphylaxis) after receipt of hepatitis B vaccine should not receive additional doses.As with other vaccines, vaccination of persons with moderate or severe acute illness, with or without fever, should be deferred until the illness resolves (192).Vaccination is not contraindicated in persons with a history of MS, Guillain-Barré syndrome, autoimmune disease (e.g., systemic lupus erythematosis or rheumatoid arthritis), or other chronic diseases. Pregnancy is not a contraindication to vaccination.

Limited data indicate no apparent risk for adverse events to developing fetuses when hepatitis B vaccine is administered to pregnant women (193).Current vaccines contain noninfectious HBsAg and should cause no risk to the fetus. # Future Considerations Implementation of the recommendations and strategies in this document should ultimately lead to the elimination of HBV transmission in the United States.New information will have implications for this effort, and adjustments and changes are expected to occur. # Long-Term Protection and Booster Doses Studies are needed to assess long-term protection after vaccination and the possible need for booster doses of vaccine.The longest follow-up studies of vaccine protection have been conducted in populations with an initially high endemicity of HBV infection (i.e., >8% prevalence of chronic infection) (130).Implementation of hepatitis B vaccination programs in populations with a high endemicity of HBV infection has resulted in virtual elimination of new HBV infections by providing vaccine-induced immunity to susceptible persons.In these populations, ongoing exposure of vaccinated persons to persons with chronic HBV infection might complicate future efforts to assess long-term hepatitis B vaccine efficacy.Assessment of efficacy provided by hepatitis B immunization after 15-20 years will require studies among populations that continue to have exposures to HBsAg-positive persons (e.g., communities of immigrants from highly endemic countries, populations of injection-drug users, or health-care workers) and studies among populations with a low prevalence of infection. # Immunization Escape Mutants Mutations in the S gene of HBV can lead to conformational changes in the a determinant of the HBsAg protein, which is the major target for neutralizing anti-HBs.These variants have been detected in humans infected with HBV, and concern has been expressed that these variants might replicate in the presence of vaccine-induced anti-HBs or anti-HBs contained in HBIG (194,195).Although no evidence suggests that S gene immunization escape mutants pose a threat to existing programs using hepatitis B vaccines (196), further studies and enhanced surveillance to detect the emergence of these variants are high priorities for monitoring the effectiveness of current vaccination strategies. # Recommendations for Hepatitis B Vaccination of Infants, Children, and Adolescents This section outlines updated ACIP recommendations and associated implementation strategies for hepatitis B vaccina-tion of infants, children, and adolescents.These recommendations have been summarized (Box 3). # Prevention of Perinatal HBV Infection and Management of Pregnant Women # Recommendations # Prenatal HBsAg Testing - All pregnant women should be tested routinely for HBsAg during an early prenatal visit (e.g., first trimester) in each pregnancy, even if they have been previously vaccinated or tested. -Women who were not screened prenatally, those who engage in behaviors that put them at high risk for infec-tion (e.g., injection-drug use, having had more than one sex partner in the previous 6 months or an HBsAg-positive sex partner, evaluation or treatment for a sexually transmitted disease , or recent or current injectiondrug use) and those with clinical hepatitis should be tested at the time of admission to the hospital for delivery. -All laboratories that provide HBsAg testing of pregnant women should use an FDA-licensed or -approved HBsAg test and should perform testing according to the manufacturer's labeling, including testing of initially reactive specimens with a licensed neutralizing confirmatory test.When pregnant women are tested for HBsAg at the time of admission for delivery, shortened testing protocols may be used and initially reactive results reported to expedite administration of immunoprophylaxis to infants. -Women who are HBsAg positive should be referred to an appropriate case-management program to ensure that their infants receive timely postexposure prophylaxis and followup (see Case-Management Programs to Prevent Perinatal HBV Infection).In addition, a copy of the original laboratory report indicating the pregnant woman's HBsAg status should be provided to the hospital where delivery is planned and to the health-care provider who will care for the newborn. -Women who are HBsAg positive should be provided with or referred for appropriate counseling and medical management (Appendix A).HBsAg-positive pregnant women should receive information concerning hepatitis B that discusses -modes of transmission; -perinatal concerns (e.g., infants born to HBsAgpositive mothers may be breast fed); -prevention of HBV transmission to contacts, including the importance of postexposure prophylaxis for the newborn infant and hepatitis B vaccination for household, sexual, and needle-sharing contacts; -substance abuse treatment, if appropriate; and -medical evaluation and possible treatment of chronic hepatitis B. - When HBsAg testing of pregnant women is not feasible (i.e., in remote areas without access to a laboratory), all infants should receive hepatitis B vaccine <12 hours of birth and should complete the hepatitis B vaccine series according to a recommended schedule for infants born to HBsAg-positive mothers (Tables 2 and 3). # Management of Infants Born to Women Who Are HBsAg Positive - All infants born to HBsAg-positive women should receive single-antigen hepatitis B vaccine ( The mother should have blood drawn as soon as possible to determine her HBsAg status; if she is HBsAg positive, the infant should receive HBIG as soon as possible (no later than age 1 week). -Full-term infants who are medically stable and weigh >2,000 g born to HBsAg-negative mothers should receive single-antigen hepatitis B vaccine before hospital discharge. -Preterm infants weighing <2,000 g born to HBsAgnegative mothers should receive the first dose of vaccine 1 month after birth or at hospital discharge. # After the birth dose - All infants should complete the hepatitis B vaccine series with either single-antigen vaccine or combination vaccine, according to a recommended vaccination schedule (see Tables 3 and 4). -Infants born to HBsAg-positive mothers should be tested for HBsAg and antibody to HBsAg after completion of the hepatitis B vaccine series at age 9-18 months. # Vaccination of children and adolescents - All unvaccinated children and adolescents aged <19 years should receive the hepatitis B vaccine series. (0.5 mL) <12 hours of birth, administered at different injection sites.The vaccine series should be completed according to a recommended schedule for infants born to HBsAg-positive mothers (Table 3).The final dose in the vaccine series should not be administered before age 24 weeks (164 days). -For preterm infants weighing <2,000 g, the initial vaccine dose (birth dose) should not be counted as part of the vaccine series because of the potentially reduced immunogenicity of hepatitis B vaccine in these infants; 3 additional doses of vaccine (for a total of 4 doses) should be administered beginning when the infant reaches age 1 month (Tables 3 and 4). -Postvaccination testing for anti-HBs and HBsAg should be performed after completion of the vaccine series, at age 9-18 months (generally at the next well-child visit). Testing should not be performed before age 9 months to avoid detection of anti-HBs from HBIG administered during infancy and to maximize the likelihood of detecting late HBV infection.Anti-HBc testing of infants is not recommended because passively acquired maternal anti-HBc might be detected in infants born to HBVinfected mothers to age 24 months. -HBsAg-negative infants with anti-HBs levels >10 mIU/mL are protected and need no further medical management.-HBsAg-negative infants with anti-HBs levels 6 weeks born to HBsAgpositive mothers to complete the vaccine series after receipt of a birth dose of single-antigen hepatitis B vaccine and HBIG. # Management of Infants Born to Women with Unknown HBsAg Status - Women admitted for delivery without documentation of HBsAg test results should have blood drawn and tested as soon as possible after admission. -While test results are pending, all infants born to women without documentation of HBsAg test results should receive the first dose of single-antigen hepatitis B vaccine (without HBIG) <12 hours of birth (Tables 2 and 3). -If the mother is determined to be HBsAg positive, her infant should receive HBIG as soon as possible but no later than age 7 days, and the vaccine series should be completed according to a recommended schedule for infants born to HBsAg-positive mothers (Table 3).-If the mother is determined to be HBsAg negative, the vaccine series should be completed according to a recommended schedule for infants born to HBsAgnegative mothers (Table 3).-If the mother has never been tested to determine her HBsAg status, the vaccine series should be completed according to a recommended schedule for infants born to HBsAg-positive mothers (Table 3).Administration of HBIG is not necessary for these infants. -Because of the potentially decreased immunogenicity of vaccine in preterm infants weighing <2,000 g, these infants should receive both single-antigen hepatitis B vaccine and HBIG (0.5 mL) if the mother's HBsAg status cannot be determined <12 hours of birth.The birth dose of vaccine should not be counted as part of the 3 doses required to complete the vaccine series; 3 additional doses of vaccine (for a total of 4 doses) should be administered according to a recommended schedule on the basis of the mother's HBsAg test result (Table 3). # Vaccination of Pregnant Women - Pregnant women who are identified as being at risk for HBV infection during pregnancy (e.g., having more than one sex partner during the previous 6 months, been evaluated or treated for an STD, recent or current injectiondrug use, or having had an HBsAg-positive sex partner) should be vaccinated. -Pregnant women at risk for HBV infection during pregnancy should be counseled concerning other methods to prevent HBV infection. # Implementation # Delivery Hospital Policies and Procedures - All delivery hospitals should implement policies and procedures (Box 4) to ensure 1) identification of infants born to HBsAg-positive mothers and infants born to mothers with unknown HBsAg status (see Prenatal HBsAg Testing), and 2) initiation of immunization for these infants).Such policies and procedures should include the following standing orders: -for all pregnant women, review of HBsAg test results at the time of admission for delivery; -for women who do not have a documented HBsAg test result, HBsAg testing as soon as possible after admission for delivery; -identification and management of all infants born to HBsAg-positive mothers; -identification and management of all infants born to mothers with unknown HBsAg status; and -for all infants, documentation on the infant's medical record of maternal HBsAg test results, infant hepatitis B vaccine administration, and administration of HBIG (if appropriate). -Delivery hospitals should enroll in the federally funded Vaccines for Children (VFC) program to obtain free hepatitis B vaccine for administration of the birth dose to newborns who are eligible (i.e., Medicaid eligible, American Indian or Alaska Native, underinsured, or uninsured). # Case-Management Programs to Prevent Perinatal HBV Infection - States and localities should establish case-management programs (Box 5), including appropriate policies, procedures, laws, and regulations, to ensure that -all pregnant women are tested for HBsAg during each pregnancy, and -infants born to HBsAg-positive women and infants born to women with unknown HBsAg status receive recommended case management. -The location of these programs and the methods by which they operate will depend on multiple factors (e.g., population density and annual caseload of HBsAg-positive women).Programs may be located in state or local health departments, private health-care systems (e.g., health maintenance organizations), or institutions (e.g., correctional facility systems).Program administrators will need to work with prenatal care providers, delivery hospital staff, pediatric care providers, private health-care systems, and health departments. # Universal Vaccination of Infants # Recommendations - All infants should receive the hepatitis B vaccine series as part of the recommended childhood immunization schedule (Table 5 - On a case-by-case basis and only in rare circumstances, the first dose may be delayed until after hospital discharge for an infant who weighs >2,000 g and whose mother is HBsAg negative. -When such a decision is made, a physician's order to withhold the birth dose and a copy of the original laboratory report indicating that the mother was HBsAg negative during this pregnancy should be placed in the infant's medical record.-For infants who do not receive a first dose before hospital discharge, the first dose should be administered no later than age 2 months.-Situations in which the birth dose should not be delayed include any high-risk sexual or drug-using practices of the infant's mother during pregnancy (e.g., having had more than one sex partner during the previous 6 months or an HBsAg-positive sex partner, evaluation or treatment for an STD, or recent or current injection-drug use) and expected poor compliance with follow-up to initiate the vaccine series. -Preterm infants weighing <2,000 g and born to HBsAgnegative mothers should have their first vaccine dose delayed until 1 month after birth or hospital discharge (Table 4).For these infants, a copy of the original laboratory report indicating that the mother was HBsAg negative during this pregnancy should be placed in the infant's medical record. -The vaccine series should be completed according to a recommended schedule with either single-antigen vaccine or a combination vaccine that contains the hepatitis B vaccine antigen (e.g., Hib-hepatitis B or DTaP-IPVhepatitis B) (Table 2).The final dose in the vaccine series should not be administered before age 24 weeks (164 days). -Administration of 4 doses of hepatitis B vaccine to infants is permissible in certain situations (e.g., when combination vaccines are administered after the birth dose). -In populations with currently or previously high rates of childhood HBV infection (i.e., Alaska Natives; Pacific Islanders; and immigrant families from Asia, Africa, and other regions with intermediate or high endemic rates of infection ), the first dose of hepatitis B vaccine should be administered at birth and the final dose at age 6-12 months. # Implementation - All delivery hospitals should implement standing orders for administration of hepatitis B vaccination as part of routine medical care of all medically stable infants weighing >2,000 g at birth (Box 4). - All delivery hospitals should implement policies and procedures for management of infants weighing <2,000 g at birth, including the following: -ensuring initiation of postexposure immunization of infants born to HBsAg-positive mothers and infants born to mothers not screened for HBsAg prenatally (see Prevention of Perinatal HBV Infection and Management of Pregnant Women), and -documentation of maternal HBsAg test results on the infant's medical record. -Prenatal care education should include information regarding the rationale for and importance of newborn hepatitis B vaccination. -States are encouraged to adopt regulations or laws that require hepatitis B vaccination for entry into child care and also for entry into kindergarten and/or elementary school to ensure high vaccine coverage among infants and children. # Vaccination of Children and Adolescents Who Were Not Previously Vaccinated # Recommendations - Hepatitis B vaccination is recommended for all children and adolescents aged <19 years. -Children and adolescents who have not previously received hepatitis B vaccine should be vaccinated routinely at any age with an appropriate dose and schedule (Tables 2 and 5).Selection of a vaccine schedule should consider the need to achieve completion of the vaccine series.In all settings, vaccination should be initiated even though completion of the vaccine series might not be ensured. # Implementation - To ensure high vaccination coverage among children and adolescents, the following measures are recommended: -All children aged 11-12 years should have a review of their immunization records and should complete the vaccine series if they were not previously vaccinated or were incompletely vaccinated.-All children and adolescents aged <19 years (including internationally adopted children) who were born in Asia, the Pacific Islands, Africa, or other intermediate-or high-endemic countries (Figure 1 and Box 2) or who have at least one parent who was born in one of these areas should have a review of their immunization records and should complete the vaccine series if they were not previously vaccinated or were incompletely vaccinated. # Management of Persons Identified as HBsAg Positive - All persons with HBsAg-positive laboratory results should be reported to the state or local health department. -To verify the presence of chronic HBV infection, HBsAgpositive persons should be retested.The absence of immu-Chronically infected persons are at high risk for chronic liver disease and are a major reservoir of hepatitis B virus (HBV) infection.Foreign-born persons, especially persons from Africa, Asia, and the Pacific Islands, have high- rates of chronic HBV infection.During delivery of recommended hepatitis B vaccination services (e.g., HBsAg screening of pregnant women and serologic testing to assess susceptibility), vaccination providers will identify persons who are HBsAg positive.These persons require counseling and medical management for chronic HBV infection to reduce their risk for chronic liver disease.Their susceptible household, sexual, and needle-sharing contacts also need to be vaccinated against hepatitis B. Few programs have been implemented to identify HBsAgpositive persons, provide or refer these persons for appropriate medical management, and provide vaccination to their contacts (1).Extending these services to persons identified as HBsAg positive will help prevent serious sequelae in chronically infected persons and enhance vaccination strategies for elimination of HBV transmission.This Appendix addresses case finding and management of persons with chronic HBV infection in the context of vaccine delivery.The recommendations are not intended to represent a comprehensive prevention program for chronically infected persons. # Case Finding in the Context of Vaccination Service Delivery - All foreign-born persons (including immigrants, refugees, asylum seekers, and internationally adopted children) born in Asia, the Pacific Islands, Africa, and other regions with high endemicity of HBV infection (Box A-1) should be tested for HBsAg, regardless of vaccination status. -For all persons born in high-endemic countries who are applying for permanent U.S. residence, HBsAg screening and appropriate follow-up on the basis of HBsAg test results should be included as part of the required overseas premigration and domestic adjustment-of-visa status medical examination process (2).HBsAg-positive persons should be considered eligible for migration and adjustment-of-visa status and counseled and recommended for follow-up medical evaluation and management in U.S. resettlement communities. 2 and 6) Persons who are not fully vaccinated should complete the vaccine series. -

Sex partners of HBsAg-positive persons should be counseled to use methods (e.g., condoms) to protect themselves from sexual exposure to infectious body fluids (e.g., semen or vaginal secretions) unless they have been demonstrated to be immune after vaccination (i.e., anti-HBs >10 mIU/mL) or previously infected (anti-HBc positive). -To prevent or reduce the risk for transmission to others, HBsAg-positive persons should be advised concerning the risks for -perinatal transmission to infants born to HBsAgpositive women and the need for such infants to receive hepatitis B vaccine beginning at birth (see Prevention of Perinatal HBV Infection and Management of Pregnant Women) and -transmission to household, sexual, and needle-sharing contacts and the need for such contacts to receive hepatitis B vaccine. -HBsAg-positive persons should also be advised to -use methods (e.g., condoms) to protect nonimmune sex partners from acquiring HBV infection from sexual activity until the sex partners can be vaccinated and immunity documented; -cover cuts and skin lesions to prevent the spread of infectious secretions or blood; -refrain from donating blood, plasma, tissue, or semen (organs may be donated to HBV-immune or chronically infected persons needing a transplant); and -refrain from sharing household articles (e.g., toothbrushes, razors, or personal injection equipment) that could become contaminated with blood. -To protect the liver from further harm, HBsAg-positive persons should be advised to -avoid or limit alcohol consumption because of the effects of alcohol on the liver; -refrain from beginning to take any new medicines, including over-the-counter and herbal medicines, without consulting their health-care provider; and -obtain vaccination against hepatitis A if chronic liver disease is found to be present. -When seeking medical or dental care, HBsAg-positive persons should be advised to inform those responsible for their care of their HBsAg status so they can be evaluated and their care managed appropriately. -Other counseling messages: -HBV is not spread by breastfeeding, kissing, hugging, coughing, ingesting food or water, sharing eating utensils or drinking glasses, or casual contact.-Persons should not be excluded from school, play, child care, work, or other settings on the basis of their HBsAg status unless they are prone to biting (4).-Involvement with a support group might help patients cope with chronic HBV infection. # Appendix B Immunization Management Issues response has been achieved (see Postvaccination Testing for Serologic Response). -Hepatitis B vaccine and other vaccines administered during the same visit should be administered in different injection sites.When more than one injection must be administered in the same limb, the anterolateral thigh is usually the preferred site, with injections separated by 1"-2" to avoid overlap in local reactions. -For persons at risk for hemorrhage (e.g., persons with hemophilia), the risk of bleeding after intramuscular injection can be minimized by use of a 23-gauge (or smaller) needle, application of direct pressure to the injection site for >2 minutes, and administration of vaccine immediately after infusion of coagulation factor.Subcutaneous administration of vaccine can be considered for these persons but might result in lower response and an increased local reaction. -Hepatitis B vaccine should be stored at 35°-46° F (2°-8° C) and should not be frozen. -A vaccine information statement (VIS) must be provided to recipients of hepatitis B vaccine.The National Childhood Vaccine Injury Act of 1986 (42 U.S.C. § 300aa-26) requires vaccine providers to give a copy of the most current vaccine-specific VIS to all recipients (children or their guardians) of vaccines that are included on the # Hepatitis B Immune Globulin (HBIG) Dose and Administration - The standard dose of HBIG is 0.5 mL for postexposure prophylaxis of infants born to hepatitis B surface antigen (HBsAg)-positive women and 0.06 mL/kg for all other applications. -HBIG may be administered simultaneously with hepatitis B vaccine but in a different injection site. -HBIG is administered by intramuscular injection.For infants, HBIG should be administered intramuscularly # Hepatitis B Vaccine Dose and Administration - Recommended vaccine doses vary by product, age of recipient, and needs of special populations (see Table 2).Administration of single-antigen or combination vaccine simultaneously with other childhood vaccines produces no clinically significant interference in antibody responses (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).Although the antigen contents of vaccines differ, vaccines made by different manufacturers are interchangeable, except for the 2-dose schedule used for adolescents aged 11-15 years, for which only Recombivax HB is approved.Combination vaccines are not approved for use as a birth dose because of potential suppression of the immune response to subsequent doses of the Haemophilus influenzae type b (Hib) component in Comvax ( 14) and possible decreased immunogenicity of the diphtheria component of Pediarix when administered at birth. -Hepatitis B vaccine should be administered by intramuscular injection.Injection into the buttock is associated with decreased immunogenicity (15)(16)(17)(18).Intradermal administration can result in a lower seroconversion rate and final concentration of antibody to hepatitis B surface antigen compared with intramuscular administration; limited data are available to assess long-term protection from this route of administration (19,20). -The anterolateral thigh muscle is the recommended site of administration for neonates (aged <1 month) and infants (aged 1-12 months).For toddlers (aged 1-2 years) and older children, either the anterolateral thigh or the deltoid muscle may be used if the muscle mass is adequate.The deltoid muscle is the preferred site of administration for adolescents. -For intramuscular injection, the needle should be long enough to reach the muscle mass and prevent vaccine from seeping into subcutaneous tissue, but not so long as to involve underlying nerves and blood vessels or bone (21). The appropriate needle length is usually 5 /8" for neonates, 7 /8"-1" for infants, and 7 /8"-1 1 /4" for toddlers, older children, and adolescents.A 22-to 25-gauge needle should be used. -Hepatitis B vaccine administered by any route or site other than intramuscularly in the anterolateral thigh or deltoid muscle should not be counted as valid and should be repeated unless serologic testing indicates that an adequate in the anterolateral thigh using a 22-25-gauge needle that is 7 /8"-1" in length.For older children and adolescents, an appropriate muscle mass (i.e., deltoid or gluteal) should be chosen in which to deliver the larger volumes of HBIG required for these age groups by using a needle length appropriate for the person's age and size (21). -Vaccination with certain live-virus vaccines (measles, mumps, rubella, and varicella) should be deferred for at least 3 months after administration of HBIG because HBIG can inhibit the response to these vaccines (21). -HBIG should be stored at 35°-46° F (2°-8° C) and should not be frozen. # Unknown or Uncertain Vaccination Status - A reliable vaccination history is defined as a written, dated record (personal, school, physician, or immunization registry) of each dose of a complete series. # Interrupted Vaccine Schedules - When the hepatitis B vaccine schedule is interrupted, the vaccine series does not need to be restarted. -If the series is interrupted after the first dose, the second dose should be given as soon as possible, and the second and third doses should be separated by an interval of at least 8 weeks. -If only the third dose is delayed, it should be administered as soon as possible, after age 24 weeks (164 days). -It is not necessary to restart the vaccine series for infants switched from one vaccine brand to another, including combination vaccines. # Minimum Dosing Intervals and Management of Persons Who Were Incorrectly Vaccinated - The third dose of vaccine must be administered at least 8 weeks after the second dose and should follow the first dose by at least 16 weeks; the minimum interval between the first and second doses is 4 weeks.In infants, administration of the final dose is not recommended before age 24 weeks (164 days). -Inadequate doses of hepatitis B vaccine (see Table 2) or doses received after a shorter-than-recommended dosing interval should be readministered. # Accelerated Vaccine Schedules - The Food and Drug Administration (FDA) has not approved accelerated schedules in which hepatitis B vaccine is administered more than once in a month.If clinicians choose to use an accelerated schedule (i.e., doses at days 0, 7, and 14 days), the patient should also receive a booster dose at least 6 months after the start of the series to promote long-term immunity. # Hemodialysis Patients and Other Immunocompromised Persons - Standard hepatitis B vaccine doses (see Table 2) are approved by FDA for vaccination of all persons aged <20 years.For hemodialysis patients and other immunocompromised persons, higher doses might be more immunogenic, but no specific recommendations have been made. -Serologic testing of hemodialysis patients and other immunocompromised persons is recommended 1-2 months after administration of the final dose of the primary vaccine series to determine the need for revaccination (see Postvaccination Testing for Serologic Response). In addition, booster doses of vaccine might be needed (see Booster Doses). # Prevaccination Serologic Testing for Susceptibility - Because of the low prevalence of HBV infection among infants, children, and adolescents born in the United States, prevaccination testing for susceptibility usually is not indicated for these age groups. -Prevaccination testing for susceptibility is recommended for unvaccinated household, sexual, and needle-sharing contacts of HBsAg-positive persons. -Anti-HBc is the test of choice for prevaccination testing. - Persons tested for anti-HBc and found to be anti-HBc negative are susceptible and should complete the vaccine series. -Persons found to be anti-HBc positive should be tested for HBsAg.HBsAg testing may be performed on the same specimen collected for anti-HBc testing.If the HBsAg test result is positive, the person should receive appropriate management (see Appendix A). -In most situations, the first vaccine dose should be administered immediately after collection of the blood sample for serologic testing. # Postvaccination Testing for Serologic Response Recommendations for postvaccination testing of infants born to HBsAg-positive women are provided in this report (see Management of Infants Born to Women Who Are HBsAg Positive).This section provides recommendations for postvaccination testing of other persons. - Serologic testing for immunity is not necessary after routine vaccination of infants, children, or adolescents. -Testing after vaccination is recommended only for the following persons whose subsequent clinical management depends on knowledge of their immune status: -health-care workers; -chronic hemodialysis patients, HIV-infected persons, and other immunocompromised persons (e.g., hematopoietic stem-cell transplant recipients or persons receiving chemotherapy), to determine the need for revaccination and the type of follow-up testing; and -sex partners of HBsAg-positive persons, to determine the need for revaccination and the need for other methods of protection against HBV infection. -Testing should be performed 1-2 months after administration of the last dose of the vaccine series by using a method that allows determination of a protective level of anti-HBs (>10 mIU/mL). - Persons found to have anti-HBs levels of >10 mIU/mL after the primary vaccine series are considered to be immune. -Immunocompetent persons have long-term protection and do not need further periodic testing to assess anti-HBs levels.-Immunosuppressed persons might need annual testing to assess anti-HBs levels (see Booster Doses). -Persons found to have anti-HBs levels of <10 mIU/mL after the primary vaccine series should be revaccinated.Administration of three doses on an appropriate schedule (Table 7), followed by anti-HBs testing 1-2 months after the third dose, is usually more practical than serologic testing after one or more doses of vaccine. and 3). - Persons who are in the process of being vaccinated but who have not completed the vaccine series should receive the appropriate dose of HBIG and should complete the vaccine series. -Children and adolescents who have written documentation of a complete hepatitis B vaccine series and who were did not receive postvaccination testing should receive a single vaccine booster dose. # Source with Unknown HBsAg Status - Unvaccinated persons ( # INSTRUCTIONS ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.CDC designates this educational activity for a maximum of 3.25 hours in category 1 credit toward the AMA Physician's Recognition Award.Each physician should claim only those hours of credit that he/she actually spent in the educational activity.Continuing Education Unit (CEU).CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training.CDC will award 0.3 continuing education units to participants who successfully complete this activity.Continuing Nursing Education (CNE).This activity for 3.8 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # Goal and Objectives This report updates the immunization strategy to eliminate hepatitis B virus (HBV) transmission in the United States.The report includes new recommendations and implementation strategies for immunization of infants, children, and adolescents.The goal of the report is to provide guidance for health-care professionals to implement these recommendations and strategies to prevent perinatal HBV transmission, to promote universal vaccination of infants as part of the routine childhood vaccination schedule, and to promote vaccination of children and adolescents who were not previously vaccinated.Upon completion of this educational activity, the reader should be able to a) identify ways to maintain high hepatitis B surface antigen (HBsAg) screening rates among pregnant women, b) describe the components of a case management program for HBsAg-positive women, c) describe methods to ensure that newborn infants of HBsAg-positive mothers and mothers with unknown HBsAg status receive appropriate immunoprophylaxis, d) describe how to structure programs to increase the number of infants who receive a birth dose of hepatitis B vaccine, e) list ways to increase vaccine coverage among adolescents, and f) identify ways to increase rates of HBsAg screening and hepatitis B vaccination of foreign-born persons.To receive continuing education credit, please answer all of the following questions. # Which of the following statements regarding the hepatitis B vaccination schedule in infants and children are true? (Indicate all that apply.) A. Administration of the final dose to infants is not recommended before age 24 weeks.B. A vaccine series started with a birth dose of single-antigen vaccine cannot be completed with 3 doses of combination vaccine.C. No differences in immunogenicity have been observed when one or two doses of hepatitis B vaccine produced by one manufacturer are followed by dose(s) from a different manufacturer.D. Currently licensed formulations for both single-antigen vaccines have been demonstrated to produce high (>95%) levels of seroprotection among infants, children, and adolescents when administered in different schedules.E. All of the above.without HBIG) beginning at birth is frequently used in areas where implementation of maternal HBsAg testing is difficult (e.g., in Alaska, Pacific Islands, and developing countries).D. Although rates of perinatal HBV transmission are higher from HBeAgpositive mothers compared with HBeAg-negative mothers, testing of HBsAg-positive pregnant women for HBeAg is not warranted for the management of the infant because postexposure prophylaxis is recommended for all infants born to HBsAg-positive women.E. All of the above. # Which best describes your professional activities: A All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. All MMWR references are available on the Internet at .Use the search function to find specific articles.

# Introduction Planning for and responding to the range of possible consequences following the emergence of a novel influenza A virus is complex.These viruses can spread quickly and explosively worldwide, as did the influenza pandemics in 1918, 1957, 1968, and 2009 (1,2); cause limited outbreaks, such as the influenza A(H3N2) variant (H3N2v) virus in the United States associated with agricultural fairs in the summer months of 2011, 2012, and 2013 (3); or continue causing limited animalto-human transmission of virus, such as the influenza A(H5N1) and influenza A(H7N9) viruses in Asia (4,5).Furthermore, novel influenza A viruses, even when transmissible in a closed setting, do not always result in a pandemic, such as the 1976 influenza A(H1N1) outbreak in Fort Dix, New Jersey, and the 2011-2013 H3N2v outbreak in the United States (3,6).Identifying and responding to this wide range of situations require systematic frameworks that describe the progression of events; weigh the risk of emergence and potential public health impact of the novel virus; evaluate the potential for ongoing # Updated Preparedness and Response Framework for Influenza Pandemics Prepared by Rachel Holloway 1 Sonja A. Rasmussen, MD 1 Stephanie Zaza, MD 2 Nancy J. Cox, PhD 3 Daniel B. Jernigan, MD 3 with the Influenza Pandemic Framework Workgroup 1 Influenza Coordination Unit, Office of Infectious Diseases 2 Division of Adolescent and School Health, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention 3 Influenza Division, National Center for Immunization and Respiratory Diseases # Summary The complexities of planning for and responding to the emergence of novel influenza viruses emphasize the need for systematic frameworks to describe the progression of the event; weigh the risk of emergence and potential public health impact; evaluate transmissibility, antiviral resistance, and severity; and make decisions about interventions.On the basis of experience from recent influenza responses, CDC has updated its framework to describe influenza pandemic progression using six intervals (two prepandemic and four pandemic intervals) and eight domains.This updated framework can be used for influenza pandemic planning and serves as recommendations for risk assessment, decision-making, and action in the United States.The updated framework replaces the U.S. federal government stages from the 2006 implementation plan for the National Strategy for Pandemic Influenza (US Homeland Security Council.National strategy for pandemic influenza: implementation plan.Washington, DC: US Homeland Security Council; 2006.Available at ).The six intervals of the updated framework are as follows: 1) investigation of cases of novel influenza, 2) recognition of increased potential for ongoing transmission, 3) initiation of a pandemic wave, 4) acceleration of a pandemic wave, 5) deceleration of a pandemic wave, and 6) preparation for future pandemic waves.The following eight domains are used to organize response efforts within each interval: incident management, surveillance and epidemiology, laboratory, community mitigation, medical care and countermeasures, vaccine, risk communications, and state/local coordination. Compared with the previous U.S. government stages, this updated framework provides greater detail and clarity regarding the potential timing of key decisions and actions aimed at slowing the spread and mitigating the impact of an emerging pandemic.Use of this updated framework is anticipated to improve pandemic preparedness and response in the United States.Activities and decisions during a response are event-specific.These intervals serve as a reference for public health decision-making by federal, state, and local health authorities in the United States during an influenza pandemic and are not meant to be prescriptive or comprehensive.This framework incorporates information from newly developed tools for pandemic planning and response, including the Influenza Risk Assessment Tool and the Pandemic Severity Assessment Framework, and has been aligned with the pandemic phases restructured in 2013 by the World Health Organization.transmissibility, antiviral resistance, and disease severity; and can be used to develop time-sensitive decisions about interventions (e.g., community mitigation measures, medical countermeasures, and vaccines).Preparedness and response frameworks provide a common basis for planning across different jurisdictions and ensure transparency in decisions made and actions taken. Significant progress has been made toward developing pandemic plans, as well as preparedness and response frameworks, during the past decade.Efforts by the World Health Organization (WHO), CDC, other U.S. government agencies, and state and local jurisdictions have addressed pandemic preparedness planning.Lessons regarding gaps in U.S. influenza decision-making frameworks have become evident with each event and exercise (7).The recent emergence of human disease caused by H3N2v in the United States (3) and H7N9 in China ( 5) has demonstrated the need to align existing documents and frameworks into one useful tool that can be used to guide ongoing planning and response efforts. # Background Frameworks describing the progression of influenza pandemics have evolved over time.The 2005 WHO global pandemic plan introduced the concept of pandemic phases (8).Six phases were used to describe the evolving risk of efficient human-to-human transmission as a basis for defining a pandemic. In November 2005, the president of the United States released a national strategy for pandemic influenza (9), and the associated implementation plan was released in May 2006 (10).These documents introduced the concept of using stages to determine the response to pandemic influenza, including stage 0 (new domestic animal outbreak in an at-risk country), stages 1-3 (human outbreaks suspected, confirmed, and widespread overseas), and stages 4-6 (first case in a human in North America, spread throughout the United States, and recovery and preparation for subsequent waves).The U.S. government stages provided greater specificity for U.S. preparedness and response efforts than the WHO phases and facilitated initial planning efforts by identifying objectives, actions, policy decisions, and message considerations for each stage.The stages provided a general overview of the approach to a pandemic response; however, detailed pandemic response planning requires a greater level of specificity to determine federal, state, and local response actions during the course of a pandemic.In addition, the stages framework presumed geographic spread from outside the United States into the United States.In 2007, CDC developed the CDC intervals, a common framework from which CDC and other federal, state, and local governments and agencies could plan and coordinate their pandemic response actions.The 2007 CDC intervals refined the stages framework in the following ways: - Provided greater detail to reflect the progression of a pandemic, including when decisions and actions might occur - Provided improved definitions to identify the transition points between intervals to reduce variability in interpretation - Considered that pandemic influenza might emerge inside or outside of the United States - Accommodated the likely asynchrony of pandemic stages and progression in different jurisdictions to allow for local, state, regional, and national actions appropriate to jurisdiction-specific conditions - Provided a structure that allowed for planning for multiple waves The resulting document (Proposal for the Use of Intervals, Triggers, and Actions in CDC Pandemic Influenza Planning, 2008) was revised, published as an appendix to the U.S. Department of Health and Human Services pandemic influenza operational plan (11), and used during the 2009 H1N1 pandemic to describe progression of the pandemic and to help guide the response.This report provides an update to the 2008 framework to reflect experiences with 2009 H1N1 and recent responses to localized outbreaks of novel influenza A viruses. The revised framework also incorporates the recently developed Influenza Risk Assessment Tool (IRAT) (12) and Pandemic Severity Assessment Framework (PSAF) (13).IRAT makes an assessment of potential pandemic risk for a novel virus on the basis of the likelihood of emergence and the public health impact if it were to emerge.Emergence refers to the risk of a novel (i.e., new in humans) influenza virus acquiring the ability to spread easily and efficiently in humans.Public health impact refers to the potential severity of human disease caused by the virus (e.g., deaths and hospitalizations), as well as the impact on society (e.g., missed workdays, strain on hospital capacity and resources, and interruption of basic public services) if a novel influenza virus were to begin spreading efficiently and sustainably among humans (12).After a novel virus has achieved efficient and sustained transmission, PSAF can be used to characterize the potential impact of a pandemic relative to previous influenza epidemic and pandemic experiences.PSAF replaces the Pandemic Severity Index as a severity assessment tool (13). In 2013, WHO released interim guidance for pandemic influenza risk management, which includes restructured WHO phases (14).The revised WHO phases are based on virologic, epidemiologic, and clinical data.WHO uses the phases to describe evolving situations pertaining to the circulation of novel influenza viruses.The WHO phases are distinct from declarations of either a public health emergency of international concern (15) or a pandemic and are not specifically aligned with national risk management decisions.In the interim guidance, WHO strongly advises countries to use local circumstances and information provided by the WHO global assessments to develop their own national risk assessments (13). The framework described in this report is a revision of the 2008 CDC interim guidance (11) to 1) update the novel influenza virus pandemic intervals as the basis for U.S. planning efforts; 2) align the intervals with the new WHO phases; 3) add and align tools to aid in decision-making and actions throughout the progression of an event; 4) serve as recommendations for U.S. risk assessment, decision-making, and action as advised by WHO; and 5) replace the U.S. government stages with six intervals for pandemic influenza planning.This framework is designed for decision-making by federal, state, and local health authorities and is not meant to be prescriptive or comprehensive. The # Novel Influenza A Virus Pandemic Intervals The novel influenza A virus pandemic intervals are based on what is known about past influenza transmission and on experience from recent events (e.g., 2009 H1N1 pandemic, H3N2v in the United States, H7N9 in China, and continuing sporadic human cases of H5N1).Typically, epidemic curves are used to monitor an outbreak as it is occurring, describe the outbreak retrospectively, and document the timing of interventions relative to the acceleration and deceleration of the outbreak.Modeled epidemic or pandemic curves also can be used to describe potential events over time.Using these models for forecasting purposes might be particularly valuable for anticipating conditions and identifying actions that might flatten or otherwise attenuate the epidemic or pandemic curve. For the purposes of responding to novel influenza viruses and potential pandemics, the six intervals (investigation, recognition, initiation, acceleration, deceleration, and preparation) represent events that occur along a hypothetical pandemic curve (Figure).Pandemic curves differ by duration and intensity depending on many factors, including the geographic area in which they occur, the season of their emergence, and related population dynamics.The WHO pandemic influenza phases, which can be used to describe and communicate worldwide disease progression, provide a general view of the emerging epidemiologic situation essentially by aggregating epidemic curves from around the world.The CDC intervals serve as additional points of reference to provide a common orientation and clearer epidemiologic picture of what is taking place and when to intervene.The intervals are flexible enough to accommodate the likely asynchrony of pandemic progression in different areas to allow for local, state, and federal actions appropriate to jurisdiction-specific conditions (e.g., a jurisdiction with cases versus a jurisdiction with no cases but that is close to an area with cases).State and local health authorities might even elect to implement interventions asynchronously within their jurisdictions by focusing early efforts on communities that are first affected.The state/local initiation, acceleration, deceleration, and preparation indicators can be asynchronous to the federal indicators (Appendix). For state and local planning, the intervals describe the progression of the pandemic within communities and provide a detailed framework for defining when to respond with various actions and interventions at any point in a pandemic.These actions should be proportionate to the transmissibility and severity of the emerging virus.The intervals are further stratified into eight domains so that the trajectory of planning and response activities for any one domain can be more easily followed.The eight domains are incident management, surveillance and epidemiology, laboratory, community mitigation, medical care and countermeasures, vaccine, risk communications, and state/local coordination.The intervals also might be valuable as a common reference point because they can be used to link the status of a pandemic with specific interventions. U.S. experiences during recent novel influenza events were useful for testing the concepts in the proposed intervals and the decisions and actions that were implemented during those intervals.The public health impact of novel influenza virus strains can differ substantially, both in geographic spread and mortality.For example, the 2009 H1N1 outbreak was caused by a highly transmissible novel influenza virus that emerged in North America and resulted in a pandemic (2), whereas the H3N2v virus, which also emerged in North America, caused approximately 300 cases in humans and limited outbreaks involving domestic animal-to-human transmission (3).The H7N9 outbreak was caused by a novel influenza virus that emerged outside of U.S. borders and had high mortality but has not spread to other countries thus far (5).These experiences have provided opportunities to test the validity and usefulness of the intervals and the recommendations for public health actions triggered by each interval to ensure that they are applicable in a diverse range of scenarios. # Pandemic Interval Definitions To define the intervals, the relationship between the timing of the broad WHO phases and the more detailed planning intervals was examined (Figure).In addition to the relationship to the WHO phases, the intervals are characterized by specific transmission-related indicators (Table ) and by the types of response activities that should occur within each interval (Appendix). Progression through the intervals is not exclusively linear.For example, identification of a novel influenza A virus does not necessitate progression to the next interval (the recognition interval) if the virus does not demonstrate the potential for ongoing transmission.Similarly, after the preparation interval, subsequent waves of outbreaks will prompt federal, state, and local public health officials to reenter the acceleration, deceleration, and preparation intervals.The duration of each pandemic interval might vary from weeks to months depending on the characteristics of the virus and the public health response. # Investigation Interval: Investigation of Novel Influenza Cases The investigation interval is initiated by the identification and investigation of a novel influenza A infection in humans or animals anywhere in the world that is judged by subjectmatter experts to have potential implications for human health (Appendix ).Public health actions focus on targeted surveillance and epidemiologic investigations to identify human infections and assess the potential for the virus to cause severe disease in humans, including person-to-person transmission, co-investigations of animal outbreaks with animal health representatives, and consideration of case-based control measures (i.e., antiviral treatment and antiviral postexposure prophylaxis of contacts for infected humans and isolation of humans and animals who are infected).After recognition of a case of novel influenza infection in a human, as occurred with the H7N9 and H3N2v viruses, animal investigations subsequently identified circulation of influenza viruses in birds and swine, respectively, and identified the reservoir of these previously unrecognized novel influenza viruses.CDC conducts an IRAT assessment during the investigation interval to characterize the potential for emergence, and if the virus does emerge, the severity of human infection (12).Generally, identification of human cases of novel influenza A infection are reported to WHO in accordance with the International Health Regulations (15). # Recognition Interval: Recognition of Increased Potential for Ongoing Transmission The recognition interval is initiated when increasing numbers of human cases or clusters of novel influenza A infection are identified anywhere in the world, and the virus characteristics indicate an increased potential for ongoing human-to-human transmission (Appendix ).Public health actions concentrate on control of the outbreak, with a focus on potential use of case-based control measures, including treatment and isolation of ill persons and voluntary quarantine of contacts. # FIGURE.Preparedness and response framework for novel influenza A virus pandemics: CDC intervals # Initiation Interval: Initiation of the Pandemic Wave The initiation interval begins when human cases of a pandemic influenza virus infection are confirmed anywhere in the world with demonstrated efficient and sustained humanto-human transmission (Appendix ).The definition of efficient and sustained transmission is established during an event based on the epidemiologic characteristics of the emerging virus.For example, efficient transmission could be defined as a household or an institutional attack rate of ≥20% in more than two communities, and sustained could be defined as transmission of virus for three or more generations in more than one cluster.Continued implementation of case-based control measures and routine personal protective measures (e.g., hand hygiene) is essential, as is enhanced surveillance for detecting additional cases of the novel virus to determine when community mitigation measures will be implemented.If possible, PSAF results (13) should be used to ensure that actions are proportional to the severity of the disease caused by the virus. # Acceleration Interval: Acceleration of the Pandemic Wave The acceleration interval is indicated by a consistently increasing rate of pandemic influenza cases identified in the United States, indicating established transmission (Appendix [ # Preparation Interval: Preparation for a Subsequent Pandemic Wave The preparation interval is characterized by low pandemic influenza activity, although outbreaks might continue to occur in certain jurisdictions (Appendix ).Primary actions focus on discontinuing community mitigation measures; facilitating the recovery of the public health, health-care, and community infrastructure; resuming enhanced surveillance protocols to detect subsequent waves; evaluating the response to the initial wave; and preparing for potential additional waves of infection.Because this interval can last from weeks to months, planning and preparation for a subsequent pandemic wave should reflect this variability.A pandemic is declared ended when evidence indicates that influenza, worldwide, is transitioning to seasonal patterns of transmission (8).Like the 2009 H1N1 strain, pandemic strains might circulate for years after the pandemic, gradually taking on the behavior and transmission patterns of seasonal influenza viruses.

# Assessing Risks to Enhance Decision-Making In addition to describing the progression of a pandemic, certain assessments, interpretations, and findings (i.e., indicators) are used to define the transition points between the intervals (Table ).Within each interval, certain actions can be determined for state, local, and federal governments.Each indicator also initiates a set of important decisions that affect actions in the current and subsequent intervals.These decisions can range from formal generation and analysis of options to more informal but equally important discussions among subject-matter experts, pandemic response leaders, and various stakeholders (Appendix). Decisions about appropriate actions require information regarding the real or potential impact of the novel virus on public health.Within any interval, decisions about which actions should be considered should take into account numerous factors, such as virus transmission parameters, severity of disease among different age and risk groups, availability and effectiveness of control measures and treatment options (e.g., community interventions, antivirals, and vaccines), and impact on health care, schools, businesses, and the community. Although data needed to make decisions might be limited during the earliest intervals, delaying action might weaken the effectiveness of the response.Therefore, estimating the likelihood of risks, particularly the risks of transmissibility, severity, and antiviral resistance, is critical (12,13,22).In addition, certain actions, such as the decision to produce a pandemic vaccine, require extensive preparation or time to implement, mandating that decision-making be initiated and completed as early as possible before the intervals when those actions need to occur and usually long before adequate data are available to support the need for those actions with certainty. CDC developed two risk assessment tools for the decisionmaking framework, IRAT (12) and PSAF (13).Both are designed to be used during the initial intervals when data are limited, to allow for iterative updates as new information becomes available and to accommodate various potential scenarios.Once completed, results of both tools are communicated to federal, state, and local decision-makers to guide public health actions (Appendix). # Influenza Risk Assessment Tool When a novel influenza A virus is identified in humans but is not circulating widely in the human population, it is important to evaluate 1) the risk that the virus will develop efficient and sustained human-to-human transmission and 2) the risk that the virus will substantially affect public health.IRAT was developed to facilitate such an assessment (12).Therefore, the indicator for the investigation interval, which is a newly identified influenza A virus in animals or identification of a novel influenza A virus recovered from humans, can serve as an initial trigger to conduct IRAT scoring. IRAT is used by the U.S. government and the WHO Global Influenza Surveillance and Response System as a risk assessment process that involves data gathering, discussion, and consensus building among subject-matter experts to assign a risk score.Ten predefined risk elements are given a risk score.These 10 elements fall into three categories: 1) attributes that pertain to the biologic properties of the virus (four elements), 2) attributes of the population (three elements), and 3) attributes of the ecology and epidemiology of the virus (three elements) (12).A team of experts assigned to each particular element provides a risk score for the virus for that element.A weight is then applied to the element scores for each of the two risk questions (i.e., emergence and impact).The results of this process can be used to decide whether and how to act and communicate concerns regarding both emergence and potential public health impact.As new information becomes available, the scoring can be repeated.This process has been used to assess recently emerging viruses such as H3N2v and H7N9 for vaccine development, manufacturing, and stockpile decisions.After a novel virus has achieved efficient and sustained transmission, PSAF can then be used to characterize the potential impact of a pandemic relative to previous influenza epidemic and pandemic experiences. # Pandemic Severity Assessment Framework Once a novel influenza virus has emerged and is circulating in human populations, the risk posed by the pandemic can be assessed.In 2007, as part of the interim guidance for community mitigation strategies, the Pandemic Severity Index was introduced as a tool to define the severity of a future influenza pandemic.To facilitate risk communication, the index had five categories similar to the hurricane severity scale, ranging in severity from category 1 (moderate severity) to category 5 (most severe) and was based on a hypothetical 30% attack rate and ranges of case-fatality ratios associated with a particular novel influenza virus (16).Experiences from the 2009 H1N1 pandemic identified that early data on the less severe but highly transmissible characteristics of the virus in the community were limited.Consequently, the Pandemic Severity Index, which based severity solely on mortality, tended to overestimate severity because more severe cases are likely to be reported at the initiation of a pandemic.Building on those lessons, PSAF was developed to characterize the potential impact of a pandemic relative to previous influenza epidemic and pandemic experiences (13).PSAF can be used early in a pandemic and assessments can be repeated as information changes.Although IRAT focuses on risk of emergence and potential for impact if emergence occurs, PSAF focuses on epidemiologic parameters of transmissibility and severity after a virus has emerged with efficient and sustained transmission and requires a sufficient number of cases and clusters in humans to allow for the assessment to be completed.Depending on the number of cases, size of clusters, and the geographic location of outbreaks, the trigger for using PSAF might be as early in the pandemic as the recognition interval but is more likely to be triggered during the initiation interval and regularly updated as the pandemic progresses. PSAF is based on transmissibility and clinical severity parameters and uses different scales for initial assessments in an emerging pandemic, and for later, more refined assessments.The initial assessment, performed early in the outbreak when epidemiologic data are limited, uses a dichotomous scale of low-moderate versus moderate-high transmissibility and severity.The later assessment, performed when more reliable data are available, is more refined, using a 5-point scale for transmissibility and a 7-point scale for clinical severity.After available data are assessed on these scales, the overall results are plotted with the measures of transmissibility along a y-axis and the measures of severity along an x-axis and compared with referent points such as previous pandemics or particularly severe influenza seasons (13).In the very early stages of an emerging pandemic, public health officials reiterate the importance of early treatment of ill persons as well as community mitigation measures to slow the spread of influenza, including voluntary isolation (i.e., ill persons staying home when sick), respiratory etiquette, hand hygiene, and guidance on treatment with antivirals.The results of PSAF assessments help national, state, and local decision-makers determine whether to implement additional community mitigation measures, including those that can be very disruptive and might have a more serious economic and societal impact on individual persons and communities (e.g., school dismissals or quarantine of contacts). # Using the Intervals, Influenza Risk Assessment Tool, and Pandemic Severity Assessment Framework The use of transmission-defined intervals and tools such as IRAT and PSAF to assess risks and potential impact provides information that can guide decision-making and actions across different jurisdictions and levels of government and help inform appropriate risk communication strategies.A list of some of the key decisions and options for action that are triggered by progression through each interval are described (Appendix).Planning and response efforts for recent novel influenza A viruses and pandemics have been organized into eight domains to ensure that subject-matter expertise is properly applied to all aspects of the event.The decisions and actions are further stratified into these domains so that the trajectory of planning and response activities for any one domain can be more easily followed.The eight domains are incident management, surveillance and epidemiology, laboratory, community mitigation, medical care and countermeasures, vaccine, risk communications, and state/local coordination.The tables are not meant to be prescriptive or comprehensive but rather to identify numerous priority issues that need to be addressed during each interval.The circumstances of each situation dictate the timing of decisions and actions. # Discussion The updated influenza pandemic framework provides six intervals and indicators for public health decision-making and actions during the progression of a novel influenza A virus from emergence through pandemic.The intervals are based on events that occur along a hypothetical epidemic curve.Although the actual shape of a future epidemic curve cannot be accurately predicted and might be modified by interventions, the use of an idealized curve permits generally applicable intervals to be defined.The concept of describing intervals of a pandemic can be applied to a single outbreak occurring in an individual state or a community, or information from multiple outbreaks can be aggregated to describe the situation at the national level. Because the resources and demographics among different regions and states in the United States vary widely, defining detailed indicators that address every potential situation is impossible.Certain indicators might not be scalable to all levels of government, and others do not have corresponding actions from every participant group.However, the proposed intervals, triggers for decision-making, and actions are meant to be flexible enough to allow for the implementation of local, state, and federal actions appropriate to jurisdiction-specific conditions. This framework is designed to assist with decision-making but does not diminish or replace the role of scientific expertise, particularly as a novel influenza outbreak unfolds.An effective pandemic response is based on numerous assumptions and actions that must be continuously reassessed with accumulated data as the pandemic progresses.The content of this framework is intended to support and organize planning and response efforts at the federal, state, and local levels.The use of common concepts is critical for tracking the course of the pandemic, for communication, and for implementing timely, coordinated response efforts.The following tables provide a list of some key decisions and potential actions to consider in response to the spread of a novel influenza virus capable of causing a worldwide pandemic.Specific decisions and actions might be triggered as each jurisdiction moves from one interval to another.For many interventions and activities, federal, state, and local preparedness and response actions begun during one interval should be continued and enhanced during subsequent intervals.Because predicting how a particular virus will spread is exceedingly difficult, the examples that follow might need to be scaled back or otherwise modified so that responses are proportionate to the threat.The following tables are not meant to be prescriptive or comprehensive but rather to provide examples of priority issues that should be addressed during each interval. # Influenza Pandemic Framework Workgroup Lyn Planning for many of the actions suggested in the tables that follow should be part of ongoing pandemic preparedness programs at the federal, state, and local levels.This document assumes that previous pandemic planning has occurred in each jurisdiction; these plans should be reviewed, updated, and adapted to fit the characteristics of the emerging threat.Pandemic planning is based on numerous assumptions and actions that should be continuously reassessed as the pandemic progresses.The circumstances of each situation dictate the timing of decisions and actions. See table footnotes on page 12. # TABLE 1.Novel influenza A virus pandemic (investigation interval): investigation of novel influenza A infection in humans or animals # Domain # State/Local Federal Incident management - Review state/local response plans. - Coordinate activities and response plans with state animal health officials, as appropriate. -Review and exercise all aspects of influenza response. - CDC and the World Health Organization (WHO) convene international experts to implement the Influenza Risk Assessment Tool- to assess the risk for emergence of the novel virus, as well as the potential impact of the virus. # Community mitigation - Emphasize the importance of personal protective measures (e.g., voluntary isolation by staying home when ill, respiratory etiquette, and hand hygiene) in limiting spread of influenza. -If human-to-human transmission is suspected, consider recommending isolation of ill persons and voluntary quarantine of close contacts (e.g., household members). -Enhance all usual influenza pandemic preparedness activities with schools and businesses. - Promote community mitigation preparedness activities, especially voluntary home isolation of ill persons, respiratory etiquette, hand hygiene, and infection control. -Review all guidance documents and update as needed for the situation (e.g., recommendations on community mitigation measures and other nonpharmaceutical interventions designed to slow the spread of the virus in the community or within certain populations and settings at high risk for infection). -Provide guidance for border health and travelers' health activities as appropriate for the situation. -Evaluate the need to implement border controls, travel advisories, or both; conduct travel volume and pattern analyses. # Investigation Interval (Table 1) State/Local indicator: Identification of novel influenza A infection in humans or animals in the United States with potential implications for human health.Federal indicator: Identification of novel influenza A infection in humans or animals anywhere in the world with potential implications for human health. -Review all guidance documents and update as needed for the situation (e.g., comprehensive medical care and countermeasure guidance for policy makers, clinicians, health-care organizations, employers, and public health); disseminate guidance for diagnosis and treatment of ill persons and infection-control measures to states and professional organizations. -Consider which immediate steps are needed to establish medical countermeasure stockpiles (e.g., antivirals, respiratory protective devices, ventilators, and Emergency Use Authorizations). # Vaccine - Evaluate all usual influenza pandemic preparedness activities, including a review and update of vaccine distribution and administration plans, process for rapid contract negotiation and staffing, mechanisms to identify and provide vaccine and document vaccination for critical infrastructure personnel and other possible priority groups for vaccination, and plans and staffing for mass vaccination clinics and points of dispensing. -Review all guidance documents, update as needed for the situation, and communicate to key stakeholders. # Recognition Interval (Table 2) State/Local indicator: Increasing number of human cases or clusters of novel influenza A infection in the United States with virus characteristics indicating increased potential for ongoing human-to-human transmission.Federal indicator: Increasing number of human cases or clusters of novel influenza A infection anywhere in the world with virus characteristics indicating increased potential for ongoing human-to-human transmission. Unaffected states should continue preparation efforts.

The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms.A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research.The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact.Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation.To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.# The accelerated discovery of genes for common diseases fuels expectations that genomic information will become an integral component of personalized health care and disease prevention.1,2 Several companies now offer personal genomics (PG) tests directly to consumers (DTC).For our purposes, we define PG tests as those that provide comprehensive genetic risk profiles for many diseases or targeted genetic risk profiles for specific conditions (e.g., breast cancer).Such tests can include single or multiple genes, linked or causative single nucleotide polymorphisms, functional assays, and full gene or genome sequencing.PG tests can be requested by a physician or provided DTC.3 DTC marketing of PG tests can bypass the need for clinicians to order and/or interpret genetic tests, although companies differ in the extent to which they offer genetic counseling, and some states mandate provider involvement.Some scientists have voiced concerns regarding the current scientific foundation for the clinical validity (CV) and clinical utility (CU) of PG tests and the potential impact on our health care system.4 PG tests may lead to a medical testing "cascade effect" with unwarranted diagnostic, pharmacologic, and surgical interventions.5 The cascade effect has been well described for various radiology procedures (such as total body computed tomographic scans).There are also public health concerns regarding costs and possible patient harms if such cascade effects lead to unfounded preferences for pharmaceuticals or reduced motivations to pursue healthy lifestyles (see also discussion of personal utility later).Conversely, others have argued that PG tests can empower consumers and their providers in health promotion, as well as early disease detection and management, making the health care system more proactive.6 The emergence of PG tests coincides with increasing access and demand for health information.7 The arguments both for and against the use of PG must be informed by appropriate scientific research on benefits and risks.8 # The workshop To discuss the scientific foundation for using PG tests in risk assessment and disease prevention, a multidisciplinary workshop was convened by several Institutes of the National Institutes of Health and the Centers for Disease Control and Prevention.The workshop sought to enhance dialogue among various stakeholders, identify gaps in knowledge, and suggest research areas.Multiple viewpoints and disciplines were represented, including industry, consumer, clinical, epidemiology, genetics, communication, social, and behavioral sciences.The following questions were discussed using case studies. (1) Is there evidence of public and provider interest in PG testing? (2) What evidence is needed to determine whether genetic information from PG tests adds to existing risk algorithms in predicting health outcomes? (3) What evidence is needed to determine whether PG tests can improve clinical outcomes? (4) What type of research is needed to determine CV and CU of PG tests?Details of the workshop can be accessed online.9 Not included in this report are the workshop discussions of government oversight, policy, and regulation of DTC genetic tests.These issues are also being considered by various advisory groups such as the Institute of Medicine and the Department of Health and Human Services' Secretary's Advisory Committee on Genetics, Health, and Society.In particular, Secretary's Advisory Committee on Genetics, Health, and Society published recommendations for oversight of genetic tests in 2008.10 # A framework for scientific evaluation of personal genomics The potential utility of PG tests for risk assessment and health improvement can be viewed by stages of disease natural history and points of intervention (Table 1) 11 .For primary prevention, genetic information may inform decision making for minimizing risk exposures, improving health behaviors and lifestyle factors, or providing prophylactic surgery, chemoprevention, or other customized interventions.Genetic information also can be useful in early disease detection (secondary prevention), in targeting treatments (tertiary prevention), and improving survival and psychosocial outcomes (quaternary prevention).Key assumptions for the scientific foundation for PG are that risk assessment should be followed by effective and safe interventions that can reduce morbidity, improve health, or other measurable utility endpoints; and that genetic information based on the combination of variants across the genome should be evaluated like other biological markers for screening or risk assessment.Finally, these assumptions must also be put in the context of well-known principles of population screening, especially as applied to genetic risk factors for asymptomatic individuals.These principles include public health importance, knowledge of the natural history of the disorder, availability of effective interventions, and full considerations of the ethical, legal, and social and policy issues surrounding these technologies.12 Multidisciplinary translation research is needed to connect gene discovery to improved health outcomes via four overlapping phases of research, denoted T1 to T4.13 T1 research entails the development of candidate genetic tests based on discovery, replication, and clinical and epidemiologic characterization.T2 research involves the evaluation of these tests for validity and utility and the development of evidence-based recommendations for their use.T3 research involves evaluating best approaches for diffusion, dissemination, and implementation of tests into practice.T4 research entails assessing the population impact including effectiveness and economic value of these tests in real-world settings. The evaluation of genetic tests across the four translation research phases has been described using the ACCE framework (analytic validity, CV, CU, and ethical, legal, and social implications).14 This framework was formalized by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group, 15 an independent panel that reviews available data on validity and utility of genomic applications and produces evidence-based recommendations. The EGAPP working group adapted the methods of the US Preventive Services Task Force (USPSTF) for genomic applications.The USPSTF is a long-standing independent panel that has developed numerous evidence-based recommendations relevant to clinical preventive services.20 The EGAPP working group developed methods for assessing genetic tests for different applications (diagnostic, screening, risk assessment, prognostic, and pharmacogenomics) for both genetic disorders and common diseases.The group is currently reviewing two topics related to PG tests (Type 2 diabetes and coronary heart disease).21 As discussed later, issues of CV and CU are qualitatively and quantitatively different for PG tests designed for risk assessment compared with diagnostic tests for genetic disorders with high penetrance. The workshop focused on CV and CU.Participants only briefly covered analytic validity because current genomic assays have high sensitivity and specificity for measured genetic variants.However, participants agreed that oversight is still needed to ensure laboratory quality of tests and the testing process.10 The evaluation of CV and CU is an ongoing and iterative process that occurs throughout the translation continuum, including evaluating early efficacy and effectiveness in real-world settings.As discussed recently by Wideroff et al.,22 research on dissemination, diffusion, effectiveness, and impact should be considered as part of a robust health services research agenda for genomic technologies. # Establishing clinical validity in personal genomics The CV of a genetic variant is defined by its relationship with a phenotype or a health outcome, singly or in combination with other variants and environmental factors.Two steps are needed in evaluating CV: (1) establishing credible genetic associations and (2) assessing genetic disease associations in relation to the predictive value, especially vis-à-vis existing risk factors. # Credibility of genetic associations: Replication and knowledge synthesis Variants identified by candidate gene studies and genome-wide association studies (GWAS) tend to be common (allele frequencies >5%) with small effect sizes (odds ratios <1.5).23 Many variants are not known to alter biological function and may be in linkage disequilibrium with unknown disease-related variants.24 Resequencing is beginning to identify rare potentially functional mutations that may underlie common variant disease associations. Currently, much of the heritability for common diseases is unexplained.23,24 However, we expect the current landscape to change rapidly as more variants are discovered and gene-gene and geneenvironment interactions are used to refine risk estimates.Population-based case-control and cohort studies are crucial for establishing credible risk estimates of genetic variants.28,29 In addition, the cumulative evidence for genetic associations should be rigorously evaluated by systematic reviews and meta-analyses that determine if differences exist across populations. Consensus guidelines for grading cumulative evidence on genetic associations use three criteria: amount of evidence, replication, and protection from bias.32 The amount of evidence can be defined by sample size, false discovery rate, or Bayesian credibility.32 Consistency of replication across different datasets and populations also must be considered (most published GWAS have built-in replication).Protection from bias can be difficult to determine.Typical biases include phenotype mis-classification, population stratification, and selective reporting. The cumulative assessment of genetic associations in available PG tests is still a moving target.For example, in a 2008 analysis of genetic associations included in PG tests, Janssens et al.33 found that of 56 genes tested, 24 (43%) had not been subjected to meta-analyses.For the remaining 260 meta-analyses, 60 (38%) were nominally statistically significant.The use of different single nucleotide polymorphisms to assess risk for the same disease has occasionally resulted in divergent results given to individuals. Currently, several companies offering PG tests use genetic risk factors that have been replicated in multiple studies and have worked together toward industry-wide standards. However, such standards are still work-inprogress and not uniformly accepted or applied. Access to credible and rapidly updated information on genetic associations is difficult to deliver and urgently needed.One such approach is the HuGE Navigator, an online, continuously updated database of citations on human genome epidemiology.41 As of June 25, 2009, the knowledge base contained 43,515 genetic association studies, 1046 meta-analyses, 368 GWAS, 5593 genes, and 2204 disease terms.The HuGE Navigator allows users to view disease-and gene-centered pages to navigate to online databases (e.g., University of California at Santa Cruz Genome Browser, 42 Gene Tests, 43 and PharmGKB 44 ). # Using genetic association in risk assessment and disease prediction Even if a genetic association is highly credible, how useful is the information for risk assessment and disease prediction?An important aspect of CV is the degree to which variants can distinguish between those who will develop an outcome from those who will not.Measures of sensitivity, specificity, positive predictive value, and negative predictive value are needed.45 Predictive values depend on the definition and prevalence of the outcome, characteristics of the tested population, penetrance, and genetic/allelic heterogeneity.Even for predominantly single gene conditions, such as hereditary breast cancer, heterogeneity can lower the positive predictive value and therefore the validity of genetic variants.46 Decision analyses for using absolute risk models to determine appropriate interventions may give more insight than standard statistical analyses.47 Three considerations affect the CV of a PG test: the degree to which predicted risks fits observed data (calibration); the ability of the test to separate those who are truly at risk from those who are not (discrimination); and change in risk assignment compared with no testing (reclassification).These considerations are prerequisites to evaluating CU (see later). Calibration assesses whether predicted risks from models that include genetic variants and other factors are correct.48,49 Calibration is especially important when models have untested or incorrect assumptions (e.g., independent, multiplicative effects; no interactions; and applying effect sizes obtained from various studies to the tested population). Discrimination assesses the overlap in risk distributions of people who will develop the disease and those who will not.For good discrimination, a broad distribution of risks is required.The area under the curve (AUC) is one measure of the discriminative ability of a test. It is generated by plotting all sensitivity-specificity combinations for all possible cut-off values of the predicted risks.Because of small effect sizes, most genetic variants included in the current genome profiles have low discriminative accuracy and contribute only marginally to AUC compared with existing risk factors. Many more genetic variants are needed to increase the discriminative ability and predictive value of PG.57,58 Reclassification refers to the proportion of persons who change risk categories when prediction models are updated to incorporate new genetic variants.If risk categories are defined according to cut points used to indicate type or intensity of interventions, reclassification can impact clinical management (see discussion of clinical utility later).However, if individuals do not change risk categories, as a result of adding genetic information, reclassification will not be clinically useful.One has to consider also the number of individuals who are in risk categories where reclassification would make a difference.Studies with few such individuals (e.g., where all persons have low risk, far from the cut-off where reclassification would influence decision making) may not be able to arrive at robust estimates of the extent and correctness of reclassification.Analyses of the AUC should be integrated with analyses of risk reclassification to maximize information on the use of new markers for risk prediction.59,60 The evidence on risk reclassification based on the genetic markers is rapidly growing.For example, the association of a variant on chromosome 9p21.3 (rs10757274) with cardiovascular disease has been extensively replicated but has been shown to be a significant risk classifier for future cardiovascular disease in some studies but not in others. # Establishing clinical utility in personal genomics CU is a measure of the net health benefits of PG tests (benefits minus harms).The cumulative assessment of CU and the level of certainty associated with the assessment depend on the clinical scenarios under consideration.65 CU evaluation should follow principles of comparative effectiveness research.66 The CU of PG tests may be evaluated for their ability to improve outcomes when either added to or substituting current approaches.For example, what kinds of nongenetic interventions could serve as adequate benchmarks for genomic information to be compared; and what study designs would be needed to assess the impact of PG tests on health care resources-e.g., resources for case management for those found to have increased risk?For any particular scenario, the balance of benefits and harms will depend on the factors such as the predictive value of genomic information, the availability and performance measures of other risk assessment tools, the acceptability, cost and efficacy of proven interventions to reduce risk, and possibly other factors such as potential stigmatization as well perceived personal value of the information.These issues are discussed in the population screening literature.12 Some suggest considering the "personal utility" of PG, in which genetic and other health information may be useful to individuals even in the absence of effective interventions.For example, in a series of publications from the Risk Evaluation and Education for Alzheimer disease study (the REVEAL Study), Green and coworkers have evaluated different methods for communicating genetic information to people at risk of Alzheimer Disease (AD).Even though there are no proven effective interventions to remediate risk, the results of these studies indicate that some people perceived this information to be useful by allowing them to prepare their families and arrange personal affairs including long-term care.Moreover, those who opted for testing did not generally experience adverse psychological effects from test results provided as part of a genetic counseling protocol, even when they learned they were at high risk for AD. In evaluating the role of personal utility, it will be crucial to develop appropriate metrics to consider the impact of different indices of individual perceived value of personalized genomics on health-related benefits, costs, and harms associated with testing and interventions, both to individuals and the society at large.72 Finally, the impact of personal utility on appropriate use of health care resources will have to be further explored. # Direct and indirect evidence of clinical utility: When do we need clinical trials? There is much to learn about how genetically guided risk reclassification can improve health outcomes.Well-calibrated models that can reclassify people into higher risk groups that require different interventions may provide indirect evidence of CU but these have been rarely available in the PG field.However, we must also consider how such reclassification, especially with small changes in risks due to small effect sizes affects the need to change interventions (e.g., cholesterol lowering drugs or screening for cancer detection), and how such changes can alter the balance of benefits and risks, as well as the economic implications of testing.There is also the possibility of frequent risk reclassification based on the additional genetic variants, as demonstrated in a prospective population-based study of Type 2 diabetes risk using 18 genetic variants in addition to age, sex, and body mass index (Janssens, personal communication, 2009).The utility of learning about risk updates must be considered and its impact assessed, particularly when lifestyle and nutrition recommendations and medical decisions can vary accordingly. An unresolved question is whether observational studies can provide sufficient CU information without randomized clinical trials (RCTs).Lord et al.73 argue that CV studies suffice to show CU if a new diagnostic test is safer or more specific than, but of similar sensitivity to, an old test.

However, if a new test is more sensitive than an old test, it can lead to the detection of additional cases of disease (often milder or earlier onset).Results from the treatment trials that enroll only patients detected by the old test may not apply to these extra cases.RCTs may be needed, unless we can be satisfied that the new test detects the same spectrum and subtype of disease as the old test and that intervention response is similar across the spectrum of disease. Hypotheses for CU often come from biological and clinical data suggesting that response to interventions (e.g., pharmacogenomics) may work differently for population groups.74,75 The question is whether this information will translate into net health benefits in practice.76 To assess the CU of genetic tests, the EGAPP working group has developed analytic frameworks similar to those developed by the USPSTF, with key questions to frame the evidence; clear definitions of clinical and other outcomes of interest; explicit search strategies; use of hierarchies to characterize data sources and study designs; quality assessment of individual studies, synthetic assessment of all available evidence, linkage of evidence to recommendations; and avoidance of conflicts of interest.15 For most genomic applications (and many other diagnostic tests), direct evidence about the effectiveness and value of testing is rarely available from RCTs.For recent evaluations, the group has constructed a chain of evidence linking the strength of the association between a genotype and disorder of interest (CV) to evidence that test results can change intervention decisions and improve net health benefits (CU).So far, the group has tackled genomic applications in symptomatic patients and their families rather than the asymptomatic population at large, the main target group for PG, although similar chains of causal reasoning and evidence synthesis can be applied.For example, based on the biological reasoning, CYP450 testing was proposed as a test for adults with nonpsychotic depression before treatment with selective serotonin reuptake inhibitors.The EGAPP Working Group reviewed evidence for validity and utility of testing and found that CYP450 genotypes were not consistently associated with clinical response to selective serotonin reuptake inhibitor treatment or adverse events, and that no clinical trials had been conducted to evaluate benefits and harms.Thus, CYP450 testing was not recommended for this clinical situation.16 Another example is genetic testing to inform anticoagulation therapy with warfarin.The CYP2C9 and VKORC1 genes are implicated in warfarin and vitamin K metabolism, and variants in these genes are consistently associated with warfarin bleeding complications.Without large, well-designed clinical trials, however, it is not known if genotyping to determine warfarin dosing could reduce adverse consequences of hemorrhage or thrombosis or could improve health outcomes such as reduced rates of hospitalization or mortality.77 Recently, the International Warfarin Pharmacogenetics Consortium developed an algorithm for estimating warfarin dose based on both clinical and genetic data from a broad population cohort study.78,79 In evaluating CU, economic issues also should be considered.For example, Eckman et al.80 concluded that warfarin-related genotyping is unlikely to be cost effective for typical patients with atrial fibrillation (marginal cost effectiveness exceeded $170 000 per quality-adjusted life year).However, testing for warfarin dosing may be cost effective in patients at high risk for hemorrhage.80 Economic models that include sensitivity analyses need to be revisited frequently given the declining prices of PG tests and the rapid rise in health care costs. RCTs can be used to develop direct evidence for CU of PG in relation to both behavioral and pharmacological interventions.RCTs could be used to identify subgroups of individuals based on the PG profiles where interventions are most effective and to apply intervention only in those subgroups.RCTs also could be used to identify subgroups of individuals based on the PG profiles with side effects, so that reduced dosages or alternative interventions can be used.Even if no differences in the effects of interventions exist by genotype, RCTs can be used to assess whether genotype-based interventions can be more effective overall if they improve adherence to available interventions that are designed for the general population. Examples of research questions amenable to RCTs are given in Table 2.RCTs have rarely been conducted to assess the CU of genetic information in changing behavior.Studies that have examined health behavior change have generally found that genetic risk information by itself is insufficient to promote complex behavior changes such as smoking cessation and alteration of dietary and exercise habits (see later).However, an emerging body of evidence suggests that genetic risk information may increase preferences for biological interventions over health behavior changes when both are viable options.81 For example, some studies have suggested that individuals presented with genetic risk information are more likely to affirm the importance of pharmaceutical treatments for conditions like heart disease and depression over lifestyle change or psychotherapy.In the REVEAL study, where no proven treatments are available to prevent AD participants learning that they were APOEe4 + were more likely than their APOEe4 − counterparts to report engagement in suspected but not proven AD risk reduction activities (e.g., vitamin E 71 ).The potential for both health benefits and harms of these activities needs to be evaluated. An example of an ongoing RCT is a primary care-based study to assess the CU of TCF7L2 testing for Type 2 diabetes in altering behavior and health measures in prediabetic patients (Ginsburg, personal communication).Secondary goals are to measure whether changes in perceived risk and beliefs about genetics are associated with behavior change after genetic testing and to determine whether a genetics-guided clinical trial would change primary care physicians' beliefs and understanding of genetics and their role in practice, especially vis-à-vis existing approaches to diabetes control that do not use genetic information. # The behavioral and social research dimensions of clinical utility Behavioral research conducted to date on the CU of genetic information has focused largely on the potential of genetic information to increase perceptions of vulnerability to adverse health outcomes.A considerable literature exists around genetic testing for rare hereditary cancers.85,86 Usually, persons considering genetic testing for rare genetic disorders want to know what tests are offered, what the results might mean for themselves and their families, what information they will have access to, where they can go for more information, and whether any of the information is actionable and whether action can lead to improved outcomes. In considering PG tests, the target group is mostly asymptomatic people in the population.87,88 With relatively high innumeracy levels, education and awareness are critical for decision making by providers and consumers.Traditionally, mass media approaches have been used to increase awareness of health issues.89 However, emerging technologies now offer new approaches to personalized communication.For example, health communication with tailored health messages sent to mobile phones can be useful in conveying information about alcoholrelated risks.90 In theory, educational approaches could be tailored not only to individual demographics, psychosocial beliefs, abilities, and preferences but also to genomic information.However, to date, rigorous evaluations of these technologies have been infrequent.Research is needed to develop effective and context-based approaches to communicate genetic information to promote comprehension of genetic information, informed decision making about testing and adopting healthy behaviors.Such research will need to incorporate best practices from the risk communication literature on how to emphasize actionable health messages from those that are inconclusive or potentially misleading.91,92 Early studies evaluating the use of single gene variants to convey personalized risks for lung cancer to cigarette smokers have shown no benefit for smoking cessation.93,94 McBride et al.8 are evaluating a prototypic "multiplex" genetic susceptibility test similar to those marketed DTC.The goal of this project is to evaluate the characteristics of individuals who are most interested in such testing and whether the information provided by PG can spur individuals to seek additional risk assessments (e.g., family history and behavioral risk assessments) and/or additional health services (e.g., well care visits).Although the multiplex study does not directly involve measurement of health outcomes, it will provide valuable information on social and psychological differences between those who opt to be tested versus those who decline testing, whether individuals who opt for such testing are able to accurately interpret their test results, whether interpretation of test results is associated with positive or negative emotions or changes in risk perception, and whether PG test results lead individuals to seek other personal health risk information.8 Another opportunity in this line of research is determining whether participants communicate such test results to their primary care providers and if so, how this information impacts service delivery in primary care.Some have expressed concern that an unintended consequence of the DTC model may be "raiding the medical commons," as consumers who are encouraged to "ask their doctor" may bring PG test information to providers who are unequipped to interpret the information, which consumes time and resources, may take away from preventive services of established value, and may result in ordering unwarranted procedures or interventions.5 As we consider the potential utility of PG, we must use a multidisciplinary approach that moves beyond the focus on the psychological effects of risk communication to understand the value of PG in behavioral change.Existing but limited public health interventions, such as promoting energy balance to prevent obesity, have not been completely effective at the population level.Clinical trials evaluating weight loss interventions consistently show high attrition rates because individuals have difficulty adhering to recommendations for energy balance.95 It is unclear, but crucial to learn, whether PG information could be used to tailor interventions that promote weight loss.96 PG information also may enable us to further deconstruct behavioral phenotypes to identify and measure pathways that influence health behaviors.In turn, this information could offer new behavioral targets for intervention. # Recommendations for establishing the scientific foundation for personal genomics Workshop participants made five broad recommendations to enhance the scientific foundation for using PG as a tool for improving health.Specific areas of discussion are also published online.9 Develop and implement scientific standards for personal genomics Several companies are collaborating in developing standards for PG tests.This work should be expanded to include transparent criteria for analytic standards, clinical standards on selection of genetic variants with high credibility, use of appropriate data to interpret reported allelic odds ratios in terms of overall risk compared with appropriate reference populations, and model calibration and evaluation of risk distributions for health conditions included in PG tests.The current statement from three companies represented at the workshop is available.40 In addition, standards for evaluating the CV and utility of PG tests need to be developed by independent panels (see fourth recommendation below). # Develop and implement a multidisciplinary research agenda Multiple scientific disciplines are needed to develop the PG field (Table 3).In addition to biological studies that can point to therapeutic and preventive interventions, epidemiologic studies are needed for risk characterization, especially of gene-gene and gene-environment interactions.Study cohorts must be quite large to have adequate statistical power.97 Clinical and population studies using communication, behavioral, and social sciences are needed across the translation continuum to assess the effectiveness of genetic information for consumers and providers.We need a robust health services research agenda that includes dissemination research to assess the uptake of evidence-based practice into routine care and outcomes research to improve the quality and effectiveness of health services.Also, we need public health surveillance and assessment of cost effectiveness and impact on health disparities.Current federal genomic initiatives in translation research should be enhanced.New models of translation research should be explored such as current collaborations among industry, academia, consumers, and government.104 # Enhance credible knowledge synthesis and dissemination of information to providers and consumers Timely cumulative knowledge synthesis, based on standardized formats and systematic, evidence-based processes, is needed to summarize and update information on genetic associations and to document their CV and CU.Such information needs to be translated in an accessible fashion and disseminated to consumers, providers, and policy makers to inform decision making.Given the rapid pace of discovery in the PG field, new mechanisms may be needed to provide rapid turnaround of evidence reviews, to keep all stakeholders current relative to the best available data.This will require enhanced public and provider education. # Link scientific research on validity and utility to evidence-based recommendations for use of personal genomic tests The evidence threshold for implementing personal genomic information into clinical practice and disease prevention must be considered by independent panels that have no conflict of interest and use rigorous systematic evaluations.The current dilemma is that setting the evidence bar fairly low allows diffusion of genomic discoveries in practice, before there is adequate information on CV and CU.Consequently, payers may not cover testing costs.Conversely, setting the evidence bar too high may result in tests with high validity and utility but with lower financial incentive for innovation by developers.Paradoxically, this could lead to fewer developed tests and potentially diminished health benefits from PG tests.105 Because PG tests potentially affect a large number of asymptomatic persons in the population, extra caution is needed to establish appropriate evidentiary thresholds.Such screening tests can expose large numbers of healthy people to potential harms from false-positive results (such as anxiety and "labeling," as well as additional invasive testing and treatment) or from falsenegative results (such as false reassurance and attendant lapses in personalized risk factor reduction efforts).As a result, independent groups formulating evidence-based clinical recommendations such as the USPSTF have required a high level of certainty that the benefits of screening outweigh the harms and therefore have set a high evidence bar for recommending preventive services.To achieve an appropriate linkage between evidence and practice, independent panels such as EGAPP and USPSTF should provide rapid and timely assessments to determine in a systematic and transparent fashion whether a PG test and its associated interventions does more good than harm in specific population groups or on a population-wide basis.In preventive services, the USPSTF has had a major role for more than three decades and has conducted formal analyses of hundreds of preventive interventions.The task force has generally set a high evidentiary bar for preventive tests used in asymptomatic populations.EGAPP has recently established methods and processes for genomic-related applications.The field of PG will greatly benefit from such independent evaluations. # Consider the value of personal utility Finally, as discussed earlier, we should continue to explore individuals' and population subgroups' notions of perceived personal utility of PG (e.g., advantages of learning about genomic risk) and to assess whether personal utility may impact measures of CU (e.g., via improved adherence to recommendations).However, these perceptions of utility will need to be considered in the context of broader societal costs.In order for personal utility to be scientifically supported, objective metrics must be developed and applied in rigorous multidisciplinary observational studies and RCTs.These metrics should include measurable benefits, harms, as well as costs of PG testing and interventions. In conclusion, to make the best use of PG for improved health outcomes, the CV and CU of these tests must be understood by consumers, providers, and policy makers.Scientific standards for evaluating these tests must be established and a mechanism put in place to provide authoritative, unbiased, timely reviews of new discoveries.Clinical, epidemiologic, communication, behavioral, social, and economic studies of PG must be rigorously pursued.Finally, these scientific standards have to be examined in the context of principles of population screening with full consideration of the ethical, legal and social, economic, and policy issues. Examples of research questions in personal genomics that can be addressed in randomized controlled trials a 1 Do health outcomes from medical or lifestyle interventions compared with a control group differ among genetic subgroups? 2 Do health outcomes from specific medications compared with the control medication or placebo differ among genetic subgroups? 3 What are the health outcomes from a specific intervention or treatment, in a specific high-risk genetic subgroup, compared with a control intervention or usual care? What is the efficacy of a genetically based treatment approach (e.g., adjusting drag dose based on genetic information) compared with a standard clinical approach? What health behavior changes and/or psychosocial outcomes result from differing approaches to risk communication? 6 Does providing patients with information about their genetic risk result in improved adherence to prescribed behaviors or medications? What are the best approaches for genetic risk communication and informed decision making in genetic testing? 8 Does provision of DTC PG testing influence health care service demand and delivery, especially in primary care? a Some of the questions can be addressed using existing RCTs.

The Occupational Safety and Health Act of 1970 (Public Law 91-596) states that the purpose of Congress expressed in the Act is "to assure so far as possible every working man and woman in the Nation safe and healthful working conditions and to preserve our human resources...by," among other things, "providing for research in the field of occupational safety and health...and by developing innovative methods, techniques, and approaches for dealing with occupational safety and health problems."Later in the Act, the National Institute for Occupational Safety and Health (NIOSH) is charged with carrying out this policy.One method by which NIOSH responds to this charge is to publish recommendations for control of occupational safety and health hazards.the Occupational Safety and Health Administration (OSHA) for cons Occupational Safety and Health Centers for Disease Control iii ACKNOWLEDGMENTS The contributions to this publication by NIOSH staff, other Federal agencies, the review consultants, the reviewers selected by the American Industrial Hygiene Association (AIHA) and the Society for Occupational and Environmental Health (SOEH), and consultants William C. Nicoll and Robert B. O'Connor, M.D. are gratefully acknowledged.The Division of Standards Development and Technology Transfer, National Institute for Occupational Safety and Health, had primary responsibility for the development of this publication.The initial development was performed by Paul A. Schulte and Charles H. Gorski.The publication was completed by Howard R. Ludwig.Contributors to this document and previous unpublished versions of it are listed below and on the following pages.The NIOSH review of this publication was provided by Robert W.# These publications critically review the scientific and technical information available on the prevalence of hazards, the existence of safety and health risks, and the adequacy of hazard control methods in an industry. The information and recommendations presented should facilitate development of specific procedures for hazard control in individual workplaces. In addition, these publications list the Federal standards applicable to the industry and the specific hazardous substances that are present in its work environment. In the Interest of wide dissemination of this information, NIOSH distributes these publications to other appropriate governmental agencies, organized labor, industry, and public interest groups. We welcome suggestions concerning the content, style, and distribution of these documents. This document provides guidance for protecting workers involved in the manufacture of paint and allied coating products. It was prepared by the staff of the # II.CHARACTERISTICS OF THE PAINT AND ALLIED COATING PRODUCTS The handling of raw materials and finished products; dispersion of pigment or resin particles; thinning, tinting, and shading; filling; and laboratory functions are some of the operations in the paint and allied coatings industry that will be discussed in this publication.The recommendations are broad-based to accommodate variations between facilities and the wide range of operations and processes encountered.Many of the recommendations, such as those addressing the use of personal protective equipment, machine guarding, container labeling, and worker training, are consistent with the Occupational Safety and Health Administration (OSHA) General Industry Standards contained in 29 CFR 1910.Other recommendations, such as those concerning substitution of raw materials, engineering controls, or safe lifting techniques are addressed only generally in OSHA standards or not at all. The recommendations are intended to enable management and labor to develop better work practices and training programs that will result in safer working environments. Chapter II provides a discussion of basic characteristics for those persons who are not familiar with this industry.The document in its entirety provides safety and health information for organized labor; managers, technical consultants, and occupational safety and health personnel of companies involved in this industry; and the field staffs of various governmental agencies (i.e., NIOSH, OSHA, and EPA) responsible for the safety and health of workers. # II.C H A R A C T E R I S T I C S O F T H E P A I N T A N D A L L I E D C O A T I N G P R O D U C T S I N D U S T R Y A. Overview Paint and allied coating products constitute a general class of materials whose primary functions are the protection and decoration of surfaces.Coatings are also used for fire retardation, color coding, electrical insulation, and temperature control , In the most narrow sense, "paint" refers only to pigmented products such as interior (wall), exterior (house), masonry, and traffic coatings; terms for other coatings include enamel, undercoater, primer, sealer, varnish, lacquer, stain, and industrial finishes.Historically, however, the term "paint" has sufficed as the common description for coating materials consisting of a covering material (pigment), a film-forming material (usually an oil or resin), and viscosity modifiers (thinners and solvents). The terms "organic surface coating," "paint and coating," or "chemical coating" are increasingly being used to describe a variety of products that are used for the protection or decoration of surfaces. Related to the various types of surface coatings are allied products such as putties and paint and varnish removers. The major types and end uses of paint and coating products are shown in Table II-l. The manufacture of most coatings basically involves the incorporation of pigment particles in a film-forming matrix, thinning and adjusting the resultant product, and dispensing it into containers of various sizes for shipment and sale. The manufacture of varnishes, which contain no pigments, is a different type of batch process which involves mixing ingredients and "cooking" them in a reactor vessel or kettle.Definitions of various terms used in the coatings industry are listed in the Glossary (Appendix A). # Thousands of different raw materials are used in the manufacture of approximately 20,000 different coating products . The need for so many raw materials and products results from the great diversity of surfaces requiring treatment.There are numerous small manufacturers because paint-making is still largely a batch process that does not readily lend itself to automation or continuous flow processing , Few firms sell nationwide because of high shipping costs, the difficulty of maintaining production schedules, and other distribution problems. # I. Industry Trends Growth in the total production of the U.S. paint and allied coating products industry has been about 2% annually since 1967 and is expected to continue at this rate through 1990 . In 1981, over 900 companies produced architectural coatings, approximately 250 companies made product coatings for original equipment manufacturers, and approximately 250 companies made special purpose coatings . The largest companies are active in all coatings categories; whereas, the smaller companies may specialize in only one segment of the industry . # Air pollution regulations limiting the amount of volatile organic compounds that can be used in coatings and the rapid rise in solvent prices are responsible for the trend in the coatings industry to replace conventional low-solids, volatile organic solvent-based coatings with high-solids (i.e., over 70%) or low solvent or water-based formulations such as radiation-curable coatings, powder coatings, two-part catalyzed systems, and nonaqueous dispersions [1,2,6 In addition to the air pollution emission potential of various coating systems, a factor in their selection is the amount of energy required for application and for engineering controls to reduce occupational exposure. Because of relatively high energy efficiencies, the use of high-solids and radiation-curable coatings is expected to increase , # E x t e n t of E x p o s u r e According to the 1978 Annual Survey of Manufacturers , the paint and allied coating products industry in the United States employed about 61,500 workers in 1,700 individual plants.About 60% of the paint facilities had fewer than 20 workers, and only about 3% of the facilities (i.e., about 50) had more than 250 workers .These coatings include paints, lacquers, and powders and are applied during the manufacturing process to the surfaces of products made from metal, wood, or plastic.About 60-65% of these coatings have been solvent-based, but in recent years applications for water-based, high-solids, powder coatings, and two-part catalyzed systems have been increasing , "Special purpose coatings" may be stock-type or shelf goods, but they are formulated specifically for refinishing and specialty applications or for environmental conditions such as extreme temperatures or corrosivechemical atmospheres . These coating types include high-performance industrial maintenance paints, automotive and machinery refinishes, and traffic paints and can be either solvent-or water-based , # J o b C l a s s i f i c a t i o n s A scheme for the classification and description of jobs in this industry has been developed by Discher et al. . # A revised version of this classification is presented in Table II-2. A similar description of job classifications in the varnish manufacturing process is shown in Table II-3.In many smaller plants, one worker might perform a number of different jobs rather than just one particular task. # Raw materials handlers Transport and store raw materials in the plant. # Prebatch assemblers Weigh and assemble raw materials (usually dry) for the mixer, primarily in the raw materials storage and mixing areas. # Mixers (including mill operators) Load mixing tanks or mills.Responsible for quality control checks for dispersion.May be responsible for cleaning the mills. # Tinters (including thinners, shaders, and body adjus ters) Responsible for the dispersed paint quality.Add solvents, driers, preservatives, and tinting paste. Responsible for quality control for color, viscosity, etc. # Fillers Fill paint containers. # Set up the filling line (if mechanized). # Tank and tub cleaners Clean portable tanks and tubs. # Laboratory personnel Test raw materials.Responsible for finished product testing and for research and development. # thers Includes packagers, maintenance personnel, shippers, and loading personnel in the warehouse. # Adapted from Discher et al. # Varnish cookers Cook varnish and maintain reaction conditions (applies only to open-kettle process). # Filter press opera tors Filter and reduce the varnish and clean the presses. # Fillers Fill varnish containers. # Laboratory personnel Test raw materials.Responsible for finished product testing and for research and development. # Others Includes packagers, maintenance personnel, shippers, and loading personnel in the warehouse. # Adapted from Discher et al. # B. Raw Materials Liquid paint is a suspension of pigment particles in a mixture of film-former and volatile solvent. The solvent, which reduces viscosity to allow easy application, and the film-former hold the pigment in the dried film and cause it to adhere to the coated surface. The pigment confers hiding and coloring power as well as durability to the dried film. Various additives are used to obtain particular characteristics. Although drying is usually accomplished through evaporation of the solvent, drying may also be by polymerization of the film-former through oxidation (e.g., with oils and alkyds), by coalescence (e.g., with latexes), or by chemical reactivity (e.g., with epoxy resins) . In 1980, an estimated 9.5 billion pounds of raw materials (excluding water) were used in the manufacture of paint and allied coating products , The four general categories of raw materials used (film-formers, pigments, solvents, and additives) are identified in Figure II-2. Linseed oil is the primary drying oil utilized as a film-former. # F I G U R E II-2.R A W M A T E R I A L S U S E D IN T H E M A N U F A C T U R E OF C O A T I N G Natural resin film-formers constituted less than 1% of all film-formers consumed in 1977 , in contrast to about 50% prior to World War II , Some of these natural resins include rosins and shellac. # Pigments Pigments are incorporated into coatings to impart color, opacity, and properties such as durability, corrosion inhibition, and mildew control or to be a filler or extender .They are finely powdered solids that are essentially insoluble in the medium in which they are dispersed.Almost all of the pigments utilized in the U.S. (99%) are inorganic with titanium dioxide accounting for about one-third of total pigments used .Pigments are generally classified as white (opaque) pigments, colored and black pigments, extenders (non-opaque), and miscellaneous (mainly metallic powders). They are less expensive than many other types of organic solvents and have many uses. An organic solvent-based coating material that contains no hydrocarbon solvent is unusual.Hydrocarbon solvents used in the paint industry are classified as either aliphatic naphthas or aromatics. Aliphatic naphtha solvents such as mineral spirits or Varnish Makers' and Painters' (VM&P) naphtha are predominantly paraffins, with a smaller but appreciable content of cycloparaffins (naphthenes such as cyclopentane and cyclohexane).These solvents may also contain as much as 20-30% aromatics , Mineral spirits constitute about three-fourths of all hydrocarbon solvents used in the paint and allied coating products industry overall. The aromatic hydrocarbon solvents such as toluene, xylene, high flash solvent naphthas, and aromatic naphthas predominantly exhibit higher solvency than aliphatic solvents. # b. Oxygenated Solvents Oxygenated solvents are so designated because of the presence of oxygen which contributes polarity (a difference in the electric charge on various portions of the materials). This polarity is the fundamental difference between oxygenated and hydrocarbon solvents, which are essentially nonpolar. Because # A d d i t i v e s Many substances that contribute to the ease of manufacture, the stability of the paint in the package, the ease of application, or the quality or appearance of the applied film are used in relatively small quantities in paint formulations. These # e. A n t i -s k i n n i n g A g e n t s Skinning refers to the drying of a coating, but at the wrong time and in the wrong place (e.g., while it is still packaged). Oxidative polymerization of the film-formers at the air-liquid interface can lead to the formation of a solid or gelatinous skin on the surface. reactions.Production is begun by mixing the pigment, film-former, and solvent (organic solvent or water).This is followed by the dispersion operation, which is a manipulation of the mixture to achieve pigment particle separation, wetting, and stabilization. The performance of the finished product depends on the maintenance of uniform interparticle distances in the dried film . A variety of equipment is used to effect dispersion. The trend currently is to use equipment in which the paint formulation can be continuously mixed and dispersed, followed by thinning in the same unit , After dispersion, the resultant material is tested for viscosity, color, and other physical properties while being adjusted or thinned. After passing this inspection, the batch is strained and loaded into containers. The manufacture of varnishes is one of the most complex processes in a coatings plant, primarily because of the large variety of different raw materials, products, and cooking formulae used , Varnishes are classified on the basis of the resins used. Oleoresinous varnishes are solutions of both oils and resins; whereas, spirit varnishes such as shellac are formed by dissolving a resin in a solvent. Varnish manufacture essentially consists of heating or cooking materials in a reactor vessel or kettle and then thinning and filtering the final product , 1.Paints a. Materials Handling Materials handling occurs primarily at both ends of the production process. Raw materials are available as liquids, solids, powders, pastes, and slurries. # b. Dispersion The assembly of raw materials is followed by the mixing of pigments with film-formers, solvents, and additives and the dispersion of the pigment particles in the liquid matrix. Dispersion consists of a deagglomeration or separation of aggregates of individual particles, the wetting of particles with solvent and film-former, and uniformly distributing particles in the liquid phase. Types of dispersion equipment include high-speed shaft-impeHer dispersers, dough mixers, and a variety of mills such as roller, stone, pebble, media, stator-rotor, attritor, Uniroll, resonant, vibratory, and Kady® . After the dispersion operation, it may be necessary to clean the mills and tanks before a new batch is introduced. Tank and mill cleaning can involve hand and power tools as well as caustic cleaners and solvents.c. T h i n n i n g , T i n t i n g , a n d S h a d i n g Thinning operations involve the further addition of a film-former or solvent to the batch following the mixing and dispersion operations.These operations may be performed in stationary tanks or in portable change cans.Tinting and shading operations involve adding color to white bases or adjusting the color of solid color bases that have been formulated as complete products. After these operations, the quality of the paint must be checked by sample collection and laboratory analysis. # d. Filling Operations and Finished Product Handling After the desired paint quality is achieved, the paint is strained or filtered to remove foreign material. Fabric or metal screen filters, vibrating or variable-speed centrifugal clarifiers, vibrating screens, and cartridge filters can be used. After filtering, the coating is either manually or machine-filled into cans that are subsequently sealed, labeled, packed, and stored or shipped. # Lacquers Lacquers differ from most other coatings in that the film dries or hardens entirely by evaporation.Therefore, it is impractical to manufacture lacquers in the customary manner because volatilization of the solvents results in deposits of a dry, solid film on processing equipment . Thus, production is carried out in enclosed equipment such as tanks or mixers to reduce solvent loss, ensure ease of cleanup, and provide fire safety. However, lacquer is produced in the same general manner as paint. # Varnishes All varnishes (i.e., oleoresinous and spirit) are solutions of film-formers in organic solvents.The manufacture of oleoresinous varnishes involves a cooking stage to render the oil and resin more compatible, to develop high molecular weight molecules or polymers, and to obtain solubility in the thinner or solvent.

The manufacture of spirit varnishes usually involves cold cutting the resin with the solvent; however, mild heat may be used occasionally , Varnish is cooked in portable kettles or in large reactors, although kettles are now used only to a limited extent and primarily by smaller manufacturers . Large closed reactors with capacities of 1,000 to 8,000 gallons are more common . # a. Operation of Kettles In facilities where portable kettles are still used, resin and oil or resin alone is added to the kettle and then heated to about 600°F (316°C). Natural resins must be heated prior to adding the oils to make the resin more compatible with the oils. All materials are poured in over the top of the kettle (150-375 gallon capacity).During the cooking phase, the kettles are covered with retractable hoods with exhaust pipes that may be fitted with solvent condensers.After the materials are cooked, the kettles are moved to rooms where the kettles are cooled quickly, often by water spray, and thinner and driers are added . # b. Operation of Reactor Vessels Varnish production is different when reactor vessels are used instead of kettles. Most reactors range in size from 500 to 8,000 gallons .Reactors are designed to give exact process control and usually can handle a variety of different varnishes, operate over a wide range of temperatures, and be cleaned easily. Varnish reactor vessels are similar to batch reactor equipment used in the chemical process industry. The vessels are fitted with agitators, manholes, sight-glasses, lines to charge liquid reactants, condensers, temperature measuring devices, sampling devices, discharge lines, and heat sources. # c. Filtering Filtration of the thinned resin is the final step before the varnish is packaged.This is normally done while the resin is still hot.The filter press is the most commonly used filtering device . # Powder Coatings Powder coatings are solventless systems based on the melting and subsequent fusion of resin and other additive particles onto surfaces of heated objects. Powder coatings, which may be either thermosetting or thermoplastic, are made from various types of resins such as epoxies, polyethylene, polyesters, polyvinyl chloride, and acrylics. # Three methods have been used to manufacture powder coatings: dry blending, extrusion melt-mixing, and a combination of the two.Dry blending of powder coating ingredients is usually accomplished by placing all components (powdered resin, pigments, additives, and powdered curing agents) into a cooled pebble mill with high density porcelain grinding media. The extrusion melt-mixing method involves premixing the dry components to ensure homogeneity and to reduce particle size. The mix is placed in a specially-designed extruder where it is heated until molten. The molten material is then deposited on a cooling belt, and when it has cooled to a friable state, it is transferred to a coarse granulator. The granulated material is then passed through a fine grinder and particle size classifier and packaged. Figure shows a typical layout for the manufacture of powder coatings by the extrusion melt-mixing method.A wider range of pigments is used with interior stains. # Radiation-Curable Coatings # Radiation The film-fortners for interior stains are usually very low-solids alkyd resin solutions. Generally, the manufacture of stain is similar to that of paint. # Allied Coating Products Many of the allied or sundry products of the coatings industry are manufactured in the same plants as paint, with few variations in the processes previously discussed in this section. # a. Putties The manufacture of putties involves the dispersion of calcium sulfate in oils and adjustment with small amounts of solvent in a dough-type mixer or in a mixer known as a putty chaser . The viscous putty is usually put into containers directly from the dispersion stage. # Laboratory Functions Analytical and developmental laboratory functions are integral to the manufacture of coatings. Four functional types of laboratories are found in coatings manufacture: analytical, quality control, formulation or product development, and research and development . Many companies combine the various laboratory functions in one space; whereas, others separate each function. Analytical laboratories receive samples of incoming raw materials to be tested for conformity with purchase specifications. Other analytical laboratory functions include the analysis of competing products and "bad batches" of paint. Quality control laboratories test the product before it is packaged for various physical characteristics such as weight per gallon, viscosity, color, and drying time. In the formulation or product development laboratory, existing products are refined. This differs from the research and development laboratory which is involved with basic research and the development of completely new classes of products. # III.HEALTH AND SAFETY HAZARDS DURING THE MANUFACTURE OF PAINT AND ALLIED COATING PRODUCTS # A. Injury and Illness Statistics The number and severity of injuries and illnesses in the Paints, Varnishes, Lacquers, Enamels, and Allied Coating Products Industry (SIC code 285) may be estimated from information reported by the Bureau of Labor Statistics (BLS), U.S. Department of Labor . Table III-l shows the average annual employment and injury and illness incidence rates (per 100 full-time workers) from 1980 through 1982 for total cases, lost workday cases, nonfatal cases without lost workdays, and lost workdays in SIC code 285. , 1980-1982 Average Incidence Rates per 100 Full-time Workers These data show an annual total of approximately 7,570 injuries and illnesses (employment times total case incidence rate divided by 100) in paint manufacturing facilities. Per 100 full-time workers, paint manufacturers had an average injury and illness incidence rate of 12.0 and an average lost workday incidence rate (severity rate) of 74.3, which are about the same as the average rates exhibited by "All Manufacturing" industries. # Also -f interest are data included in Table III-2, which address occupational injury and illness rates by employment size in the paint and allied coating products industry. The highest incidence rates occurred in facilities with 20-249 workers. The most prevalent sources of injuries and illnesses were boxes, barrels, containers, packages, etc. (33.3%), working surfaces (10.7%), and chemicals (9.0%). The most common types of accidents were overexertion (31.3%), struck by an object (15.4%), and struck against an object (9.6%).Sprains and strains (40.5%) were the most prevalent nature of injury, followed by contusions and bruises (15.2%), and cuts, lacerations, punctures, etc. (10.4%). The back (24.4%) and fingers (11.5%) were the parts of the body most frequently affected . In an attempt to better elucidate accident causal factors, 38 "sources of injury" (which included 81% of the total cases) were cross-tabula ted with the "type of accident," "nature of injury," and "part of body affected."These data are summarized in Table III-5. Another analysis of the SDS data is summarized in Table III-6 where 15 occupational groupings (which included 81% of the total cases) were similarly cross-indexed. Mention needs to be made of some of the data constraints of the SDS reporting system. Although there are about 300 subcategories of "sources of injury," and 425 occupational classification codes, in many instances the subgroupings are still not useful for the purpose of quantifying accidents specific to paint manufacturing. For instance, there might not be specific SDS categories for the inclusion of equipment typically used in the paint industry which would necessitate its being grouped into a broad category such as "Machines, Not Elsewhere Classified." Similarly, although there is an occupational classification for mixing operatives, individual facilities when filling out the workers' compensation form could have coded paint mixers in a number of other categories (e.g., miscellaneous operatives, machine operatives, not specified, etc.). A further difficulty encountered in the data base, when using it for analysis of accident causal factors, is that, by definition, the "source of injury" is the object identified as most responsible for causing the injury. This may, in fact, not be directly associated with the actual cause of the accident. For example, if a worker cuts his finger while using a knife, the "source of injury" is the knife, which also is the tool most clearly associated with the cause of the accident. However, if a worker falls from a ladder and fractures his leg on the floor, the "source of injury" is the floor, which probably contributed very little to the actual cause of the accident. However, once the constraints of the SDS data are recognized, the information included can be applied to further identify some of the hazards associated with occupations, tasks, tools, and equipment used in paint manufacturing. In Table III-5 the most frequent subcategories for each major heading are listed; all subcategories relate to the "source of injury" in the first column and are not expected to total with it. In Table III As would be expected, Table III-5 indicates that injuries related to materials handling (i.e., containers, handtrucks, dollies, skids, pallets, etc.)were most often caused by overexertion and by being struck by falling objects. Sprains, strains, contusions, bruises, cuts, and lacerations were the most common injuries; the back and fingers were the parts of the body most frequently affected. An interesting finding was that 60% of the injuries caused by chemicals (i.e., 615 of 1,027) were from skin contact (absorption); 47% of these injuries were chemical burns of the skin. Analysis of the SDS data by "occupation" yielded similar results.As Table III-6 indicates, various types of containers (i.e., barrels, boxes, crates, etc.)were the most common sources of injury (20-30%) in almost every occupational grouping. As before, overexertion and "struck by or against" type accidents were the most prevalent, with the most common injuries also being sprains, contusions, and cuts.Exposure to chemicals again accounted for a significant proportion of injuries in many of the occupational groups, usually resulting in chemical burns of the skin.Nonproduction workers (clerks, salesmen, managers, chemists, secretaries, etc.),who make up about 51% of the workforce in SIC code 285 , accounted for 13% of the cases in the SDS file . Conversely, production workers were involved in 87% of the injuries and illnesses in paint and allied coating products manufacturing although comprising only about 49% of the total workforce.Further analysis of the SDS data showed that workers under 26 years of age accounted for about one-third of the injuries and illnesses and that workers under 31 years of age accounted for over half (51.6%). Although only about one-third of the SDS cases had length of service data, 36.9% of those injuries occurred within the first year with the company, 5 0 .4 % within the first 2 years, and 69.9% within the first 5 years . The types and numbers of illnesses in the SDS data base are shown in Table III-7.Dermatitis was the most common illness noted (41.2%). The SDS data show that only 5.7% of the total number of injuries and illnesses were due to illnesses . However, occupational illness data from the SDS suffer from the same degree of identification as that experienced in the BLS annual survey of occupational injuries and illnesses. Recognition of occupational illness depends on the "state of the art."Nevertheless, despite the underestimate of the incidence of occupational illnesses, it is evident that reducing injuries should be a high priority of the paint and allied coating products industry.Workers in paint and allied coating products facilities may be exposed to a wide variety of hazardous conditions during the performance of their jobs.The majority of these hazards exist, to some extent, throughout industry, although certain characteristics in the paint industry may magnify the degree of risk. The hazards associated with the manufacture of paint and allied coating products involve materials handling; toxic, flammable, or explosive substances; and physical agents such as electrical shock, noise, heat, and cold. These hazards can be present at various stages of production. In this section, there will be a discussion of the hazards involved with the storage and handling of raw materials and finished products for the industry in general, followed by other hazards associated with specific types of paint and allied coating products manufacture.Inhalation is a primary route of exposure for materials handlers, but skin exposure and ingestion are also possible. Dry materials such as pigments and additives can become airborne when containers leak or are ruptured and when materials are transferred.Loading pigments into grinding equipment and discarding empty bags can cause the surrounding plant areas to become contaminated with dust.Solvents are volatile and their vapors can escape when transferred in the open or if containers develop minor leaks or are accidentally ruptured.Because of both toxicity and danger of fire, solvent spills present a serious hazard to workers. Many substances used in paint and allied coating products are highly volatile and flammable or are explosive. The fire and explosion risk is high wherever organic solvents are present. Combustible material can be ignited by a spark or by high temperatures. Sources Preventing the accumulation of static electricity in the handling of liquid raw materials requires special techniques and precautions.Static electricity may be produced when nonconducting liquids flow through pipes or hoses; when liquids fall through the air in droplets or as a spray; when liquids are splashed around in tanks --in the mixing, pouring, pumping, filtering, and agitation of liquids; or when air or other gases bubble through liquids , In addition to potential exposures to the m a n y raw materials handled, carbon monoxide emitted from engine exhausts may be a hazard on loading and shipping docks.Exposures may be greater in the winter when loading areas are often enclosed to minimize heat loss. 2.M a n u f a c t u r e of P a i n t s a n d L a c q u e r s There are a number of potential hazards that confront workers in the various processes involved in the manufacture of paints and lacquers. # a. Dispersion Pigment and resin particles may enter the breathing zones of workers when mixer and mill hoppers are filled. Airborne particles may also result when the mixers and the mills are operated.Workers may also be exposed to solvents during the loading, operation, and cleaning of mills. A noise hazard may be associated with the use of ball and pebble mills, especially when the mills are improperly adjusted, as well as with the use of high-speed dispersers. The noise levels at dispersion equipment such as Kady® mills have been found to range from 109-114 dBA . Several mills operating simultaneously will have a combined sound pressure level greater than any individual mill. Ball mills that do not have vibration isolators can be the source of structure-borne vibrations that could be reradiated by other objects in the building , Cleaning the dispersion equipment involves the use of solvents and may result in potential exposure by inhalation or skin absorption.Cleaning may be performed manually or by automatic solvent wash.Since roller mills are often cleaned manually, there is also the potential hazard of catching and crushing arms and fingers between rollers. To Maintenance operations involve many of the same hazards associated with cleaning operations. Nitrocellulose, which is used in lacquer production, is one of the most flammable materials used in the coatings industry; it will not burn when wet with water but becomes flammable when water is extracted and replaced with alcohol .When nitrocellulose is dry, it burns very rapidly and can be ignited by friction or impact , b. Thinning, Tinting, and Shading Although exposure to additives either as dusts or vapors can also occur, solvent exposure is the primary hazard associated with these adjustment procedures. Since quality control checks are often made during these operations, exposures can also occur during sampling and transport of samples to the laboratory.c. F i l l i n g Solvent exposure is also the primary hazard of filling operations.Such exposures may result from direct evaporation of the solvent as the coatings flow into containers or from the cleaning and maintenance of the filling apparatus, particularly the filters used in the first step of the operation. Extensive noise can be generated by the vibrating screens used for filtering. Packaging the products usually involves automated equipment with moving parts that may catch on clothing. Burns or vapor exposure may also result from the use of hot, melted glues to secure packaging and labels. # d. Handling Finished Products Safety hazards involved in handling finished coating products are similar to those involved in handling raw materials (e.g., lifting, slippery working surfaces, poor clearance, reduced visibility, etc.). Finished products are usually in sealed metal containers and present little respiratory hazard. Automatic depalletizers are a potential source of excessive noise. # Manufacture of Varnishes Varnish production requires an external source of heat and, therefore, differs from paint and lacquer production.Temperatures associated with the manufacture of varnish are often 2 0 0°-6 0 0°F (93°-316°C) and cause the formation of gaseous substances during varnish cooking . # a. Kettle and Reactor Operation Hazards The major hazards associated with the cooking stage in varnish production involve airborne exposures while loading the vessels or emissions while processing. Loading or charging the reactor vessel is usually done by pumping in the liquid reactants such as oils, glycols, or acid anhydrides. When dry materials are added, they can release irritant dusts or vapors of maleic, phthalic, or fumaric anhydride. Splattered molten anhydride can harm eyes and skin.Moreover, temperature changes at vents and orifices must be avoided so that vapors of these materials will not condense and form pressure plugs. # Since these reaction vessels are mostly closed systems, only inadvertent or fugitive emissions present a hazard to workers during the reaction phase.In a few cases, however, open kettles may still be used in the manufacture of varnishes.Some of the emissions given off during the cooking of varnishes include acrolein, phenol, aldehydes, ketones, glycerin, fatty acids, and carbon dioxide .

Maximum reactor vessel emissions occur during "sparging," when an inert gas is blown through the reactor to remove the water of reaction.Emissions from solvent cooking operations do not vary significantly with the size of the reactor, but are more a result of the volatility of the solvent being used and the size and efficiency of the condenser. Startup, process upset, shutdown, and, particularly, emergencies offer further potential for worker exposure .Ambient temperatures around reactors generally are not hazardous.However, when insulation or climate controls are inadequate, ambient temperatures may rise and workers may be subject to heat stress. In direct-fired kettles or reaction vessels, the constant heating and cooling can cause metal fatigue and subsequent cracks in the vessel.These cracks can be sources of vapor leaks and fire hazards. Also, open kettles, especially portable ones, pose the hazard of burns from contact with hot surfaces or from splattering material. # b. Thinning and Filtering Exposure to solvents may occur during the thinning stage of varnish production. Thinning is usually done in separate tanks but may be performed in the varnish or resin kettle itself. Solvent exposure may also occur during filtering but is more likely during the subsequent cleaning of the filters. # c. Equipment Cleaning The cleaning of equipment (e.g., reactors, kettles, thinning tanks, filters, etc.)is another source of worker exposure to toxic substances. Cleaning operations in confined spaces are especially hazardous. Workers may be exposed by skin contact or inhalation.Equipment is also sometimes cleaned with hot caustic solutions that may affect the skin, eyes, and respiratory tract. The cleaning of filters may be performed manually or by automatic washing with solvents. Respiratory exposure to diatomaceous earths and dusts from other finely ground materials used as filter aids is possible. # Manufacture of Powder Coatings Many of the same types of hazards found during the manufacture of paints or varnishes also exist in the production of powder coatings. Dust exposure can occur during the charging of hoppers, mixers, and grinders and in packaging. The fine particle sizes associated with powder coatings increase the possibility of dust explosions , Inhalation of resin powders, pigments, curing agents, and other additives is the primary health hazard associated with the production of powder coatings. 5.M a n u f a c t u r e of R a d i a t i o n -C u r a b l e C o a t i n g s Since the manufacture of radiation-curable coatings, which dry or cure as a result of radiation such as infrared, ultraviolet, and electron beam, is similar to that of other paints, so are most of its hazards.Radiation-curable coatings, however, contain reactive monomers in place of solvents. In addition, ultraviolet-curable coatings also contain photoinitiators. Both reactive monomers and photoinitiators may have acute or delayed effects on the skin, eyes, and respiratory tract causing skin sensitization and other effects . Because of the likelihood of acute effects resulting from skin or eye contact with some components of radiation-curable coatings, this type of coating is manufactured in enclosed equipment. Enclosed equipment is also necessary to prevent vaporization of some components that have relatively high vapor pressures. Various types of hazards are associated with acrylate monomers used in radiation-curable coatings. Acrylates cause irritation of the eyes, nose, throat, lungs, and skin. In # Laboratory Functions In addition to the hazards associated with the manufacture of coatings, the operations associated with laboratory functions may also expose workers to other chemical substances (e.g., reagents) and physical agents such as ultraviolet or infrared radiation, heat, cold, and ionizing radiation used in curing processes and in exposure tests. A potentially hazardous practice in laboratories involves spraying a coating to match colors. Often no exposure controls are used, and exposure to airborne coatings is likely. This situation is easily remedied by providing a spray booth with negative pressure to remove the overspray and thus protect the worker. # C. Adverse Health Effects OSHA has promulgated occupational exposure standards for many of the chemicals used in the manufacture of paint and allied coating products.NIOSH has also evaluated many of these materials and has published Criteria Documents and other reports which have recommended occupational safety and health standards for them, including occupational exposure limits. The current OSHA standards and the NIOSH-recommended exposure limits, as well as pertinent health effects, are listed in Appendix B. The materials used in coatings vary greatly in their toxicity. Some have been shown to be biologically inert, and others are proven or potential occupational carcinogens. Pigments are usually handled as finely divided solids that can readily become airborne; adhere to skin, hair, and clothing; and generally coat the work area with dust. The primary routes of exposure to pigments are inhalation, skin contact, and eye exposure. Ingestion of pigments can result from eating, smoking, or drinking in the work areas as well as from swallowing material gathered by the mucociliary clearance mechanism in the respiratory tract. The volatility of m a n y organic solvents and resins at room temperature accounts for the likelihood that workers will be exposed to them by inhalation. Exposure to solvents and resins by s k i n contact and skin absorption is also common. An epidemiological study was conducted on a cohort of 16,243 men from 32 plants who were employed in the manufacture of paint or varnish for at least one year after January 1, 1946. The total mortality data of these workers compared favorably with that of the United States white male population (i.e., 2,633 deaths observed, standardized mortality ratio of 86). However, a statistically significant increased mortality risk from colon and rectal cancer (65 and 26 deaths observed, SMR's of 138 and 139, respectively) were found.The workers were also divided into seven subgroups on the basis of the type of exposure. In one of these subgroups (the pigment workers) there was a significant increase of liver cancer (7 deaths observed, SMR of 273, p<0.05). Lacquer workers had increased, although not significant, liver cancer and leukemia (SMR's of 255 and 212, respectively). The investigators concluded that work in this industry presented no major health hazard.However, there were no analyses performed which took into account either exposure or latency. Without such analyses, positive findings would likely be obscured by the dilution of the study population with persons with inadequate exposure and latency for chronic disease to manifest.There is no basis for the author's conclusions. # IV.M E T H O D S F O R W O R K E R P R O T E C T I O N The occupational hazards that have been identified in the paint and allied coating products industry fall into three categories: (1) accidents, (2) fires and explosions, and (3) exposures to toxic substances and physical agents. Injuries are reported among coatings industry workers about 18 times more frequently than illnesses and are the major cause of lost worktime . The possibility of fires and explosions exists where solvents and other flammable materials are used. Workers who manufacture paint and allied coating products are also potentially exposed to numerous toxic solvents, pigments, film-formers, and additives. Possible adverse health effects resulting from exposure to m a n y of these materials, particularly components of some of the more recently developed products, are unknown. In addition, workers are exposed to more than one substance at a time, and the possible synergistic or additive effects have not been determined. # A. Prevention of Accidents To protect workers in the coatings industry, a critical objective is to reduce injuries.Sprains, strains, contusions, bruises, cuts, and lacerations constitute about 66% of the total injuries and illnesses in the coatings industry , The largest source of injuries and illnesses (about 33%) is associated with the handling of boxes, barrels, and containers .Accidents are caused by improper lifting, carrying a load that is too heavy, incorrect gripping, failure to wear appropriate protective clothing, and slips and falls resulting from sudden changes in friction between the shoes and the floor. It is evident that reducing the number of injuries should be a high priority in the paint and allied coating products industry. Grimaldi and Simonds suggested that the causes of all injuries can be divided into two categories: unsafe physical conditions and unsafe personal acts. Unsafe physical conditions are due to defects in the condition of equipment, errors in design, faulty planning, or omission of essential safety requirements for maintaining a relatively hazard-free physical environment. Unsafe physical conditions were grouped by Grimaldi and Simonds o Removing safety devices or altering their operation so that they are ineffective. - Operating equipment at unsafe speeds. - Using unsafe or improper equipment (e.g., using a chisel with a "mushroomed" head, using the hands instead of a brush to remove chips from cutting machines, or using a screwdriver of incorrect size for the slot in the screwhead).o More stable qualities in the makeup of the workforce (i.e., more older, married workers with longer time on the job) were found. Safety control programs that have the preceding characteristics of workforces with low accident rates and that are oriented toward minimizing the number of unsafe conditions and acts should tend to reduce the number and severity of accidents and injuries in the coatings industry. Hazard control programs are most effective when they include both specific corrective actions and demonstrable involvement by senior management. Also, involvement of workers in decision processes leads to improvements in safety compliance . # Proper Lifting Overexertion in the workplace accounts for a large number of disabling injuries. Most of these injuries involve the act of manually handling materials. A detailed analysis of hazard identification and control involved in lifting is given in the NIOSH technical report, Work Practices Guide for Manual Lifting .It recommends that a job analysis be conducted for tasks associated with increased risk of injury; a detailed procedure for evaluating the analysis for lifting tasks is presented . For workers to safely perform lifting jobs, employers should institute training, ergonomic/engineering controls, the use of materials handling aids and equipment, and the selection of appropriate individuals as discussed in the following sections. # a. T r a i n i n g The training of workers in proper materials handling techniques is generally accepted as a potentially useful technique for reducing injuries. A The container itself affects safety directly through its weight and size and indirectly through the limitations it imposes on methods of holding and carrying it. Containers should be as small as possible.A compact load minimizes the compressive forces on the back because the center of gravity of the load can be brought close to the spinal column . Worker/container coupling affects the ability to exert forces on the object, to maintain grip, and to exercise control --all vital to safe handling.The major problems with most handles are insufficient hand clearance, sharp edges which can cut into the hand, and a handle diameter that is too small. Handle diameter should range from 2.5-3.8 cm (1.0-1.5 in).Handle width should be at least 11.5 cm (4.5 in) with 5.0 cm (2 in) clearance all around the handle. If gloves are used, at least 2.5 cm (1 in) should be added to the width and the clearance . Worker/floor surface coupling is important for maintaining stability and preventing slips, trips, and falls. Accidents can be reduced by using good housekeeping procedures to reduce transient changes in surface friction such as spills, worn spots, and loose or irregular floors . Although manual materials handling operations rarely demand the fine visual discrimination of delicate assembly work, lighting can have a large effect on surface texture and depth perception.Low, angled illumination is recommended for enhancing surface texture to warn workers of changes in surface friction. Color contrasts should be used on the edges of steps, loading docks, and ramps. # c. Materials Handling Aids and Equipment The use of materials handling aids (rollers, jacks, and platforms) and mechanical equipment (conveyors, cranes, hoists, hand trucks, and forklifts) can be helpful or necessary in many lifting tasks.Particularly useful are conveyors and other devices which convert lifting into sliding tasks. The potential benefits of these devices, however, must be weighed against potential safety problems such as suspended loads with cranes and the many hazards in the use of hand-operated trucks and forklifts . # d. Selection of Appropriate Individuals To avoid worker-job mismatch, selection of individuals for some jobs is considered desirable.Criteria for selection are lacking, however. For many industries the principal method has been self-selection by the workers based on their initial tolerance for the demands of the job, a poor choice for obvious reasons. Other selection methods that have been used are questionnaires on health and medical history; and tests of visual, auditory, and pulmonary function, of blood pressure, mobility, etc.,often with the addition of a chest x ray.However, such tests have poor predictive power. In particular, x rays of the musculoskeletal system have little value in identifying workers who develop back injuries, and their routine use in screening employees is discouraged by medical authorities .The most useful procedure is a medical history coupled with an objective test of performance capacity (e.g., strength testing). # M a c h i n e G u a r d i n g / R e d e s i g n An important area of occupational safety and health is that which protects the operator from the hazards of machine operations. OSHA requires in 29 CFR 1910.212 that one or more methods shall be provided to protect the operator and other workers in the machine area from hazards such as those created by point of operation, in-running nip points, rotating parts, flying chips, sparks, power transmission equipment, etc.Guards shall be affixed to the machine where possible. Workers who use powered handtools in chipping operations are exposed to hand-arm vibration and potential risk of developing vibration syndrome (also known as vibration white finger and Raynaud's phenomenon).Vibration syndrome has adverse circulatory and neural effects in the fingers; the signs and symptoms include numbness, pain, and blanching (turning pale and ashen) . NIOSH recommends that jobs be redesigned to minimize the use of vibrating tools and that powered handtools be redesigned to minimize vibration . # Noise Control Noise must be controlled wherever it is excessive, both as a means of preventing accidents and as protection from hearing loss. The noise in dispersion and filling operations is of special concern as is the use of powered handtools to chip layers of coatings from the insides of containers . Under the provisions of the OSHA Occupational Noise Standard (29 CFR 1910.95), protection against the effects of noise exposure shall be provided when the sound levels exceed those shown in Table IV # S O U N D P R E S S U R E L E V E L S (dBA) A T D I F F E R E N T L O C A T I O N S A R O U N D A B A L L M I L L (Copyright by Communication Channels, Inc. Reprinted with permission by the Department of Health and Human Services. Further reproduction prohibited without permission of copyright holder.) # P O S ITIO N G H iG H R EA D IN G W AS T A K E N W IT H W ASH S O LV E N T IN A STEEL B A LL M ILL; LOW R E A D IN G W AS FOR A W ATER JA C K E T E D LIN E D PEBBLE M IL L U S IN G H IG H D EN SITY G R IN D IN G BALLS. # B. P r e v e n t i o n of F i r e s a n d E x p l o s i o n s Many of the organic substances used in the manufacture of paint and allied coating products are highly flammable, and some are also explosive. Thus, fires and explosions are a constant threat in most manufacturing operations where solvents and other flammable materials are used. # Static Electricity The handling of the flammable or explosive liquid raw materials used in the coatings industry requires special techniques and precautions to prevent the accumulation of static electricity. The object of such measures is .to provide a means whereby charges may recombine harmlessly before sparking potentials are attained or to avoid spark gaps where harmful discharges could occur . During the transfer of the solvents from one container to another (whether in bulk or in small amounts), effective bonding and grounding should be used to prevent the accumulation of static electricity , "Bonding" is the process of connecting two or more conductive objects together by means of a conductor , "Grounding" is the process of connecting a conductive object to the ground and is a specific form of bonding , Fill pipes should go to the bottom of tanks, drums, etc.,to minimize the generation of static electricity in the free fall of flammable solvents .Drums cleaned by steam should be electrically bonded to steam lines, and the entire assembly should be grounded. Before drums are emptied, they should be supported and blocked to prevent movement. Examples of bonding and grounding arrangements are shown in Figures IV-2, IV-3, IV-4, IV-5, and IV-6.Services. # FIGURE IV-2.BONDING AND GROUNDING FOR A MECHANICAL PUMPING DEVICE HOSE MAY BE EITHER C O N D U C T IN G OR N O N C O N D U C T IN G .

C O N D U C T IN G H OSE A N D N O Z ZLE IN C O N T A C T W ITH C O N T A IN E R -NO O TH ER B O N D Further reproduction prohibited without permission of copyright holder.) # F L E X IB L E AIR DUCT ( M E T A L -F A B R IC ) HANGING FROM R IG ID DUCT S Y S T E M FIGURE IV-6.TYPICAL GROUNDING ARRANGEMENT FOR THINNING OR MIXING EQUIPMENT (Copyright by The Sherwin-Williams Company. # Reprinted with permission by the Department of Health and Human Services. Further reproduction prohibited without permission of copyright holder.) # Work Practices Procedures and precautions for preventing fires and explosions include: (1) regular inspection of equipment and storage tanks, (2) immediate repair of leaks, pumps, and lines, (3) periodic testing of pressure equipment, and (4) ventilation to reduce vapor concentrations. Containers of solvents or hot resins should be tightly covered at all times except when material is transferred. Containers of not more than five gallons capacity, having a spring-closing lid and spout cover and so designed to safely relieve internal pressure when subjected to fire exposure, should be used to hold working amounts of solvents. Since small amounts of residue may remain and present a fire hazard, containers that have held solvents should be thoroughly cleaned with steam and then drained and dried before re-use. Fittings and open heaters should be prohibited except in specified areas. Fire hazards around tank trucks and cars can be reduced by turning off their motors and not starting them during loading or unloading operations. Good housekeeping is also imperative to prevent fires. After eliminating potential sources of ignition, spills should be cleaned up immediately after the area is ventilated. Stopping leaks and spills will eliminate fire hazards and help conserve raw materials, keep chemicals out of the effluent system, and reduce worker exposure.Combustible materials such as cleaning rags should be disposed of in metal containers filled with water .Specific OSHA requirements for the storage and handling of flammable and combustible liquids are given in 29 CFR 1910.106. # C. Controlling Exposures to Toxic Substances Exposure to the thousands of raw materials (i.e., pigments, solvents, film-formers, and additives) used in the paint and allied coating products industry also poses a potential hazard. A variety of technologies such as process enclosure, modification of existing equipment, mechanical pumping systems, local exhaust ventilation, hazardous substance identification systems, protective clothing and equipment, and implementation of safe work practices can be used to control exposures to toxic substances. The conclusions of a NIOSH-sponsored study indicate that the coatings industry relies on relatively well-known technology and uses equipment and procedures that are commonly used in a wide variety of other industries. The effectiveness with which the coatings industry has controlled worker exposure to toxic substances can be evaluated somewhat by reviewing the records of OSHA compliance investigations. For the industries within the SIC code 2851, data are available from OSHA health inspections completed during the period June 1979 to January 1984. Table IV-2 indicates the numbers of different samples collected and whether the concentrations found were above or below the Federal occupational standard in effect at the time , The majority of tests (94%) showed that the concentrations of the substances evaluated were within applicable Federal standards. On the basis of these tests, it can be concluded that it is probably feasible in the coatings industry, through engineering controls and effective work practices, to limit exposures to most hazardous substances to within Federal s tandards. To identify specific hazards, comprehensive industrial hygiene evaluations (including appropriate measurements) should be conducted. Such evaluations should be conducted at least yearly or when any change in process, raw material, or engineering control occurs which could result in increased exposure to toxic substances. The results of these evaluations should be used to guide employers in implementing effective work practices and engineering controls, worker training, medical surveillance, and the use of personal protective clothing and equipment. # Informing Workers of Hazards OSHA on November 21, 1983, promulgated an occupational safety and health standard titled "Hazard Communication."Under the provisions of this standard (29 CFR 1910(29 CFR .1200 The hazard communication program is to be written and is to be made available to workers and their designated representatives.Chemical manufacturers, importers, and distributors are required to ensure that containers of hazardous chemicals leaving their workplaces are labeled, tagged, or marked with the identity, appropriate hazard warnings, and the name and address of the manufacturer or other responsible party. Employers must ensure that labels on incoming containers of hazardous chemicals are not removed or defaced unless they are immediately replaced with other labels containing the required information. Each container in the workplace must be prominently labeled, tagged, or marked with the identity of hazardous chemicals contained therein along with hazard warnings appropriate for worker protection. If there are a number of stationary containers within a work area which have similar contents and hazards, the employer may post signs or placards which convey the hazard information required rather than individually labeling each container. Employers may use various types of standard operating procedures, process sheets, batch tickets, or other such written materials as substitutes for individual container labels on stationary process equipment. However, these written materials must contain the same information as is required on the labels and must be readily accessible to workers in the work areas. Pipes or piping systems are exempted altogether from the OSHA labeling requirements although NIOSH recommends that filler ports and outlets be labeled. In addition, NIOSH recommends that a system should be set up to ensure that pipes containing hazardous materials are identified to avoid accidental cutting and discharge of hazardous materials. Employers are not required to label portable containers into which hazardous chemicals are transferred from labeled containers and which are intended only for the immediate use of the worker who performs the transfer. According to the OSHA definition of "immediate use," for the exemption to apply, the container must be under the control of the worker performing the transfer and must be used only within the workshift in which it is transferred. The OSHA Hazard Communication standard requires chemical manufacturers and importers to develop a material safety data sheet (MSDS) for each hazardous chemical they produce or import.Employers in the manufacturing sector (which includes paint and allied coating products manufacturing) are required to obtain or develop a MSDS for each hazardous chemical used in their workplaces.The MSDS is required to provide specific information such as the chemical and common names for the hazardous chemical. For hazardous chemical mixtures, each component which comprises 1% or more and which is itself a health hazard must be listed.Any chemical which is determined to be a carcinogen must be listed if it is present in quantities of 0.1% or greater. Ingredients present in concentrations of less than one percent must also be listed if there is evidence that the permissible exposure limit may be exceeded or if it could present a health hazard in those concentrations. Additional information on the MSDS must include data on the physical and chemical characteristics of the hazardous chemical, known acute and chronic health effects, precautionary measures, and emergency and first aid procedures.The NIOSH publication, A Recommended Standard--An Identification System for Occupationally Hazardous Materials , can be used as a guide when preparing the MSDS.Required information can be recorded on the "Material Safety Data Sheet" shown in Appendix C, or on a similar form. Employers are to establish a training program for all workers exposed to hazardous chemicals. Training is to be provided at the time of initial assignment and whenever a new chemical hazard is introduced into their work area. Workers are to be informed of specific hazards involved in any operations in their work areas where hazardous chemicals are present. This may be done by individual chemical or by categories of hazards, but in any case the worker is to be aware that information is available on the specific hazards of individual chemicals through the MSDS. Workers are also to be trained regarding methods and observations that may be used to detect the presence or release of hazardous chemicals (e.g., monitoring conducted by the employer, continuous monitoring devices, visual appearance or odor of hazardous chemicals when being released, etc. Bulk handling methods for liquid raw materials which include techniques for bulk storage, piping, mechanical pumping (rather than pouring), and metering liquids minimize the opportunity for volatile liquids to contact ambient air. Systems for the bulk handling of pigments and other powdered materials also have been developed , The bulk handling system shown in Figure IV-8 uses bulk delivery vehicles, the transfer of materials by pipes to tanks that have lids, and built-in dust collectors and operates in the following manner. Pigment is blown from trailers or rail cars into a steel storage silo. From the silo, pigment is blown through piping to a use bin located on the roof of the manufacturing building directly over the mixing area. Weighed quantities of pigment are delivered directly or via batch dollies to mixers. A low-level sensor actuates the transfer system to feed pigment from the silo when the pigment falls to a preselected level. Pigment is added to the use bin until its level activates a flow-cutoff sensor . Despite precautions, the area around dispersion equipment often becomes quite dusty and frequent vacuum cleaning is recommended .Compressed air should not be used to remove pigment dust from clothing or work surfaces because it will result in the secondary generation of airborne dust. It is also recommended that soiled clothing not be taken home for cleaning but be cleaned either by an industrial laundry or an on-site facility. When solvents or caustic solutions are used for cleaning dispersion equipment, it is important to avoid skin, eye, and inhalation exposures, which are especially likely to occur during manual cleaning. When using caustic solutions, care should be taken during the preparation of the solution to prevent excessive heat generation; dry caustic, typically 3 pounds per gallon , should be added slowly to the water .Caustic solutions should not be superheated because of the possibility that the tank will "boil over" . Because caustics may react violently with aluminum, caustic solutions should not be used to clean out tanks that have contained aluminum paint . Special precautions should also be taken in the handling of aluminum paste or powder which can generate hydrogen gas when in contact with moisture .When this occurs in closed containers of aluminum pigments, sufficient pressure may build up to cause an explosion and fire . Spills are likely to occur during filling operations when automated equipment malfunctions. Immediate spill cleanup can reduce vapor release. Worker training programs that address techniques for spill cleanup are useful. For major spills, some useful special procedures include the use of protective equipment (e.g., rubber boots), portable ventilation, absorbent material (e.g., floor sweeping compound, sawdust, -j Contact with coatings or their components (especially radiation-curable coatings) should be avoided, if possible, but should be followed by the immediate washing of contaminated skin with soap and water, immediate flushing of exposed eyes with copious amounts of water, and quick removal of contaminated clothing. HI & LOW LEVEL IN D IC A T O R USE BIN D IS C H A R G E A S S E M B LY (FLE XIB LE) SCALE M IX IN G T A N K S DUST C O LLE C T O R D ELIVER Y PIPE -U N L O A D IN G PIPE B IN A C T IV A T O R .FEEDER C O N V E Y IN G BLOW ER Exposure of workers to toxic substances may also occur through the use of food, beverages, or tobacco products in areas where toxic substances are present. For that reason, such activities (eating, smoking, etc.)should be prohibited in those areas.Good sanitation and hygiene practices should be encouraged by worker training, posting of warning signs, supervision, and provision for adequate eating and sanitation facilities, the latter of which should include change rooms, showers, and wash basins .For all work areas in which there is a potential for emergencies involving toxic materials, the employer should take necessary steps to ensure that workers are instructed in and follow the specified procedures. Prearranged plans should be established for administering first aid and emergency medical care and for transportation of injured workers. Firefighting procedures should also be established and implemented. Personnel who may be required to shut off sources of solvents, clean up spills, and repair leaks should be properly trained in the appropriate procedures. In case of fire, solvent sources should be shut off or removed. Chemical foam, carbon dioxide, or dry chemicals should be used for fighting solvent fires, and proper respiratory protection and clothing should be worn. Nonessential workers should be evacuated from exposure areas during emergencies. Warning or alarm systems should be considered to alert workers to possible hazardous exposures during emergencies . Entry into confined or enclosed spaces where there is limited egress, such as tanks, pits, trucks and tank cars, and process vessels, should be controlled by a permit system. Permits should be signed by an authorized employer representative and should certify that preparation of the confined space, precautionary measures, and personal protective equipment are adequate. Further # Substitution of Raw Materials Occupational health hazards can also be controlled by the substitution of raw materials. Because of their potential for environmental damage or consumer injury, the use of lead, chromates, and mercury compounds and various highly volatile solvents in many applications has been reduced or eliminated with replacement by other, less hazardous substances.An example is the use of zinc metal, zinc oxide, molybdates, and phosphates instead of lead and chromates as pigments in industrial maintenance coatings or the use of cuprous oxide or organotin compounds in antifouling paints rather than organic mercury, lead, and arsenic compounds . In addition, many potent paint and varnish removers such as benzene, phenol, and cresols are no longer used , Another type of raw material substitution being utilized in paint manufacturing involves replacing dry pigments with pigment slurries . As depicted in Figure IV-9, instead of storing and handling bagged dry pigments, slurries can be pumped from railroad cars into storage tanks and then to the mixing floor as needed, thus eliminating the release of pigment dust into the workplace air and simplifying pigment dispersion , # Engineering Controls Occupational exposures to hazardous substances should be controlled at the source of the hazard wherever feasible. This can be achieved by process or equipment modification, isolation of stored materials and processes, and local exhaust ventilation. One of the most effective methods of dust control during the weighing and assembling of raw materials is a system that utilizes a closed fabricated metal booth that rests on top of the mixer and is connected by ducts to both a dust collector and an empty bag shredder. Inside the booth, a bag of pigment is placed on a table and cut open as it is pushed over a mounted metal blade.The pigment falls through the cut in the bag into the mixer, and the empty bag is lifted slightly by the worker and is drawn upward and away by suction (Figure IV-10). Another method that can effectively control dust and vapor is the use of a ventilated booth where materials are weighed or transferred.This results in reduced worker exposure and a decrease in the amount of dust and vapor released into the general workroom air.Dust-laden air that is exhausted should be collected in bag houses or forced through scrubbers or electrostatic precipitators. Vapor-laden air can be scrubbed, incinerated, condensed, or adsorbed , Portable exhaust ventilation is another common control technique.This is accomplished with a hood attached to a flexible duct that leads to a fan.The effectiveness of this type of control varies, depending on the type of hood used, its placement, and its face velocity.Portable exhaust ventilation is generally, but not necessarily, less effective than ventilated hoods that enclose or confine a contaminant because exhaust volumes are large and control can be easily upset by cross drafts in the area . # HIGH SPEED MIXING TANK R E C O V E R E D P IG M E N T R E C Y C L E FO R DA RK P R IM E R P A IN T S TO SOLID WASTE DISPOSAL Enclosed equipment, such as ball or pebble mills, is free of vapor release during operation, but this is not the case with high-speed dispersers, which are open to the air.The use of covers and lids on containers can reduce vapor emissions.This is especially true during the thinning, tinting, and shading operations when temporary containers often remain open for long periods of time while laboratory analysis and subsequent adjustments are performed. Sand mills often discharge into open portable tanks resulting in potential solvent emissions . Since vapors are emitted when containers are filled with solvent-based coatings, exhaust ventilation may be needed at the point of filling. Because of the heat required and the by-products that need to be controlled, operations in varnish manufacture differ from other operations in the paint and allied coating products industry. Both reactors and open and closed kettles are used to produce varnishes with the hazard of exposure to toxic emissions being greatest for open kettles. Emissions are generated during cooking processes when kettles are opened for charging or product sampling. Most kettles are currently fitted with retractable hoods and exhaust systems, some of which incorporate solvent condensers . Figure shows the control measures used in a typical varnish cooking room.

Ventilation systems used to control vapors are most effective when designed to control vapors generated at temperatures higher than the ambient air . Condensed vapors collect to some extent as a sticky film on the relatively cool hood and duct walls, necessitating frequent cleaning and maintenance. Hood design should provide for access to the kettle during use of the hood and should be designed to prevent contamination or exposure by the dripping of condensate from its inner surfaces .Varnish production vapor emissions can be controlled by water scrubbing, combustion, vapor incineration, high stack dispersal, or condensation , Because of the nature of the process, workers in varnish manufacturing operations may be subject to heat stress or to contact with hot surfaces. Screens or guards can be used to shield workers from contact with hot surfaces and from radiant heat. In some cases, protective qlothing (particularly gloves) is useful. With open kettles, the hot material can splatter on workers. This hazard can be prevented, however, by covering the kettles or by using enclosures or splatter-gua rd s. Measurements of the effectiveness of the system should also be made as soon as possible after any change in production, process, or control which may result in any increase in airborne contaminants. It is essential that any scheme that involves exhausting air from a work area should also provide for a positive means of bringing in at least an equal volume of air from the outside, conditioning it, and evenly distributing it throughout the exhausted area. The # Personal Protective Clothing and Equipment Workers should use appropriate personal protective clothing and equipment which must be carefully selected, used, and maintained to be effective.The SDS data indicated that 60% of the injuries or illnesses associated with chemicals or chemical compounds were caused by skin contact and 47% resulted in chemical burns. To prevent skin contact, gloves, aprons, boots, etc.should be made of materials resistant to the hazardous substances in question, particularly the solvents.Splash-proof chemical safety goggles or face shields, (20-30 cm minimum) should be worn in any operation in which there is a likelihood of a solvent, caustic, or other toxic substance being splashed into the eyes. # Medical Surveillance The medical officer responsible for the health of workers should be apprised of potential workplace hazards, based on safety and health evaluations, and appropriate medical surveillance should be conducted.The number and type of tests to be performed should be based on the substance or hazards to which the worker may be exposed.In any case, preplacement examinations should be performed and should include at least a medical and occupational history, a comprehensive physical examination, and a judgement of the worker's ability to use positive or negative pressure respirators. Emergency first-aid programs should be developed that are based on the results of the workplace occupational safety and health evaluation. Periodic examinations should be carried out at the discretion of the responsible physician based on the adverse health effects and nature of the hazards identified. Health hazards identified for which NIOSH has made specific recommendations should be addressed in accordance with those specific recommendations. Pertinent medical records of all workers should be kept by employers for at least 30 years after termination of employment.Each worker should have access to information contained in his or her own medical records.A revolving cylindrical metal mill that uses steel balls, stones, or other media to grind or disperse the pigment in the film-former. Film-forming material applied for protection or decoration of surfaces. The mixing of materials, usually liquids, without the addition of heat. The heating of the combined ingredients of a varnish. A machine that unloads a pallet of materials. A liquid that is blended with an active solvent to reduce cos t. Any heterogeneous system of solids, gases, or liquids. Oils capable of absorbing oxygen from the air and becoming solid films. A pigment that contributes little hiding to the system but does reinforce the film and alter its gloss. The nonvolatile binder portion of a coating. These may be classified as either thermoplastic or convertible (see vehicle). The lowest temperature at which a substance in an open vessel gives off enough vapors to produce a flash of fire when a flame is passed near the surface as described by American Society of Testing and Materials (ASTM) test procedures. # Flush Colors Water dispersions of organic and inorganic pigments that are supplied as organophilic pastes. The ability of a paint to obscure the background over which it is applied. Coatings that contain more than 70% nonvolatile material. Vessel used in the production of varnish. Usually indicates a material that dries by evaporation and forms a film from the nonvolatile constituents. A generic term describing stable dispersions of resin particles in a water system. An increase in the consistency of paint resulting in a rubbery or coagulated mass. A general term for a water-insoluble viscous liquid usually consisting of triglycerides. A material that has been made by a combination of oil and resin. A dispersion formed by the suspension of resin particles (usually a vinyl resin) in a liquid consisting of volatile solvents. Mills usually lined with porcelain or buhrstone in which flint pebbles or porcelain balls are used as the grinding media. A dispersion formed by the suspension of resin particles (usually vinyl) in a liquid consisting only of plasticizers. Pigmented polymer coatings applied in powder form by various techniques such as electrostatic spray, fluidized bed, flocking gun, flame spray, or cloud chamber. The phase of coatings production in which raw materials are weighed and assembled for mixing. # Coatings that dry or cure as the result of initiation of polymerization by radiation such as infrared, ultraviolet, or electron beam.Resins that soften and flow when heated and, on cooling, regain their original physical and chemical properties. # Resin # Resins that undergo a chemical change and become hard after heating and cannot be resoftened. When used as a film-former, they are often referred to as convertible film-formers. Coatings, usually urethane, formed by catalytic conversion that occurs so rapidly at ambient temperature that the components must be shipped in two separate containers. Solutions of film-formers in organic solvents, with no pigments. The liquid portion of a coating material that forms the finished film and binds the pigments in the coating (see film-former). The "%" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. # VIII.APPENDIX B SUMMARY OF HEALTH EFFECTS AND EXPOSURE LIMITS FOR SUBSTANCES POTENTIALLY PRESENT IN THE MANUFACTURE OF PAINT AND ALLIED COATING PRODUCTS # Agent This may be indicated as a range or maximum amount, i.e., "10-40% vol."or "10% max. wt."to avoid disclosure of trade secrets. Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, e.g., "100 ppm LC50-rat," "25 mg/kg LD50-skin-rabbit," "75 ppm LC man," "permissible exposure from 29 CFR 191029 CFR .1000 The data in Section III should be for the total mixture and should include the boiling point and melting point in degrees Fahrenheit (Celsius in parentheses); vapor pressure, in conventional millimeters of mercury (mmHg); vapor density of gas or vapor (air=l); solubility in water, in parts/hundred parts of water by weight; specific gravity (water=l); percent volatiles (indicated if by weight or volume) at 70°F (21.1°C); evaporation rate for liquids or sublimable solids, relative to butyl acetate; and appearance and odor.These data are useful for the control of toxic substances. Boiling point, vapor density, percent volatiles, vapor pressure, and evaporation are useful for designing proper ventilation equipment. This information is also useful for design and deployment of adequate fire and spill containment equipment. The appearance and odor may facilitate identification of substances stored in improperly marked containers or when spilled. # Section IV.Fire and Explosion Data Section IV should contain complete fire and explosion data for the product, including flash point and autoignition temperature in degrees Fahrenheit (Celsius in parentheses); flammable limits, in percent by volume in air; suitable extinguishing media or materials; special firefighting procedures; and unusual fire and explosion hazard information. If the product presents no fire hazard, insert "NO FIRE HAZARD" on the line labeled "Extinguishing Media." # Section V. Health Hazard Information The "Health Hazard Data" should be a combined estimate of the hazard of the total product.This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved. # Ill Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible.The basis might be animal studies, analogy with similar products, or human experiences.Comments such as "yes" or "possible" are not helpful.Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation. Eye Contact-some pain and mild transient irritation; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained in first aid. Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed workers. # Section VI.Reactivity Data The comments in Section VI relate to safe storage and handling of hazardous, unstable substances. It is particularly important to highlight instability or incompatibility to common substances or circumstances, such as water, direct sunlight, steel or copper piping, acids, alkalies, etc. "Hazardous Decomposition Products" shall include those products released under fire conditions. It must also include dangerous products produced by aging, such as peroxides in the case of some ethers. Where applicable, shelf life should also be indicated. # Section VII.Spill or Leak Procedures Detailed procedures for cleanup and disposal should be listed with emphasis on precautions to be taken to protect workers assigned to cleanup detail.Specific neutralizing chemicals or procedures should be described in detail. Disposal methods should be explicit including proper labeling of containers holding residues and ultimate disposal methods such as "sanitary landfill" or "incineration." Warnings such as "comply with local, state, and Federal antipollution ordinances" are proper but not sufficient.Specific procedures shall be identified. # Section VIII.Special Protection Information Section VIII requires specific information.Statements such as "Yes," "No," or "If necessary" are not informative.Ventilation requirements should be specific as to type and preferred methods. Respirators shall be specified as to type and NIOSH or Mine Safety and Health Administration approval class, i.e., "Supplied air," "Organic vapor canister," etc.Protective equipment must be specified as to type and materials of construction.Section IX.Special Precautions "Precautionary Statements" shall consist of the label statements selected for use on the container or placard. Additional information on any aspect of safety or health not covered in other sections should be inserted in Section IX. The lower block can contain references to published guides or in-house procedures for handling and storage.Department of Transportation markings and classifications and other freight, handling, or storage requirements and environmental controls can be noted. # Signature and Filing Finally, the name and address of the responsible person who completed the MSDS and the date of completion are entered.This will facilitate correction of errors and identify a source of additional information. The MSDS shall be filed in a location readily accessible to workers exposed to the hazardous substance. The # V .RESEARCH NEEDS There is Little published information on the health experience of workers engaged in the manufacture of paint and allied coating products. Additional epidemiological studies are needed to determine the morbidity and mortality experience of workers in this industry. Frequent use of volatile solvents throughout the coatings industry increases the possibility that subtle behavioral and neurological effects will occur in workers. A potential problem of chronic deterioration of the central nervous system has recently been identified in Scandinavia among workers with long-term solvent exposures .More information is needed to evaluate tnese effects.Fortunately, the need for this type of information becomes less urgent as solvent-based coatings are being progressively replaced by water-based coatings. However, it has been estimated that considerable quantities of solvents will still be used by the coatings industry in 1990 . # Documentation of the exposures that occur in operations where powder coatings and reactive coatings (e.g., radiation-curable coatings) are produced is needed since little is known of the hazards present during their manufac ture. Research is needed to develop more comfortable and effective personal protective equipment, particularly respirators. It is also important to determine the effect on respirator filter cartridge or canister life when there is a mixture of solvents in the surrounding air. Cohen A: Factors in successful occupational safety programs.J Safety Research 9(4);168-77 (1977 # IX.APPENDIX C MATERIAL SAFETY DATA SHEET The following items of information which are applicable to a specific product or material shall be provided in the appropriate block of the Material Safety Data Sheet (MSDS). The product designation is inserted in the block in the upper left corner of the first page to facilitate filing and retrieval.Print in upper case letters as large as possible. It should be printed to read upright with the sheet turned sideways. The product designation is that name or code designation which appears on the label or by which the product is sold or known by workers. The relative numerical hazard ratings and key statements are those determined by the rules in Chapter V, Part The company identification may be printed in the upper right corner if desired. # Section I. Production Identification The manufacturer's name, address, and regular and emergency telephone numbers (including area code) are inserted in the appropriate blocks of Section I. The company listed should be a source of detailed backup information on the hazards of the material(s) covered by the MSDS. The listing of suppliers or wholesale distributors is discouraged.The trade name should be the product designation or common name associated with the material. The synonyms are those commonly used for the product, especially formal chemical nomenclature. Not every known chemical designation or competitor's trade name needs to be listed. # Section II.Hazardous Ingredients The "materials" listed in Section II shall be those substances which are part of the hazardous product covered by the MSDS and which individually meet any of the criteria defining a hazardous material. Thus, one component of a multicomponent product might be listed because of its toxicity, another component because of its flammability, while a third component could be included both for its toxicity and its reactivity. Note that a MSDS for a single component product must have the name of the material repeated in this section to avoid giving the impression that there are no hazardous ingredients.Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. 8 8 97 1 1 3 1 0 8 9 9 7 1 1 4 1 0 9 0 9 8 1 1 5 1 0 91 9 8 1 1 6 1 0 92 9 9 1 1 7 1 0 9 3 9 9 1 1 8 1 0 94 9 9 1 1 9 1 0 9 5 99 1 2 0 1 0 96 9 9 1 2 1 1 0 9 7 1 0 0 , 1 0 1 1 2 2 1 0 9 8 1 0 3 1 2 3 1 0 9 9 1 0 4 1 2 4 1 0 1 0 0 1 0 4 1 2 5 1 0 GOVERNMEN' PPiNTlNG OPFlCE ' # MATERIAL SAFETY DATA SHEET 1 PRODUCT IDENTIFICATION M A N U F A C T U R E R S NAM E R E G U L A R TE LE PH O N E NO E M E R G E N C Y TELEPHO NE # PROCEDURES U N U S U A L FIRE A N D EXPLOSION H A Z A R D V HEALTH HAZARD INFORMATION H E A L T H H A Z A R D DA T A RO UTES OF EXPOSURE IN H A L A T IO

Certain venues encourage or permit the public to be in contact with animals, resulting in millions of human-animal interactions each year.These settings include county or state fairs, petting zoos, animal swap meets, pet stores, feed stores, zoologic institutions, circuses, carnivals, educational farms, livestock-birthing exhibits, educational exhibits at schools and child-care facilities, and wildlife photo opportunities.Although human-animal contact has many benefits, human health problems are associated with these settings, including infectious diseases, exposure to rabies, and injuries.Infectious disease outbreaks have been caused by Escherichia coli O157:H7, Salmonella species, Cryptosporidium species, Coxiella burnetii, Mycobacterium tuberculosis, ringworm, and other pathogens.Such outbreaks have substantial medical, public health, legal, and economic effects.This report provides recommendations for public health officials, veterinarians, animal venue staff members, animal exhibitors, visitors to animal venues, physicians, and others concerned with minimizing risks associated with animals in public settings.The recommendation to wash hands is the most important for reducing the risk for disease transmission associated with animals in public settings.Other important recommendations are that venues prohibit food in animal areas and include transition areas between animal areas and nonanimal areas, visitors receive information about disease risk and prevention procedures, and animals be properly cared for and managed.These updated 2011 guidelines provide new information on the risks associated with amphibians and with animals in day camp settings, as well as the protective role of zoonotic disease education.#Introduction Contact with animals in public settings (e.g., fairs, educational farms, petting zoos, and schools) provides opportunities for entertainment and education.The National Association of State Public Health Veterinarians (NASPHV) understands the positive benefits of human-animal contact.However, an inadequate understanding of disease transmission and animal behavior can increase the likelihood of infectious diseases, rabies exposures, injuries, and other health problems among visitors, especially children, in these settings.Zoonotic diseases (i.e., zoonoses) are diseases transmitted between animals and humans.Of particular concern are instances in which zoonoses result in numerous persons becoming ill.During 1991During -2005, the number of enteric disease outbreaks associated with animals in public settings increased (1).During 1996-2010, approximately 150 human infectious disease outbreaks involving animals in public settings have been reported to CDC (CDC, unpublished data, 2010). Although eliminating all risk from animal contacts is not possible, this report provides recommendations for minimizing associated disease and injury.NASPHV recommends that local and state public health, agricultural, environmental, and wildlife agencies use these recommendations to establish their own guidelines or regulations for reducing the risk for disease from human-animal contact in public settings.Public contact with animals is permitted in numerous types of venues (e.g., animal displays, petting zoos, animal swap meets, pet stores, feed stores, zoological institutions, nature parks, circuses, carnivals, educational farms, livestock-birthing exhibits, county or state fairs, child-care facilities or schools, and wildlife photo opportunities).Managers of these venues should use the information in this report in consultation with veterinarians, public health officials, or other professionals to reduce risks for disease transmission. Guidelines to reduce risk for disease from animals in healthcare and veterinary facilities and from service animals (e.g., guide dogs) have been developed (2)(3)(4)(5)(6).Although not specifically addressed here, the general principles and recommendations in this report are applicable to these settings. # Methods NASPHV periodically updates the recommendations to prevent disease associated with animals in public settings.The revision includes reviewing recent literature; updating reported outbreaks, diseases, or injuries attributed to humananimal interactions in public settings; and soliciting input from NASPHV members and the public.During September 2010, NASPHV members and external expert consultants met at CDC in Atlanta, Georgia.A committee consensus was required to add or modify existing language or recommendations.The 2011 guidelines have been updated with recently reported information about zoonotic disease outbreaks and prevention measures.This includes more information on indirect transmission through contact with animal environments and contaminated objects and unique challenges associated with intensive animal contact venues like farm day camps.In addition, the guidelines describe the importance of previous knowledge about disease risk in preventing illness.New or expanded disease topics include salmonellosis associated with amphibians and zoonotic influenza. # Enteric (Intestinal) Diseases Infections with enteric bacteria and parasites pose the highest risk for human disease from animals in public settings (7).Healthy animals can harbor human enteric pathogens, many of which have a low infectious dose (8)(9)(10).Enteric disease outbreaks among visitors to fairs, farms, petting zoos, and other public settings are well documented.Many pathogens have been responsible for outbreaks, including Escherichia coli O157:H7 and other Shiga toxin-producing E. coli (STEC), Salmonella enterica, Cryptosporidium species, and Campylobacter species (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).Although reports often document cattle, sheep, or goats (1,13,14) as sources for infection, live poultry (25), rodents (26), reptiles (19), amphibians (27), and other domestic and wild animals also are potential sources. The primary mode of transmission for enteric pathogens is fecal-oral.Because animal fur, hair, skin, and saliva (28) harbor fecal organisms, transmission can occur when persons pet, touch, feed, or are licked by animals.Transmission also has been associated with contaminated animal bedding, flooring, barriers, other environmental surfaces, and contaminated clothing and shoes (12,17,19,(29)(30)(31)(32).In addition, illness has resulted from fecal contamination of food (33), including raw milk (34)(35)(36)(37), and drinking water (38)(39)(40). Removing ill animals, especially those with diarrhea, is necessary but not sufficient to protect animal and human health.Animals carrying human enteric pathogens frequently exhibit no signs of illness but can still shed the organisms, thereby contaminating the environment (41).Some pathogens are shed by animals intermittently and live for months or years in the environment (42)(43)(44)(45)(46).Intermittent shedding of pathogens and limitations of laboratory testing make attempts to identify and remove infected animals unreliable as a means of eliminating the risk for transmission.Antimicrobial treatment of animals also cannot reliably eliminate infection, prevent shedding, or protect against reinfection.In addition, treatment of animals can prolong shedding and contribute to antimicrobial resistance (47). Multiple factors increase the probability of disease transmission at animal exhibits.Animals are more likely to shed pathogens because of stress induced by prolonged transportation, confinement, crowding, and increased handling (48)(49)(50)(51)(52)(53)(54).Commingling increases the probability that animals shedding pathogens will infect other animals (55).The prevalence of certain enteric pathogens is often higher in young animals (56)(57)(58), which are frequently used in petting zoos and educational programs for children.Shedding of STEC and Salmonella organisms is highest in the summer and fall, when substantial numbers of traveling animal exhibits, agricultural fairs, and petting zoos are scheduled (53,58,59). The risk for human infection is increased by certain factors and behaviors, especially in children.These factors and behaviors include lack of awareness of the risk for disease, inadequate hand washing, lack of close supervision, and hand-to-mouth activities (e.g., use of pacifiers, thumb-sucking, and eating) (60).Children are particularly attracted to animal venues but have increased risk for serious illness when they are infected.Although farm residents might have some acquired immunity to certain pathogens (61,62), livestock exhibitors have become infected with E. coli O157:H7 in fair outbreaks (17; K. Smith, DVM, Minnesota Department of Health, personal communication, 2010). The layout and maintenance of facilities and animal exhibits can increase or decrease the risk for infection (63).Factors that increase risk include inadequate hand-washing facilities (64), inappropriate flow of visitors, and incomplete separation between animal exhibits and food preparation and consumption areas (12,16,65).Other factors include structural deficiencies associated with temporary food-service facilities, contaminated or inadequately maintained drinking water systems, and poorly managed sewage-or manure-disposal (19,32,(38)(39)(40). # Outbreaks and Lessons Learned In 2000, two E. coli O157:H7 outbreaks in Pennsylvania and Washington prompted CDC to establish recommendations for enteric disease prevention associated with farm animal contact.Risk factors identified in both outbreaks were direct animal contact and inadequate hand washing (15,66).In the Pennsylvania outbreak, 51 persons (median age: 4 years) became ill within 10 days after visiting a dairy farm.Eight (16%) of these patients acquired hemolytic uremic syndrome (HUS), a potentially fatal complication of STEC infection which involves kidney failure.The same strain of E. coli O157:H7 was isolated from cattle, patients, and the farm environment.An assessment of the farm determined that no areas separate from the animal contact areas existed for eating and drinking, and the hand-washing facilities were poorly maintained and not configured for children (15). The protective effect of hand washing and the persistence of organisms in the environment were demonstrated in an outbreak of Salmonella enterica serotype Enteritidis infections at a Colorado zoo in 1996.A total of 65 cases (primarily among children) were associated with touching a wooden barrier around a temporary Komodo dragon exhibit.Children who were not ill were significantly more likely to have washed their hands after visiting the exhibit.Salmonella enterica serotype Enteritidis was isolated from 39 patients, a Komodo dragon, and the wooden barrier (19). In 2005, an E. coli O157:H7 outbreak among 63 patients, including seven who developed HUS, was associated with multiple fairs in Florida (13).Both direct animal contact and contact with sawdust or shavings were associated with illness.Persons who reported feeding animals were more likely to become ill.Persons were less likely to become ill if they reported washing their hands before eating or drinking.Among persons who washed their hands with soap and water, creating lather decreased the likelihood of illness, illustrating the value of thorough hand washing.Drying hands on clothing increased the likelihood of illness (67). During 2000-2001 at a Minnesota children's farm day camp, washing hands with soap after touching a calf and washing hands before going home decreased the likelihood for illness in two outbreaks involving multiple enteric pathogens (22).Implicated pathogens for the 84 human infections were E. coli O157:H7, Cryptosporidium parvum, non-O157 STEC, Salmonella enterica serotype Typhimurium, and Campylobacter jejuni.These pathogens and Giardia organisms were isolated from calves.Risk factors for children who became ill included caring for an ill calf and getting visible manure on their hands. Disease transmission can occur in the absence of direct animal contact if a pathogen is disseminated in the environment.In a 2002 Oregon county fair outbreak, 60 E. coli O157:H7 infections occurred, primarily among children (29).Illness was associated with visiting an exhibition hall that housed goats, sheep, pigs, rabbits, and poultry; however, illness was not associated with touching animals or their pens, eating, or inadequate hand washing.E. coli O157:H7 was likely disseminated to environmental surfaces via contaminated dust (29).In 2004, an outbreak of E. coli O157:H7 infections was associated with attendance at the North Carolina State Fair goat and sheep petting zoo (14).Health officials identified 108 patients, including 15 who developed HUS.In addition to direct contact with animals, risk factors included manure contact and hand-to-mouth behaviors.Evidence indicated that falling down or sitting on the ground in the petting zoo was associated with illness.The outbreak strain of E. coli O157:H7 was isolated from shoes and shavings collected from a stroller in households of petting zoo visitors (14). Enteric pathogens can contaminate the environment and persist in animal housing areas for long periods.For example, E. coli O157:H7 can survive in soil for months (32,42,44,68,69).Prolonged environmental persistence of pathogens was documented in a 2001 Ohio outbreak of E. coli O157:H7 infections in which 23 persons became ill at a fair facility after handling sawdust, attending a dance, or eating and drinking in a barn where animals had been exhibited during the previous week (32).Fourteen weeks after the fair, E. coli O157:H7 was isolated from multiple environmental sources within the barn, including sawdust on the floor and dust on the rafters.Forty-two weeks after the fair, E. coli O157:H7 was again recovered from sawdust on the floor.Environmental persistence of E. coli O157:H7 was also described after a 2003 outbreak in which 25 persons acquired E. coli O157:H7 at a Texas agricultural fair.The strain isolated from patients also was found in fair environmental samples 46 days after the fair ended (17).In the previously mentioned North Carolina outbreak (14), the outbreak strain of E. coli O157:H7 was isolated from animal bedding 10 days after the fair was over and from soil 5 months after the animal bedding and topsoil were removed (14,69). Improper facility design and inadequate maintenance can increase risk for infection, as illustrated by one of the largest waterborne outbreaks in the United States (39,40).In 1999, approximately 800 suspected cases of E. coli O157:H7 and/ or Campylobacter species infection were identified among attendees at a New York county fair, where unchlorinated water supplied by a shallow well was used by food vendors to make beverages and ice (40). Temporary animal exhibits are particularly vulnerable to design flaws (13,19).Such exhibits include animal displays or petting zoos added to attract visitors to zoos, festivals, roadside attractions, farm stands, farms where persons can pick their own produce, feed stores, and Christmas tree lots.In 2005, an E. coli O157:H7 outbreak in Arizona was associated with a temporary animal contact exhibit at a municipal zoo.A play area for children was immediately adjacent to and downhill from the petting zoo facility.The same strain of E. coli O157:H7 was found both in children and 12 petting zoo animals.Inadequate hand-washing facilities were reported from a temporary exhibit in British Columbia, Canada where child-care facility and school field trips to a pumpkin patch with a petting zoo resulted in 44 cases of E. coli O157:H7 infection (16).The same strain of E. coli O157:H7 was found both in children and in a petting zoo goat.Running water and signs recommending hand washing were not available, and alcohol hand sanitizers were at a height that was unreachable for some children.In New York, 163 persons became ill with STEC O111:H8, Cryptosporidium species, or both at a farm stand that sold unpasteurized apple cider and had a petting zoo with three calves (70).Stools from two calves were Shiga toxin 1 positive. Day camps at which children have prolonged close contact with livestock pose a unique challenge with regard to disease prevention.In the previously mentioned Minnesota day camp outbreak ( 22), disease transmission occurred again even though heightened prevention measures were implemented based on findings from an outbreak investigation at the same camp the year before.Similarly, in 2007, an E. coli O157:H7 outbreak occurred at a day camp in Florida where prolonged contact with livestock was encouraged (71). Recurrent outbreaks have happened because of failure to properly implement disease-prevention recommendations.Following a Minnesota outbreak of cryptosporidiosis with 31 ill students at a school farm program, specific recommendations provided to teachers were inadequately implemented (20), and a subsequent outbreak occurred with 37 illnesses.Handwashing facilities and procedures were inadequate.Coveralls and boots were dirty, cleaned infrequently, and handled without subsequent hand washing. Education of visitors to public animal contact venues about the risk for transmission of diseases from animals to humans is a critical disease-prevention measure.Awareness of zoonotic disease risks is protective against illness in outbreaks (14). Outbreaks also have resulted from contaminated animal products used for school activities.Salmonellosis outbreaks associated with dissection of owl pellets have been documented in Minnesota (72) and Massachusetts (C. Brown, DVM, Massachusetts Department of Public Health, personal communication, 2008).In Minnesota, risk factors for infection included inadequate hand washing, use of food service areas for the activity, and improper cleaning of contact surfaces.Persons in a middle school science class were among those infected in a multistate salmonellosis outbreak associated with frozen rodents purchased to feed snakes from the same Internet supplier (26). During 2005-2010, several infectious disease outbreaks were caused by contact with animals and animal products not primarily associated with public settings.However, these outbreaks have implications for animal contact venues.Turtles and other reptiles, amphibians, rodents, and live poultry (e.g., chicks, chickens, ducklings, ducks, turkeys, and geese) are recognized as sources of human Salmonella infections (19,25,27,(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83).Since 2006, three large multistate outbreaks have been linked to contact with small turtles, including a fatal case in an infant (79,80,(84)(85)(86).In addition, 14 multistate outbreaks linked with live poultry originating from mail-order hatcheries have been reported since 2005 (CDC, unpublished data, 2010).Ill persons included those who reported contact with live poultry at feed stores, schools, day cares, fairs, or petting zoos (78).During 2006During -2008, a total of 79 human Salmonella enterica serotype Schwarzengrund infections were linked to multiple brands of contaminated dry dog and cat food produced at a plant in Pennsylvania (87).Contaminated pig ear treats and pet treats containing beef and seafood also have been associated with Salmonella infections (88)(89)(90)(91). Risks from aquatic animals include direct and indirect contact with the animal, tank, water, filtration equipment, or other tank contents.Multidrug-resistant human Salmonella infections have been linked to contact with contaminated water from home aquariums containing tropical fish (92,93).A single case of Plesiomonas shigelloides infection in a Missouri infant was identified, and the organism was subsequently isolated from a babysitter's aquarium (94).A survey of tropical fish tanks in Missouri found that four (22%) of 18 tanks yielded P. shigelloides from three pet stores.During 2009-2011, approximately 200 Salmonella enterica serotype Typhimurium infections were linked to contact with African dwarf frogs, an aquatic amphibian, or their tank water or contents (C. Barton Behravesh, CDC, personal communication, 2011).Ill persons included those who reported such contact at carnivals, nursing homes, day cares, pet stores, and other retail stores (27).These findings have implications for risk for infection from aquatic exhibits (e.g., aquariums and aquatic touch tanks). # Sporadic Infections Case-control studies also have associated sporadic infections (i.e., those not linked to an outbreak) with animals including reptiles and farm animals (82,95).For example, a study of sporadic E. coli O157:H7 infections in the United States determined that persons who became ill, especially children, were more likely than persons who did not become ill to have visited a farm with cows (96).

Additional studies also documented an association between E. coli O157:H7 infection and visiting a farm (97) and living in a rural area (98).Studies of human cryptosporidiosis have documented contact with cattle and visiting farms as risk factors for infection (61,99,100). Another study identified multiple factors associated with Campylobacter infection, including consumption of raw milk and contact with farm animals (101). # Additional Health Concerns Although enteric diseases are the most commonly reported illnesses associated with animals in public settings, other health risks exist.For example, allergies can be associated with animal dander, scales, fur, feathers, urine, and saliva (102)(103)(104)(105)(106)(107)(108).Additional health concerns include injuries, exposure to rabies, and infections other than enteric diseases. # Injuries Injuries associated with animals are a well-described and important problem.For example, dog bites are a substantial community problem for which specific guidelines have been written (109).Injuries associated with animals in public settings include bites, kicks, falls, scratches, stings, crushing of the hands or feet, and being pinned between the animal and a fixed object.These injuries have been associated with big cats (e.g., tigers), monkeys, and other domestic, wild, and zoo animals. 2003).For example, a Kansas teenager was killed while posing for a photograph with a tiger being restrained by its handler at an animal sanctuary (110).In Texas, two high school students were bitten by a cottonmouth snake that was used in a science class after being misidentified as a nonvenomous species (W. Garvin, Caldwell Zoo, Texas, personal communication, 2008). # Exposure to Rabies Persons who have contact with rabid mammals can be exposed to rabies virus through a bite or when mucous membranes or open wounds become contaminated with infected saliva or nervous tissue.Although no human rabies deaths caused by animal contact in public settings have been reported, multiple rabies exposures have occurred, requiring extensive public health investigation and medical follow-up.For example, thousands of persons have received rabies postexposure prophylaxis (PEP) after being exposed to rabid or potentially rabid animals, including bats, raccoons, cats, goats, bears, sheep, horses, and dogs, at various venues: an urban public park (S. Slavinski, DVM, New York City Department of Health and Mental Hygiene, personal communication, 2010), a pet store in New Hampshire (111), a county fair in New York State (112), petting zoos in Iowa (113,114) # Other Infections Multiple bacterial, viral, fungal, and parasitic infections have been associated with animal contact, and the infecting organisms are transmitted through various modes.Infections from animal bites are common and frequently require extensive treatment or hospitalization.Bacterial pathogens associated with animal bites include Pasteurella species, Francisella tularensis (116), Staphylococcus species, Streptococcus species, Capnocytophaga canimorsus, Bartonella henselae (cat-scratch disease), and Streptobacillus moniliformis (rat-bite fever).Certain monkey species (especially macaques) that are kept as pets or used in public exhibits can be infected with simian herpes B virus.Infected monkeys are often asymptomatic or have mild oral lesions yet human exposure through monkey bites or bodily fluids can result in fatal meningoencephalitis (117,118). Skin contact with animals in public settings also is a public health concern.In 1995, a total of 15 cases of ringworm (club lamb fungus) caused by Trichophyton species and Microsporum gypseum were documented among owners and family members who exhibited lambs in Georgia (119).In 1986, ringworm in 23 persons and multiple animal species was traced to a Microsporum canis infection in a hand-reared zoo tiger cub (120).Orf virus infection (i.e., contagious ecthyma or sore mouth in sheep and goats) has occurred after contact with sheep at a public setting (121).Orf virus infection also has been described in goats and sheep at a children's petting zoo (122) and in a lamb used for an Easter photo opportunity (M. Eidson, DVM, New York State Department of Health, personal communication, 2003).Transmission of pox viruses in public settings also has been described.In the 1970s, after handling various species of infected exotic animals, a zoo attendant experienced an extensive papular skin rash from a cowpox-like virus (123).Cowpox virus transmission from rats to humans was also documented among persons who had purchased the rats as pets or had contact with them at pet stores (124).In 2003, multiple cases of monkeypox occurred among persons who contacted infected prairie dogs either at a child-care center (125,126) or a pet store (J.J. Kazmierczak, DVM, Wisconsin Department of Health and Family Services, personal communication, 2004).Aquatic animals and their environment also have been associated with cutaneous infections (127).For example, Mycobacterium marinum infections have been described among persons owning or cleaning fish tanks (128,129). Ectoparasites and endoparasites pose concerns when humans and exhibit animals interact.Sarcoptes scabiei is a skin mite that infests humans and animals, including swine, dogs, cats, foxes, cattle, and coyotes (130,131).Although human infestation from animal sources is usually self-limiting, skin irritation and itching might occur for multiple days and can be difficult to diagnose (131,132).Bites from avian mites have been reported in association with pet gerbils in school settings (133).Fleas from animals that bite humans increase the risk for infection or allergic reaction.In addition, fleas can carry a tapeworm species that can infect children who swallow the flea (134,135).Animal parasites also can infect humans who ingest materials contaminated with animal feces or who ingest or come into contact with contaminated soil.Parasite control through veterinary care and proper husbandry combined with hand washing reduces the risks associated with ectoparasites and endoparasites (136). Tuberculosis is another disease concern for certain animal settings.In 1996, a total of 12 circus elephant handlers at an exotic animal farm in Illinois were infected with Mycobacterium tuberculosis; one handler had signs consistent with active disease after three elephants died of tuberculosis.Medical history and testing of the handlers indicated that the elephants had been a probable source of exposure for most of the human infections (137).During 1989-1991 at a zoo in Louisiana, seven animal handlers who were previously negative for tuberculosis tested positive after a Mycobacterium bovis outbreak in rhinoceroses and monkeys (138).Other instances of transmission of mycobacterial species from animals to animal care staff without known transmission to the public have also been documented (139)(140)(141).The U.S. Department of Agriculture (USDA) has developed guidelines regarding removal of tuberculosis-infected animals from public settings because of the risk for exposure to the public (142). Zoonotic pathogens also can be transmitted by direct or indirect contact with reproductive fluids, aborted fetuses, or newborns from infected dams.Live-birthing exhibits, usually involving livestock (e.g., cattle, pigs, goats, or sheep), are popular at agricultural fairs.Although the public usually does not have direct contact with animals during birthing, newborns and their dams might be available for petting afterward.Q fever (Coxiella burnetii), leptospirosis, listeriosis, brucellosis, and chlamydiosis are serious zoonoses that can be acquired through contact with reproductive materials (143). C. burnetii is a rickettsial organism that most frequently infects cattle, sheep, and goats.The disease can cause abortion in animals, but more frequently the infection is asymptomatic.During birthing, infected animals shed large numbers of organisms, which can become aerosolized.Most persons exposed to C. burnetii develop an asymptomatic infection, but clinical illness can range from an acute influenza-like illness to life-threatening endocarditis.A Q fever outbreak involving 95 confirmed cases and 41 hospitalizations was linked to goats and sheep giving birth at petting zoos in indoor shopping malls (144).Indoor-birthing exhibits might pose an increased risk for Q fever transmission because of inadequate ventilation. Chlamydophila psittaci infections cause respiratory disease and are usually acquired from psittacine birds (145).For example, an outbreak of C. psittaci pneumonia occurred among the staff members at Copenhagen Zoological Garden (146).On rare occasions, chlamydial infections acquired from sheep, goats, and birds result in reproductive problems in women (145,147,148). Transmission of influenza viruses between humans and animals has implications for animals in public settings.Cases and clusters of human infection with swine influenza viruses have been reported sporadically since the 1970s (149,150); several of these cases have been acquired from swine at agricultural fairs (151)(152)(153).Conversely, transmission of human influenza viruses to swine also has been documented (154).For example, in 2009, an H1N1 influenza virus strain emerged, causing a pandemic among humans with sporadic transmission from humans to swine (155). # Recommendations Guidelines from multiple organizations were used to create the recommendations in this report (156)(157)(158).Although no federal U.S. laws address the risk for transmission of pathogens at venues where the public has contact with animals, some states have such laws (64,67,(159)(160)(161).For example, in 2005, North Carolina enacted legislation requiring persons displaying animals for public contact at agricultural fairs to obtain a permit from the North Carolina Department of Agriculture and Consumer Services (.nc.us/enactedlegislation/statutes/pdf/bysection/chapter_106/ gs_106-520.3a.pdf ). Certain federal agencies and associations in the United States have developed standards, recommendations, and guidelines for reducing risks associated with animal contact by the public in zoologic parks.The Association of Zoos and Aquariums has accreditation standards for reducing risk for animal contact with the public in zoologic parks (162).In accordance with the Animal Welfare Act, USDA licenses and inspects certain animal exhibits.These inspections primarily address humane treatment but also impact the health of the animal and safety of the public.In 2001, CDC issued guidelines to reduce the risk for infection with enteric pathogens associated with farm visits (66).CDC also has issued recommendations for preventing transmission of Salmonella from reptiles, amphibians, and live poultry to humans (27,77,78,86,163,164).The Association for Professionals in Infection Control and Epidemiology Inc. (APIC) and the Animal-Assisted Interventions Working Group (AAI) have developed guidelines to address risks associated with the use of animals in health-care settings (2,6).NASPHV has developed a compendium of measures to reduce risks for human exposure to C. psittaci and rabies virus (145,165). Studies in some localities have suggested that implementation of these recommendations could be improved (60,166,167).Stakeholders should strive to facilitate comprehensive implementation of the following recommendations. # Recommendations for Local, State, and Federal Agencies Communication and cooperation among human and animal health agencies should be enhanced and include veterinarians and cooperative extension offices.Additional research should be conducted regarding the risk factors and effective prevention and control methods for health issues associated with animal contact. To enhance uptake of these recommendations, agencies should take the following steps: # Recommendations for Education Education is essential to reduce risks associated with animal contact in public settings.Experience from outbreaks suggests that visitors knowledgeable about potential risks are less likely to become ill (14).Even in well-designed venues with operators who are aware of the risks for disease, outbreaks can occur when visitors do not understand risks and therefore are less likely to apply disease-prevention measures. Venue operators should take the following steps: - Become knowledgeable about the risks for disease and injury associated with animals and be able to explain riskreduction measures to staff members and visitors. -Become familiar with and implement the recommendations in this compendium. -Consult with veterinarians, state and local agencies, and cooperative extension personnel on implementation of the recommendations. -Develop or obtain training and educational materials and train staff members. -Ensure that visitors receive educational messages before they enter the exhibit, including information that animals can cause injuries or carry organisms that can cause serious illness (Appendices A and B). -Provide information in a simple and easy-to-understand format that is age-and language-appropriate. -Provide information in multiple formats (e.g., signs, stickers, handouts, and verbal information). -Provide information to persons arranging school field trips or classroom exhibits so that they can educate participants and parents before the visit.Venue staff members should take the following steps: - Become knowledgeable about the risks for disease and injury associated with animals and be able to explain riskreduction recommendations to visitors. -Ensure that visitors receive educational messages regarding risks and prevention measures. -Encourage compliance by the public with risk-reduction recommendations, especially compliance with hand-washing procedures (Appendix C) as visitors exit animal areas. -Comply with local and state requirements for reporting animal bites or other injuries. # Recommendations for Managing Public-Animal Contact The recommendations in this report were developed for settings in which direct animal contact is encouraged (e.g., petting zoos and aquatic touch tanks) and in which animal contact is possible (e.g., county fairs).They should be tailored to specific settings and incorporated into guidelines and regulations developed at the state or local level.Contact with animals should occur in settings where measures are in place to reduce the potential for injuries or disease transmission.Incidents or problems should be investigated, documented, and reported. # Facility Design The design of facilities and animal pens should minimize the risk associated with animal contact (Figure ), including limiting direct contact with manure and encouraging hand washing (Appendix C).The design of facilities or contact settings might include double barriers to prevent contact with animals or contaminated surfaces except for in specified animal interaction areas.Previous outbreaks have revealed that temporary exhibits are often not designed appropriately.Common problems include inadequate barriers, floors and other surfaces that are difficult to keep clean and disinfect, insufficient plumbing, lack of signs regarding risk and prevention measures, and inadequate hand-washing facilities (13,14,19,33,36).Specific guidelines might be necessary for certain settings, such as schools (Appendix D). Recommendations for cleaning and disinfection should be tailored to the specific situation.All surfaces should be cleaned thoroughly to remove organic matter before disinfection.A 1:32 dilution of household bleach (e.g., one-half cup bleach per gallon of water) is needed for basic disinfection.Quaternary ammonium compounds (e.g., Roccal or Zephiran) also can be used per the manufacturer label.For disinfection when a particular organism has been identified, additional guidance is available ().Most compounds require >10 minutes of contact time with a contaminated surface. Venues should be divided into three types of areas: nonanimal areas (where animals are not permitted, with the exception of service animals), transition areas (located at entrances and exits to animal areas), and animal areas (where animal contact is possible or encouraged) (Figure ). # Nonanimal Areas - Do not permit animals, except service animals, in nonanimal areas. -Prepare, serve, and consume food and beverages only in nonanimal areas. -Provide hand-washing facilities and display hand-washing signs where food or beverages are served (Appendix C). # Transition Areas Between Nonanimal and Animal Areas Establishing transition areas through which visitors pass when entering and exiting animal areas is critical.For areas where animal contact is encouraged, a one-way flow of visitors is preferred, with separate entrance and exit points.The transition areas should be designated as clearly as possible, even if they are conceptual rather than physical (Figure ). Entrance transition areas should be designed to facilitate education: - Post signs or otherwise notify visitors that they are entering an animal area and that there are risks associated with animal contact (Appendix B). -Instruct visitors not to eat, drink, smoke, place their hands in their mouth, or use bottles or pacifiers while in the animal area. -Establish storage or holding areas for strollers and related items (e.g., wagons and diaper bags). -Control visitor traffic to prevent overcrowding.Exit transition areas should be designed to facilitate hand washing: - Post signs or otherwise instruct visitors to wash their hands when leaving the animal area. # Animal Areas - Do not allow food and beverages in animal areas. - Do not allow toys, pacifiers, spill-proof cups, baby bottles, strollers or similar items in animal areas. -Prohibit smoking and other tobacco product use in animal areas. -Supervise children closely to discourage hand-to-mouth activities (e.g., nail-biting and thumb-sucking), contact with manure, and contact with soiled bedding.Children should not be allowed to sit or play on the ground in animal areas.If hands become soiled, supervise hand washing immediately. -Ensure that regular animal feed and water are not accessible to the public. -Allow the public to feed animals only if contact with animals is controlled (e.g., with barriers). -Do not provide animal feed in containers that can be eaten by humans (e.g., ice cream cones) to decrease the risk for children eating food that has come into contact with animals. -Promptly remove manure and soiled animal bedding from animal areas. -Assign trained staff members to encourage appropriate human-animal interactions, to identify and reduce potential risks for patrons, and process reports of injuries and exposures. - Store animal waste and specific tools for waste removal (e.g., shovels and pitchforks) in designated areas that are restricted from public access. -Avoid transporting manure and soiled bedding through nonanimal areas or transition areas.If this is unavoidable, take precautions to prevent spillage. -Where feasible, disinfect animal areas (e.g., flooring and railings) at least once daily. -Provide adequate ventilation both for animals (168) and humans. -Minimize the use of animal areas for public activities (e.g., weddings and dances).If areas previously used for animals must be used for public events, the areas should be cleaned and disinfected, particularly if food and beverages are served. -For birds in bird encounter exhibits, refer to the psittacosis compendium ( 145) for recommendations regarding disease prevention and control. -Visitors to aquatic touch tank exhibits who have open wounds should be advised not to participate.Handwashing stations should be provided. -When using animals or animal products (e.g., animal pelts, animal waste, and owl pellets) for educational purposes, only use them in designated animal areas.Animals and animal products should not be brought into school cafeterias and other areas where food and beverages are prepared, served, or consumed. -When animals are in school classrooms, specific areas must be designated for animal contact (Appendix D).Designated animal areas must be thoroughly cleaned after use.Parents should be informed of the benefits and potential risks associated with animals in school classrooms.

# Animal Care and Management The risk for disease or injury from animal contact can be reduced by carefully managing the specific animals used.The following recommendations should be considered for management of animals in contact with the public. - accredited veterinarian should be up-to-date according to local or state requirements for animals in public settings.A herd or flock inspection is a critical component of the health certificate process.Routine screening for diseases is not recommended, except for C. psittaci in bird encounter exhibits (145), tuberculosis in elephants (141) and primates, and Q fever in ruminants in birthing exhibits (169). -Rabies: All animals should be housed to reduce potential exposure to wild animal rabies reservoirs.Mammals should also be up-to-date on rabies vaccinations according to current recommendations (165).These steps are particularly critical in areas where rabies is endemic and in venues where animal contact is encouraged (e.g., petting zoos). Because of the extended incubation period for rabies, unvaccinated mammals should be vaccinated at least 1 month before they have contact with the public.If no licensed rabies vaccine exists for a particular species (e.g., goats, swine, llamas, and camels) that is used in a setting where public contact occurs, consultation with a veterinarian regarding off-label use of rabies vaccine is recommended.Use of off-label vaccine does not provide the same level of assurance as vaccine labeled for use in a particular species; however, off-label use of vaccine might provide protection for certain animals and thus decrease the probability of rabies transmission (165).Vaccinating slaughter-class animals before displaying them at fairs might not be feasible because of the vaccine withdrawal period that occurs as a result of antibiotics used as preservatives in certain vaccines.Mammals that are too young to be vaccinated should be used in exhibit settings only if additional restrictive measures are available to reduce risks (e.g., using only animals that were born to vaccinated mothers and housed to avoid rabies exposure).In animal contact settings, rabies testing should be considered for animals that die suddenly in addition to other diagnostic considerations. -Dangerous animals: Because of their strength, unpredictability, venom, or the pathogens that they might carry, certain domestic, exotic, or wild animals should be prohibited in exhibit settings where a reasonable possibility of animal contact exists.Species of primary concern include nonhuman primates (e.g., monkeys and apes) and certain carnivores (e.g., lions, tigers, ocelots, wolves and wolf hybrids, and bears).In addition, rabies-reservoir species (e.g., bats, raccoons, skunks, foxes, and coyotes) should not be used for direct contact. -Animal births: Ensure that the public has no contact with newly born animals or birthing by-products (e.g., the placenta).In live-birth exhibits, the environment should be thoroughly cleaned after each birth, and all waste products should be properly discarded.Holding such events outside or in well-ventilated areas is preferable. # Additional Recommendations - Populations at high risk: Children aged <5 years are at particularly high risk for serious infection.Other groups at increased risk include persons with waning immunity (e.g., older adults) and persons who are mentally impaired, pregnant, or immunocompromised (e.g., persons with human immunodeficiency virus/acquired immunodeficiency syndrome, without a functioning spleen, or receiving immunosuppressive therapy).Persons at high risk for infection should take heightened precautions at animal exhibits.In addition to thorough and frequent hand washing, heightened precautions could include avoiding contact with animals and their environment (e.g., pens, bedding, and manure).Animals of particular concern for transmitting enteric diseases include young ruminants, live poultry, reptiles, amphibians, and ill animals. -Consumption of unpasteurized products: Prohibit the consumption of unpasteurized or raw dairy products (e.g., milk, cheese, and yogurt) and unpasteurized apple cider or juices. # Wash Hands When Leaving Animal Exhibits - Ferrets: Do not keep in facilities with children aged <5 years, nor should children aged <5 years be allowed to have direct contact with these animals to prevent bites. -Farm animals: See General Guidelines for School Settings. Certain animals (e.g., young ruminants and baby poultry) intermittently excrete substantial numbers of germs; therefore, these farm animals are not appropriate in school or child-care settings unless meticulous attention to personal hygiene can be ensured. -Animal products: Assume that products such as owl pellets and frozen rodents used to feed reptiles are contaminated with Salmonella organisms.Owl pellets should not be dissected in areas where food is prepared, served, or consumed.Children aged <5 years should not be allowed to have direct contact with animal products. # Animals Not Recommended in School or Child-Care Settings - Inherently dangerous animals (e.g., lions, tigers, cougars, and bears). -Nonhuman primates (e.g., monkeys and apes). - Mammals at high risk for transmitting rabies (e.g., bats, raccoons, skunks, foxes, and coyotes). -Aggressive or unpredictable wild or domestic animals. - Stray animals with unknown health and vaccination history. - Venomous or toxin-producing spiders, insects, reptiles, and amphibians. # Appendix A Animals in Public Settings: Guidelines for Venue Operators and Staff Members Operators and staff members should be aware of the following risks for disease and injury associated with animals in public settings: - Disease and injuries have occurred following contact with animals and their environment. -Healthy animals can carry germs that make visitors sick. - Visitors can pick up germs when they touch animals or animal droppings or enter an animal's environment. -Visitors can rid themselves of most germs if they wash their hands immediately after leaving an animal area.Visitors should wash their hands even if they did not directly contact the animals. -The risk for developing serious or life-threatening illnesses from contact with animals is higher among certain visitors, especially young children (i.e., aged <5 years), older adults, pregnant women, and persons with weakened immune systems. Operators and staff members should take the following steps to maintain a safe environment when animals are present in public settings: - Design the venue with safety in mind by having designated animal areas, nonanimal areas, and transition areas. -Do not permit any animals other than service animals in nonanimal areas. -Provide hand-washing facilities where food and beverages are prepared, served, or consumed. -Assign trained staff members to monitor animal contact areas. - Exclude food and beverages, toys, pacifiers, spill-proof cups, and baby bottles, and prohibit smoking in animal contact areas. -Keep the animal areas as clean and disinfected as possible, and limit visitor contact with manure and animal bedding. - Allow feeding of animals only if contact with animals can be controlled (e.g., over a barrier). - Minimize use of animal areas for public activities (e.g., weddings, dances). -Design transition areas for entering and exiting animal areas with appropriate signs or other forms of notification regarding risks of animal contact and location of handwashing facilities. -Maintain hand-washing stations that are accessible to children, and direct visitors to wash their hands when exiting animal areas. -Position hand-washing stations in places that encourage hand washing when exiting animal areas. -Ensure that animals receive appropriate preventive care, including vaccinations and parasite control. -Provide potable water for animals. - Prohibit consumption of unpasteurized dairy products (e.g., raw milk) and juices. Operators and staff members should educate visitors regarding animal contact in public settings: - Inform visitors about the risks for disease and injury before they enter animal areas. -Provide simple instructions in multiple age-and languageappropriate formats. -Direct visitors to wash their hands and assist children with hand washing immediately after visiting an animal area. - Advise visitors that they should not eat, drink, or place things in their mouths after animal contact or visiting an animal area until they have washed their hands. -Advise visitors to closely supervise children and to be aware that objects such as clothing, shoes, and stroller wheels can become soiled and serve as a source of germs after leaving an animal area. -Make visitors aware that young children, older adults, pregnant women, and persons who are immunocompromised are at increased risk for serious illness. # Appendix B Suggested Sign or Handout for Visitors to Petting Zoos- Appendix C Hand-Washing Recommendations to Reduce Disease Transmission from Animals in Public Settings Hand washing is the most important prevention step for reducing disease transmission associated with animals in public settings.Hands should always be washed immediately when exiting animal areas, after removing soiled clothing or shoes, and before eating or drinking.Venue staff members should encourage hand washing as persons exit animal areas. # How to Wash Hands - Wet your hands with clean, running water (warm or cold) and apply soap; rub your hands together to make a lather and scrub them well (be sure to scrub the backs of your hands, between your fingers, and under your nails); continue rubbing your hands for at least 20 seconds; rinse your hands well under running water. -If possible, turn off the faucet using a disposable paper towel. - Dry your hands using a clean disposable paper towel or air dry them.Do not dry hands on clothing. -Assist young children with washing their hands. # Hand-Washing Facilities or Stations - Hand-washing facilities or stations should be accessible, sufficient for the maximum anticipated attendance, and accessible by children (i.e., low enough for children to reach or equipped with a stool), adults, and persons with disabilities. - Hand-washing facilities stations should be conveniently located in transition areas between animal and nonanimal areas and in the nonanimal food concession areas. -Maintenance of hand-washing facilities and stations should include routine cleaning and restocking to ensure an adequate supply of paper towels and soap. -Running water should be of sufficient volume and pressure to remove soil from hands.Volume and pressure might be substantially reduced if the water supply is furnished from a holding tank; therefore, a permanent pressurized water supply is preferable. -Hand-washing stations should be designed so that both hands are free for hand washing by having operation with a foot pedal or water that stays on after hand faucets are turned on. -Liquid soap dispensed by a hand or foot pump is recommended. - Hot water is preferable, but if the hand-washing facilities or stations are supplied with only cold water, a soap that emulsifies easily in cold water should be provided. -Communal basins, in which water is used by more than one person, are not adequate hand-washing facilities. # Hand-Sanitizing Agents - Washing hands with soap and water is the best way to reduce the number of germs on them. -If soap and water are not available, use an alcohol-based hand sanitizer that contains at least 60% alcohol. - Visible contamination and dirt should be removed before using hand sanitizers.Hand sanitizers are not effective when hands are visibly dirty. -Even when hand sanitizer is used, visitors should always wash hands with soap and water as soon as possible after being in animal areas. -Alcohol-based hand sanitizers can quickly reduce the number of germs on hands in some situations, but sanitizers do not eliminate all types of germs. # How to Use Hand Sanitizers - Apply the product to the palm of one hand. - Rub your hands together. - Rub the product over all surfaces of your hands and fingers until your hands are dry. # Hand-Washing Signs - At venues where human-animal contact occurs, signs regarding proper hand-washing practices are critical to reduce disease transmission. -Signs that remind visitors to wash hands should be posted at exits from animal areas (i.e., exit transition areas) and in nonanimal areas where food is served and consumed (Figure). -Signs should be posted that direct all visitors to hand-washing stations when exiting animal areas. -Signs with proper hand-washing instructions should be posted at hand-washing stations and restrooms to encourage proper practices. -If appropriate for the setting, hand-washing signs should be available in different languages. # Appendix D # Animal-Specific Guidelines - Fish: Use disposable gloves when cleaning aquariums, and do not dispose of aquarium water in sinks used for food preparation or for obtaining drinking water.

Cover: From top, Escherichia co//O157:H7 on sorbitol MacConkey agar, Vibrio cholerae O1 on TCBS agar, and Shige/la flexneri on xylose lysine desoxycholate agar.Funding for the development of this manual was provided by the U.S. Agency for International Development, Bureau for Africa, Office of Sustainable Development.This manual was developed as a result of a joint effort by the World Health Organization Regional Office for Africa, WHO Headquarters, and the Centers for Disease Control and Prevention as part of the activities of the WHO Global Task Force on Cholera Control.In particular, the staff of the project for Improving Preparedness and Response to Cholera and Other Epidemic Diarrhoeal Diseases in Southern Africa have worked closely with many laboratorians and epidemiologists in southern Africa to develop an integrated approach to the laboratory diagnosis of cholera and dysentery upon which this manual is based.We also appreciate the valuable assistance of Ms.# Introduction Cholera and dysentery have afflicted humankind for centuries.The epidemics they cause have affected the outcome of wars and the fates of countries.In much of the world, epidemic cholera and dysentery are uncom mon, but during the past decade these two diseases have re-emerged as causes of significant morbidity and mortality in many developing countries. Only a few pathogens cause epidemic diarrhea, although there are many that cause sporadic diarrhea.In developing countries, two etiologic agents are responsible for most epidemic diarrhea: toxigenic Vibrio choJerae serogroup O1, which causes watery diarrhea, and ShigeJJa dysenteriae serotype 1, which causes bloody diarrhea.Recently, two additional organisms have emerged to cause epidemic diarrhea, Vibrio choJerae serogroup O139, which causes watery diarrhea, and E scherichia coJi serotype O157:H7, which causes bloody diarrhea.The latter is a common agent of diarrhea only in developed countries. This manual focuses on the epidemiology of these four organisms and the laboratory methods used to identify them and to test their susceptibility to antimicrobial agents in the epidemic setting.The laboratory techniques and study methodology described provide accurate and useful information for the control of epidemics using a minimum of resources.The manual emphasizes coordination of the activities of the microbiologist and the epidemiologist in order to obtain information that can be generalized to develop effective treatment policies for these epidemic diarrheal diseases.It encourages focused studies to determine the organisms causing epidemics and their antimicrobial susceptibility patterns rather than relying on random information that may not accurately represent a situation. Often the countries that face the challenge of responding to an epidemic are those with the least resources.Therefore, the microbiology laboratory must use its resources wisely in order to have the greatest impact on reducing morbidity and mortality during an epidemic.There may be several ways to reach the end result of identifying the organism causing the outbreak or the epidemic.Often, however, a small added benefit requires a much larger expenditure of materials and time.In this manual this problem is addressed specifically.The procedures described are not new; most have been used for a number of years.However, these procedures were specifically selected for testing specimens from outbreaks rather than for general use in a clinical microbiology laboratory.The selected procedures minimize the materials needed by the laboratory while deriving the most useful information. The two most common types of epidemic diarrhea in developing countries are watery diarrhea caused by Vibrio cholerae serogroup O1 and bloody diarrhea caused by Shigella dysenteriae serotype 1 (Sd1).This chapter presents an overview of these and other organisms that cause epidemic dysentery and cholera.Knowing the epidemiology and clinical presentation of these organisms will aid in understanding the procedures presented in the following chapters. # Epidemic cholera Cholera is a secretory diarrheal disease caused by enterotoxin-producing strains of V. cholerae.Although over 150 serogroups of V. cholerae have been identified, for decades toxigenic V. cholerae serogroup O1 was the only known cause of epidemic cholera.After a large epidemic in Asia in 1992 and 1993, it became clear that toxigenic V. cholerae serogroup O139 also could cause epidemics very similar to those caused by V. cholerae O1.According to World Health Organization (WHO) guidelines, both V. cholerae O1 and O139 are now recognized causes of cholera and should be reported the same way.Isolates of non-O1 and non-O139 V. cholerae can cause illness, but they do not pose the public health threat of the O1 and O139 serogroups. Additional details on the epidemiology, historical background, clinical manifes tations and treatment of cholera are presented in Chapter 5. # Epidemic dysentery Dysentery, defined as diarrhea with visible blood, can be caused by many different organisms, including Shigella spp.,enterohemorrhagic E scherichia coli serotype O157:H7, C am pylobacter je ju n i, enteroinvasive E. coli, Salm onella spp.and, infrequently, Entam oeba histolytica.Of these organisms, the only ones known to cause large epidemics are Shigella dysenteriae serotype 1 (Sd1), and much less frequently, E. coli O157:H7.Additional details on the epidemiol ogy, historical background, clinical manifestations and treatment of Sd1 infec tion are presented in Chapter 3. Although uncommon, a species of parasitic ameba, E. histolytica, deserves mention.This organism is an occasional cause of dysentery, especially in young adults, but does not cause epidemic disease.Asymptomatic infection with E. histolytica, however, is frequent in developing countries, being present in up to 10% of healthy persons.Examination of specimens should be done by a trained microscopist since the organism must be differentiated from nonpathogenic amebae and from white blood cells, which are often mistaken for amebic trophozoites.In some epidemics of dysentery due to Sd1, E. histolytica was also identified and initially thought to be the cause.Because of this incorrect diagnosis, persons with dysentery were treated with anti-amebic drugs, resulting in continued transmission of Sd1 and excess preventable mortality.Finding E. histolytica in a bloody stool during an epidemic of dysentery does not indicate that it is the cause of the epidemic, or even that it is the cause of dysentery in an individual patient. E. coli O157:H7 has caused at least one large outbreak of dysentery in southern Africa.It is suspected to have caused additional outbreaks, but these were not confirmed by microbiologic culture.E. coli O157:H7 is included in this manual so that laboratory workers will be familiar with the organism and will be able to identify it if necessary.It may return in the future to cause additional epidemics; laboratories must be prepared to identify it. Additional details on the epidemiology, historical background, clinical manifestations and treatment of E. coli O157:H7 are presented in Chapter 7. # B. Public Health Role of the Laboratory Clinical laboratories play an especially crucial public health role during epidemics.A laboratory may be the only one in a country that can quickly provide the information needed to develop appropriate treatment policy during an epidemic.In countries with scarce resources, the role of the laboratory is to use those resources to provide the best information for developing treatment policy, rather than to focus on the diagnosis of individual patients.During an epidemic of cholera or dysentery, the laboratory has four primary roles: - Initial identification of the organism causing the epidemic - Initial determination of the antimicrobial susceptibility patterns - Monitoring for changes in antimicrobial susceptibility patterns - Defining the duration and geographic extent of the epidemic The World Health Organization (WHO) recommends that countries at risk for epidemics establish an epidemic control committee.Since the laboratory plays an important role in the identification and control of epidemics, a microbiologist should be a part of the epidemic control committee. # Initial identification of the organism causing the epidemic # Preparation/laboratory network In countries at risk for epidemics of dysentery or cholera, the laboratory's first role is to be prepared for an epidemic.This means having the supplies (or ready access to supplies) necessary to identify V. cholerae O1/O139 and Shigella.Annexes A and B in this manual list laboratory supplies required for isolation, identification, and antimicrobial susceptibility testing.A country-wide public health laboratory network should be established (see Annex C).All countries should have at least one national or central laboratory capable of identifying V. cholerae O1/O139 and Shigella, determining antimicrobial suscep tibility, and sending isolates to an international reference laboratory (Annex D). To maintain a laboratory's capability to determine the antimicrobial suscepti bility patterns of bacterial pathogens accurately and reproducibly, investments must be made in the infrastructure of the laboratory.These investments include a steady supply of the material resources needed to perform appropriate testing; a trained staff with expertise to conduct the laboratory tests and sufficient time, materials, and supplies to maintain this expertise; and quality control of the staff, supplies, and reagents.Because antimicrobial susceptibility testing is so resource intensive, WHO recommends that this testing be carried out at only one or two laboratories in the country.Peripheral laboratories may perform initial isolation of Vibrio spp.or Shigella spp.,and then refer isolates to the central or national reference laboratory for final confirmation and determination of antimicrobial susceptibility.Peripheral laboratories may also be the sites of focused studies to determine etiologic agents causing an outbreak.First-level laboratories should be supplied with transport medium and the means of sending the specimens to the next level laboratory or to the central laboratory. # Diagnosing epidemics During a suspected epidemic, the laboratory will determine the organism causing the epidemic and its antimicrobial susceptibilities.An epidemic may be suspected on clinical grounds: for instance, a surveillance system based on clinical diagnosis may note an increase in the number of cases of diarrhea.The laboratory should become involved as soon as possible to identify the causative agent.This underscores the need for good communication between the labora tory, the epidemiologists, and clinicians and other health care workers. At times, the laboratory may be the first to suspect an epidemic.Laboratory workers may note an increase in the number of stool specimens submitted, an increase in the proportion of stool specimens with blood, or the appearance of a new organism.When a laboratory worker suspects an outbreak or epidemic, he or she should contact the appropriate clinicians and public health authorities as soon as possible. Once the organism causing the epidemic is identified, it is not necessary to examine a large number of stool specimens.Patients can be treated on the basis of their syndrome. # D iag n o sin g d ysen tery epidem ics If an epidemic of dysentery is suspected, the most common cause in most parts of the world is Sd1.During an outbreak or epidemic, Sd1 is likely to be isolated much more frequently than the other organisms that cause dysentery.Therefore, a laboratory should conserve its resources and, according to WHO guidelines, once Sd1 has been confirmed as the cause of an epidemic, patients presenting with dysentery should initially be treated as if they are infected with Sd1.There is no need for the laboratory to examine the stools of all patients.Rather, it is better to take specimens from a small number of patients during an outbreak or to conduct periodic surveillance for organisms causing dysentery (see below). If Sd1 is not isolated during a suspected outbreak, the laboratory should test for E. coli O157:H7.If neither of these organisms is isolated, arrangements should be made to send specimens to a reference laboratory. Besides Sd1 and E. coli O157:H7, a number of organisms contribute in various proportions to the burden of dysentery in a country.The predominant causes of dysentery will vary by geographic location and time of year.Seasonal peaks occur and may reflect changes in the proportions of the various causative organisms.Laboratories should conduct periodic surveys of the organisms causing dysentery in order to monitor antimicrobial susceptibility patterns and to help clinicians and public health authorities develop rational guidelines for empiric treatment.Procedures for conducting such surveys are described in Annex E. # D iag n o sin g cholera epidem ics If an epidemic of cholera is suspected, the most common cause is V cholerae O1.If V cholerae O1 is not isolated, the laboratory should test for V. cholerae O139.If neither of these organisms is isolated, arrangements should be made to send stool specimens to a reference laboratory. Infection with V. cholerae O139 should be handled and reported in the same manner as that caused by V. cholerae O1.The associated diarrheal illness should be called cholera and should be reported as a case of cholera to the appropriate public health authorities. # Determining antimicrobial susceptibility patterns of epidemic organisms Antimicrobial susceptibilities should be determined for the first 30 to 50 isolates identified by the laboratory at the beginning of an epidemic.That number will provide sufficient information to develop antimicrobial treatment policy for the organism.After that, the laboratory should conduct periodic surveys to detect any changes in antimicrobial susceptibility patterns (see Annex E). The laboratory should not routinely test antimicrobial agents that are not available in the country or antimicrobial agents that are not recommended by WHO as efficacious in the treatment of cholera or dysentery (see Chapters 3 and 5).In addition, if all isolates are resistant to a particular antimicrobial agent during the first round of testing (for example, Sd1 resistance to ampicillin or trimethoprim-sulfamethoxazole), it is probably not useful to test against those agents during future surveys. Once the organisms are isolated and the antimicrobial susceptibility patterns determined, these results should be transmitted as quickly as possible to the national epidemiologist and to other public health officials.They can then be used to make rational choices for antimicrobial treatment policy. It is useful to send 10 to 20 of the initial isolates to an international reference laboratory for confirmation of the identification and antimicrobial susceptibility pattern (Annex D). # Monitoring for changes in antimicrobial susceptibility As the epidemic progresses, periodic surveys of 30 to 50 isolates of the epi demic organism should be carried out to detect any changes in the antimicrobial susceptibility pattern of the organism causing the epidemic.These should be conducted every 2 to 6 months, depending on conditions and resources.Any changes should be reported to the national epidemiologist and to other public health officials to modify the antimicrobial treatment policy.If any major changes are noted, it is useful to send isolates to an international reference laboratory for confirmation (Annex D). # Defining the duration of the epidemic The laboratory can help define the end of the epidemic, especially with cholera epidemics.In the course of an epidemic, the number of cases may decrease for several reasons: seasonal variation, transition to an endemic state, or disappear ance of cholera from an area.Cholera may nearly disappear in cool seasons, only to reappear in the summer months.The laboratory can assist in determining if the epidemic has actually ended by periodically analyzing stool specimens from patients with acute watery diarrhea.In order for an area to be declared cholera free by WHO, twice the incubation period (a total of 10 days) must pass without evidence of V. cholerae O1/O139.However, because of seasonal variation, surveillance should be maintained for at least 12 months. Similarly, seasonal variation is seen with epidemic dysentery.The laboratory can periodically analyze stool specimens from patients with dysentery to see if Sd1 is still present in a particular area. # Other duties of the laboratory during an epidemic In addition to the major duties outlined above, the laboratory can support other activities related to the epidemic. # Epidemiologic studies At times, the laboratory may be asked to provide laboratory support to an epidemiologic study.By combining epidemiologic and laboratory data, studies that examine modes of transmission or risk factors for illness can be more specific and provide better information for the control of the epidemic. # Defining the magnitude of the epidemic and improving surveillance data Cultures taken from a series of patients that meet the clinical case definition used during an epidemic can determine the predictive value of the definition.Such studies will confirm the accuracy of the case definition used for surveillance purposes and can provide a more accurate picture of the magnitude of the epidemic. In addition, the laboratory may be called upon to support other activities such as environmental monitoring for V. cholerae O1/O139.These requests place additional demands on the resources of the laboratory.Therefore, the microbiolo gist must be part of the decision-making process to determine whether the laboratory has the capacity to support the particular request and whether it is an appropriate use of the laboratory resources.Fecal specimens should be collected in the early stages of any enteric illness, when pathogens are usually present in the stool in highest numbers, and before antibiotic therapy has been started (Table 2-1).Collect stools from patients in clean containers without disinfectant or detergent residue and with tight-fitting, leak-proof lids.Specimens should not be collected from bedpans, as they may contain residual disinfectant or other contaminants.Unpreserved stool should be refrigerated if possible and processed within a maximum of 2 hours after collection.Specimens that cannot be cultured within 2 hours of collection should be placed in transport medium and refrigerated immediately. # References # Global # Placing stool in transport medium A small amount of stool can be collected by inserting a sterile cotton-or polyester-tipped swab into the stool and rotating it.If mucus and shreds of intestinal epithelium are present, these should be sampled with the swab.Immedi ately insert the swab into transport medium. (The transport medium should have been chilled for 1 to 2 hours, if possible.)The swab should be pushed completely to the bottom of the tube of transport medium and the top portion of the stick touching the fingers should be broken off and discarded.Replace the screw cap and tighten firmly.Place the tube in a refrigerator or cold box.

# Collection of rectal swabs Rectal swabs may be collected as follows: moisten the swab in sterile transport medium, insert through the rectal sphincter 2 to 3 cm (1 to 1.5 inches) and rotate, withdraw and examine to make sure there is some fecal material visible on the swab.Immediately insert the swab into cold transport medium as described in above paragraph.Place the tube in a refrigerator or cold box. The number of swabs needed will depend on the number of plates to be inocu lated.In general, if specimens will be examined for more than one pathogen, at least two stool swabs or rectal swabs should be collected per patient, and both swabs should be inserted into the same tube of transport medium. # Transport media # Cary-Blair transport medium Cary-Blair transport medium can be used to transport many enteric pathogens, including Shigella, Vibrio cholerae, and E scherichia coli O157:H7 (Figure 2-1).Cary-Blair's semisolid consistency provides for ease of transport, and the prepared medium can be stored after preparation at room temperature for up to 1 year.Because of its high pH (8.4), it is the medium of choice for transport and preservation of V cholerae. # P reparation a n d q u a lity con tro l o f C ary-B lair Prepare according to manufacturer's instructions. When Cary-Blair is prepared, it should be dispensed into containers in sufficient volume so that swabs will be covered by at least 4 cm of medium.For example, 5-to 6-ml amounts may be dispensed into 13 x 100 mm screw cap tubes.With the caps loosened, sterilize by steaming (do not autoclave) at 100°C for 15 minutes.Tighten the caps after sterilization.Cary-Blair is quite stable if stored in tightly sealed containers in a cool dark place so that the medium does not dry out.Cary-Blair may be used for up to 1 year as long as there is no loss of volume, contamination, or color change. # Other transport media Other transport media that are similar to Cary-Blair are Amies' and Stuart's transport media.Both of these are acceptable for Shigella and E. coli O157:H7, but they are inferior to Cary-Blair for transport of V. cholerae. Alkaline peptone water (APW) may be used to transport V. cholerae, but this medium is inferior to Cary-Blair and should be used only when the latter medium is not available.APW should not be used if subculture will be delayed more than 6 hours from the time of collection because other organisms will overgrow vibrios after 6 hours. Buffered glycerol saline (BGS), a transport medium that is used for Shigella, is unsuitable for transport of V. cholerae.Additional disadvantages of BGS are that it can be used for only 1 month after it is made and, being a liquid medium, is more likely to leak or spill during transport. # Storage of specimens in transport medium If transport medium has been stored at room temperature, it should be chilled, if possible, for 1 to 2 hours before use.Specimens preserved in transport medium should be refrigerated until processed.If specimens will be kept more than 2 to 3 days before being cultured, it is preferable to freeze them immediately at -70°C.It may be possible to recover pathogens from refrigerated specimens up to 7 days after collection; however, the yield decreases after the first 1 or 2 days.Prompt plating, refrigeration, or freezing of specimens in Cary-Blair is particularly important for isolation of Shigella, which is more fragile than other enteric organisms.Fecal specimens in transport medium collected from patients with cholera need not be refrigerated unless they are likely to be exposed to elevated temperatures (>40°C). # Unpreserved specimens When transport medium is not available, one option for suspect V. cholerae specimens is to soak a piece of filter paper, gauze, or cotton in liquid stool and place it into a plastic bag.The bag must be tightly sealed so that the specimen will remain moist and not dry out.Adding several drops of sterile saline to the bag may help prevent drying of the specimen.Refrigeration during transport is desirable but not necessary.This method is not suitable for transport of Shigella or E. coli O157:H7 specimens and is less effective than transport medium for preserving V. cholerae organisms. # B. Preparing Specimens for Shipment Specimen tubes should be clearly labeled with the specimen number, and if possible, the patient's name and date of collection.Write the numbers on the frosted portion of the specimen tube, using an indelible marker pen.If there is no frosted area, write the information on a piece of first-aid tape and fix this firmly on the specimen container.Patient information should be recorded on a data sheet; one copy should be sent with the specimens and another kept by the sender.A sample data sheet is provided in Annex F. If a package is to be shipped by air, refer to packaging regulations presented in the publication, D angerous G oods R egulations (DGR).International A ir Transport A ssociation (IATA).These regulations are summarized in Chapter 13, "Packing and Shipping of Clinical Specimens and Etiologic Agents."Even if the package will be shipped by other means, these regulations are excellent guidelines for packing all infectious or potentially infectious materials. # Refrigerated specimens Refrigerated specimens should be transported to the laboratory in an insulated box with frozen refrigerant packs or ice.If wet ice is used, place the tubes or containers in waterproof containers such as plastic bags that can be tightly sealed to protect the specimens from the water formed by melting ice. # Frozen specimens Frozen specimens should be transported on dry ice.The following precautions should be observed: - Place tubes in containers or wrap them in paper to protect them from dry ice.Direct contact with dry ice can crack glass tubes. -If the specimens are not in leakproof containers, protect them from exposure to carbon dioxide by sealing the screwcaps with tape or plastic film or by sealing the tubes in a plastic bag.Carbon dioxide will lower the pH of the transport medium and adversely affect the survival of organisms in the specimen. - Ensure that the cool box is at least one-third full of dry ice.If the specimens are sent by air and more than 2 kg of dry ice is used, special arrangements may be necessary with the airlines.Airlines accept packages with less than 2 kg of dry ice. -Address the package clearly, including the name and telephone number of the receiving laboratory.Write in large letters: EMERGENCY MEDICAL SPECIMENS; CALL ADDRESSEE ON ARRIVAL; HOLD REFRIGER ATED (or "FROZEN" if applicable).Be sure that all applicable labels and forms, such as those required by IATA, are correctly fixed to the outside of the package. # Chapter 3 Epidemiology of Dysentery Caused by Shigella Epidemic dysentery in developing countries is usually caused by Shigella dysenteriae serotype 1 (Sd1).Sd1 is an unusually virulent enteric pathogen that causes endemic or epidemic dysentery with high death rates.It is the most common cause of large-scale, regional outbreaks of dysentery.In recent years, Sd1 has caused epidemic dysentery in Central America, south Asia and central and southern Africa.An epidemic in Central America from 1969 to 1973 was responsible for more than 500,000 cases and 20,000 deaths.The epidemic in central and southern Africa began in 1979, initially affecting eastern Zaire, Rwanda and Burundi.In the early 1990s, epidemic dysentery moved southward, affecting first Zambia, then Malawi, Mozambique, Zimbabwe and southern Africa.A large rise in the number of cases associated with refugee camps was seen in central Africa in 1994. # A. Epidemiology of Shigella The genus Shigella is divided into four species: S. dysenteriae, S. flexneri, S. boydii, and S. sonnei.Each of these species, with the exception of S. sonnei, has several serotypes (Table 3-1).In general, S. sonnei is more common in developed countries and S. flexn eri and S. dysenteriae are more frequent in developing countries.The proportions of each species vary from country to country.Sd1 differs from the other Shigella species in several ways: - Only Sd1 causes large and prolonged epidemics of dysentery. - Antimicrobial resistance develops more quickly and occurs more frequently in Sd1 than in other Shigella species. -Infection with Sd1 causes more severe, more prolonged, and more frequently fatal illness than does infection with other Shigella species. # B. Clinical Manifestations The hallmark of infection with Sd1 is diarrhea with blood (dysentery).Shigella causes dysentery by invading and destroying cells that line the large intestine, leading to mucosal ulceration, a hemorrhagic inflammatory exudate and bloody diarrhea.Apart from bloody stools, patients with dysentery often have fever, abdominal cramps and rectal pain.However, the clinical response to infection spans a wide range, from mild to severe diarrhea with or without blood.In almost half of cases, Shigella causes acute nonbloody diarrheas that cannot be distinguished clinically from diarrhea caused by other enteric patho gens.Severity of symptoms appears to be dose related.Asymptomatic infec tions may occur, but not to the extent that they do in Vibrio cholerae O1 infections.A chronic carrier state does not occur, although the organisms may be excreted for several weeks.Sd1 infections are most often severe or fatal in young children and in the elderly and malnourished.Although most patients recover without complications within 7 days, persistent diarrhea may occasion ally occur. Infection with Sd1 can be complicated by seizures, sepsis, rectal prolapse, or toxic megacolon.A more frequent complication is the hemolytic-uremic syndrome (HUS), which is characterized by the classic triad of hemolytic anemia, thrombocytopenia and renal failure.HUS may be mild with rapid recovery, or severe, leading to kidney failure and death. # C. Treatment The mainstay of treatment for Sd1 infection is appropriate antimicrobial therapy, which lessens the risk of serious complications and death.Other supportive measures should be used as well. The # Chapter 4 Isolation and Identification of Shigella Isolation and identification of Shigella can be greatly enhanced when optimal laboratory media and techniques are employed.The methods presented here are intended to be economical and to offer laboratorians some flexibility in choice of protocol and media.Laboratories that do not have sufficient resources to adopt the methods described in this chapter should consider sending specimens or isolates to other laboratory facilities that routinely perform these procedures.When selective or differential media are incorrectly prepared, the reactions of organisms on those media can be affected.Therefore, it would be helpful to refer to Section D, "Media for isolation and identification of Shigella," for a discussion of these media, their preparation, and appropriate quality control strains. # A. Isolation Methods There is no enrichment medium for Shigella that consistently provides a greater recovery rate than use of direct plating alone. # Inoculation of selective agar Fecal specimens should be plated as soon as possible after arrival in the laboratory.Selective media may be inoculated with a single drop of liquid stool or fecal suspension.Alternatively, a rectal swab or a fecal swab may be used.If a swab is used to inoculate selective media, an area approximately 2.5 cm (1 inch) in diameter is seeded on the agar plates, after which the plates are streaked for isolation (Figure 4-2).Media of high selectivity such as XLD require more overlapping when streaking than media of low selectivity.When inoculating specimens to a plate for isolation, it is important to use the entire plate to increase the chances of obtaining well-isolated colonies.Incubate the plates for 18 to 24 hours at 35° to 37°C. After incubation, record the amount and type of growth (e.g., lactose-ferment ing or lactose-nonfermenting) on each isolation medium for each patient specimen (a sample worksheet is presented in Figure 4-3).Colonies of Shigella on MAC appear as convex, colorless colonies about 2 to 3 mm in diameter.S. dysenteriae 1 colonies may be smaller ( # B. Biochemical Screening Tests Identification of Shigella spp.involves both biochemical and serologic testing.The use of biochemical screening media is usually advisable to avoid wasting antisera.Most laboratories will find KIA (or TSI) to be the single most helpful medium for screening suspected Shigella isolates.If an additional test is desired, motility medium can be used to screen isolates before doing serologic testing.Section D in this chapter further describes these media. # Kligler iron agar and triple sugar iron agar To obtain true reactions in KIA or TSI or other biochemical tests, it is neces sary to inoculate with a pure culture.Carefully select at least one of each type of well-isolated colony on each plate.Using an inoculating needle, lightly touch only the very center of the colony.Do not take the whole colony or go through the colony and touch the surface of the plate.This is to avoid picking up contami nants that may be on the surface of the agar.If there is doubt that a particular colony is sufficiently isolated from surrounding colonies, purify the suspicious colony by streaking on another agar plate, after which the KIA or TSI slant may be inoculated. KIA and TSI are inoculated by stabbing the butt and streaking the surface of the slant.After incubation for 18 to 24 hours at 35° to 37°C, the slants are observed for reactions typical of Shigella.When incubating most biochemicals, caps should be loosened before placement in the incubator.This is particularly important for KIA and TSI.If the caps are too tight and anaerobic conditions exist, the characteristic reactions of Shigella spp.may not occur and a misleading result could be exhibited.It is also important that KIA and TSI be prepared so that the tubes have a deep butt and a long slant (see Section D). Shigella characteristically produces an alkaline (red) slant and an acid (yellow) butt, little or no gas, and no H2S (Table 4-2; Figure 4-8 b K = alkaline (purple); A = acid (yellow); an alkaline reaction (purple) in the butt of the medium indicates that lysine was decarboxylated.An acid reaction (yellow) in the butt of the medium indicates that lysine was not decarboxylated.Motility agar should be inoculated with a straight inoculating needle, making a single stab about 1 to 2 cm down into the medium.Motility agar may be inocu lated with growth from a KIA or TSI that shows a reaction typical of Shigella.Alternately, motility agar can be inoculated at the same time as the KIA or TSI slant by using the same inoculating needle without touching the colony again.The motility agar should be inoculated first, after which, the KIA or TSI is inoculated by stabbing the butt first and then streaking the surface of the slant.Do not select a second colony to inoculate the KIA or TSI after the motility agar has been inoculated since it may represent a different organism. # ID E N T IF IC A T IO N M O T c U R E A LIA A 1 B D XLD X 1 X 2 X 3 MAC M 1 M 2 M 3 XLD X 1 X 2 X 3 M AC M 1 M 2 M 3 XLD X 1 X 2 X 3 MAC M 1 M 2 M 3 XYL/LAC -= Examine after overnight incubation at 35° to 37°C.Motility is indicated by the presence of diffuse growth (appearing as clouding of the medium) away from the line of inoculation (Figure 4-9).Nonmotile organisms do not grow out from the line of inoculation.Motility reactions may be difficult for inexperienced laboratorians to read; therefore reactions should be compared with positive and negative control strains.Shigella spp.are always nonmotile (Table 4-2). The surface of the motility agar should be dry when used.Moisture can cause a nonmotile organism to grow down the sides of the agar creating a haze of growth and appearing to be motile (see Section D). Sulfide-indole-motility medium is a combination medium that is commercially available in dehydrated form (see Section D).It can be used in place of motility medium. # Motility agar # Additional biochemical screening tests Other biochemical tests such as urea medium and lysine iron agar may be used for additional screening of isolates before testing with antisera.The value of these should be assessed before using them routinely (Table 4-2, Annex G).These media, their preparation, and suggested quality control strains are described in Section D. # Urea m ed iu m Urea medium screens out urease-producing organisms such as K lebsiella and Proteus.Urea agar is inoculated heavily over the entire surface of the slant.Loosen caps before incubating overnight at 35° to 37°C.Urease positive cultures produce an alkaline reaction in the medium, evidenced by a pinkish-red color (Figure 4-10).Urease negative organisms do not change the color of the medium, which is a pale yellowish-pink.Shigella spp.are always urease negative (Table 4-2 # ).L ysin e iro n agar Lysine iron agar (LIA) is helpful for screening out H afnia spp.and certain E. coli, P roteus, and P rovidencia strains.LIA should be inoculated by stabbing the butt and streaking the slant.After incubation for 18 to 24 hours at 35° to 37°C, organisms that produce lysine decarboxylase in LIA cause an alkaline reaction (purple color) in the butt of the medium and also on the slant (Figure 4-11).H2S production is indicated by a blackening of the medium.Organisms lacking lysine decarboxylase, produce an alkaline slant (purple) and an acid butt (yellow), no gas, and no H2S. P roteus and P rovidencia spp.will often produce a red slant caused by deamination of the lysine.LIA must be prepared so that the tubes have a deep butt (see Section D). Shigella spp.

are lysine negative and characteristically produce an alkaline (purple) slant and an acid (yellow) butt, no gas, and no H2S (Table 4-2 3-1 Serologic identification is performed typically by slide agglutination with polyvalent somatic (O) antigen grouping sera, followed, in some cases, by testing with monovalent antisera for specific serotype identification.Monovalent antiserum to S. dysenteriae 1 is required to identify this serotype, which is the most frequent cause of severe epidemic dysentery.Once one colony from a plate has been identified as Shigella, no further colonies from the same specimen need to be tested.Laboratorians should be aware that some Shigella commercial antiserum is labeled or packaged differently; for example, Shigella polyvalent A, which includes antisera to serotypes 1 through 7, may also be labeled polyvalent A1.Also, monovalent antiserum may be labeled in a way that it may be confused with polyvalent antiserum; for example, monovalent antiserum to S. dysenteriae 1 may be labeled "Shigella A1" instead of "S. dysenteriae serotype 1".When using newly purchased antisera, the laboratorian should read the package insert or check with the manufacturer if the label is not self-explanatory. # Slide agglutination Because S. dysenteriae 1 (followed by S. flexneri and S. sonnei) is the most common agent of epidemic dysentery, isolates that react typically in the screening biochemicals should be screened first with monovalent A1 antiserum, then with polyvalent B antiserum, and finally in polyvalent D antiserum. Agglutination tests may be carried out in a petri dish or on a clean glass slide.An inoculating loop or needle, sterile applicator stick or toothpick is used to remove a portion of the growth from the surface of KIA, TSI, heart infusion agar (HIA), or other nonselective agar medium.Serologic testing should not be done on growth from selective media such as MAC or XLD because this may give false-negative results.Emulsify the growth in two small drops of physiological saline and mix thoroughly.Add a small drop of antiserum to one of the suspen sions.Usually approximately equal volumes of antiserum and growth suspension are mixed, but the volume of suspension may be as much as double the volume of the antiserum.To conserve antiserum, volumes as small as 10 microliters can be used.An inoculating loop may be used to dispense small amounts of antisera if micropipettors are not available (Figure 4-12).Mix the suspension and antiserum well and then tilt the slide back and forth to observe for agglutination.If the reaction is positive, clumping will appear within 30 seconds to 1 minute (Figure 4-13).Examine the saline suspension carefully to ensure that it is even and does not show clumping due to autoagglutination.If autoagglutination occurs, the culture is termed "rough" and cannot be serotyped. Cultures that react serologically and show no conflicting results in the bio chemical screening tests are reported as positive for Shigella.Serologically negative isolates that are biochemically identified as Shigella may be sent to a reference laboratory. # Quality control of antisera All lots of antisera should be quality controlled before use.Quality control of antisera is discussed in Chapter 11. # D. Media for Isolation and Identification of Shigella This section contains descriptions of all media mentioned in this chapter and discussions of their characteristics, preparation, and appropriate quality control strains.Each manufacturer's lot number of commercial dehydrated media or each # P reparation a n d q u a lity con tro l Prepare according to manufacturer's instructions. DCA medium is very heat-sensitive, and overheating during boiling should be avoided.Do not autoclave.Plates can be stored at 4°C for up to a week. For quality control of DCA, the following organisms should be adequate for confirmation of selective and inhibitory growth characteristics: E. coli may be somewhat inhibited, depending on the particular formulation used, but will produce pink colonies surrounded by a zone of precipitated bile; S. flexn eri and S. dysenteriae 1 will produce fair to good growth of colorless colonies. # Hektoen enteric agar Hektoen enteric agar (HE) is a differential selective agar that is useful for isolation of Salm onella and Shigella.It has an H2S-indicator system for selecting H2S-producing Salm onella, which produce blue-green colonies with a black center.Shigella colonies are green while rapid lactose-fermenters such as E. coli are pink to orange with a zone of bile precipitation. # P reparation a n d q u a lity con tro l Prepare according to manufacturer's instructions. Heat to boiling to dissolve, but avoid overheating.Do not autoclave.When cool enough to pour, dispense into plates.Plates can be stored at 4°C for up to 1 week. For quality control of HE, the following organisms should be adequate for confirmation of selective and inhibitory growth characteristics: E. coli should produce colonies that are pink to orange surrounded by a bile precipitate; S. flexn eri should produce fair to good growth of green colonies, but S. dysenteriae 1 colonies should be smaller. # Kligler iron agar and triple sugar iron agar Kligler iron agar (KIA) and triple sugar iron (TSI) agar are carbohydratecontaining screening media widely used for identification of enteric pathogens, including Shigella.Both media differentiate lactose fermenters from nonfermenters and have a hydrogen sulfide indicator.H2S-producing organisms will cause blackening of the medium in both KIA and TSI. KIA contains glucose and lactose.Organisms which ferment glucose cause the butt of the tube to become acid (yellow); some also produce gas.Lactosefermenting organisms will produce an acid (yellow) slant; lactose-nonfermenting organisms will have an alkaline (red) slant. TSI contains sucrose in addition to the ingredients in KIA.Organisms which ferment either lactose or sucrose will produce an acid (yellow) slant while organisms that ferment neither carbohydrate will have an alkaline (red) slant.As in KIA, glucose-fermenters produce an acid (yellow) reaction in the butt (some times with gas produced). # P reparation a n d q u a lity con tro l Prepare according to manufacturer's instructions. Dispense a quantity of medium in appropriate containers such that the volume of medium is sufficient to give a deep butt and a long slant.For example, dispense 6.5 ml of medium into 16 x 125-mm screw-cap tubes (leave caps loose), and after autoclaving allow the slants to solidify in a manner such that the medium in the butt of the tube is about 3.5 cm deep and the slant is about 2.5 cm long.Tighten caps and store at 4°C for up to 6 months. For quality control of KIA or TSI, the following organisms should be adequate for confirmation of biochemical response characteristics: E. coli should give an acid slant and butt, with the production of gas but no H2S; S. flexn eri should give an alkaline slant, acid butt, without production of gas or H2S (Figure 4-8); an H2S-producing Salm onella may be used to control this reaction. # Lysine iron agar Organisms that produce lysine decarboxylase in LIA cause an alkaline reaction (purple color) in the butt of the medium and also on the slant (Figure 4-11).H2S production is indicated by a blackening of the medium.Organisms lacking lysine decarboxylase, such as Shigella, typically produce an alkaline slant (purple) and an acid butt (yellow) no gas, and no H2S (Table 4-2).P roteus and P rovidencia spp.will often produce a red slant caused by deamination of the lysine.LIA must be prepared so that the volume of medium in the tube is sufficient to give a deep butt.It is important for LIA tubes to have a deep butt because the decarboxyla tion reaction occurs only in anaerobic conditions. # P reparation a n d q u a lity con tro l Prepare medium according manufacturer's instructions on the bottle. Dispense a quantity of medium in appropriate containers such that the volume of medium is sufficient to give a deep butt and a long slant.For example, dispense 6.5 ml of medium into 16 x 125-mm screw-cap tubes (leave caps loose), and after autoclaving allow the slants to solidify in a manner such that the medium in the butt of the tube is 3.5 cm deep and the slant is 2.5 cm long.Tighten caps and store at 4°C for up to 6 months. For quality control of LIA, the following organisms may be used: S. flexn eri should produce an alkaline slant and an acid butt without production of H2S; an H2S-producing Salm onella strain may be used to control the H2S reaction and will most likely be lysine-positive and give an alkaline reaction in the butt of the tube. # MacConkey agar MacConkey agar (MAC) is a differential plating medium recommended for use in the isolation and differentiation of lactose-nonfermenting, gram-negative enteric bacteria from lactose-fermenting organisms.Colonies of Shigella on MAC appear as convex, colorless colonies about 2 to 3 mm in diameter.S. dysenteriae 1 colonies may be smaller. Several commercial brands of MAC are available.Most manufacturers prepare several formulations of MAC, which may vary in selectivity and thereby affect the isolation of Shigella.For example, some formulations of MAC do not contain crystal violet, a selective agent; these types are not as selective and should not be used for isolation of Shigella.Oxoid MacConkey Agar No.3, Difco Bacto MacConkey Agar, and BBL MacConkey Agar are all suitable. # P reparation a n d q u a lity con tro l Prepare according to manufacturer's instructions. Sterilize by autoclaving at 121°C for 15 minutes.Cool to 50°C and pour into petri plates.Leave lids ajar for about 20 minutes so that the surface of the agar will dry.Close lids and store at 4°C for up to 1 month.If plates are to be stored for more than a few days, put them in a sealed plastic bag to prevent drying. For quality control of MAC, the following organisms should be adequate for confirmation of selective and inhibitory growth characteristics: E. coli should produce pink to red colonies with good to excellent growth; S. flexn eri should produce colorless colonies with fair to good growth, but S. dysenteriae 1 colonies may be smaller. # Motility medium Because Shigella spp.are always nonmotile, motility medium is a useful biochemical screening test.Motility is indicated by the presence of diffuse growth (appearing as clouding of the medium) away from the line of inoculation (Figure 4-9).Nonmotile organisms do not grow out from the line of inoculation.P reparation a n d q u a lity con tro l Follow manufacturer's instructions to weigh out and suspend dehydrated medium. Heat to boiling to make sure medium is completely dissolved.Dispense into tubes or other types of containers, leaving caps loose, and sterilize at 121°C for 15 min.Allow to solidify upright, forming a deep butt with no slant (e.g., about 4 to 5 ml of medium per 13 x 100-mm screw-cap tube).When the medium is solidified and cooled, leave caps loose until the surface of the medium has dried.Tighten caps and store at 4°C for up to 6 months. For quality control of motility medium, the following organisms may be used: E. coli is motile, while Shigella spp.are nonmotile.The surface of the medium should be dry when used.If moisture has accumulated in the tube, carefully pour it out before inoculating the tube.Moisture can cause a nonmotile organism to grow down the sides of the agar creating a haze of growth and appearing to be motile. # Sulfide-indole-motility medium Sulfide-indole-motility medium (SIM) is a commercially available combination medium that combines three tests in a single tube: hydrogen sulfide (H2S) production, indole production, and motility.The indole reaction is not useful for screening suspected Shigella isolates because strains vary in their reactions in this test.It is inoculated in the same way as motility agar, by using a needle to stab about 1 to 2 cm down into the medium, and is incubated overnight at 35° to 37°C.The motility reaction is read the same as for motility medium.As in KIA or TSI, H2S production is indicated by blackening of the medium.Indole production can be tested by either the filter paper method or by adding Kovac's reagent to the tube. # P reparation a n d q u a lity con tro l Follow manufacturer's instructions to weigh out and suspend dehydrated medium.Heat to boiling to make sure the medium is completely dissolved.Dispense into tubes and sterilize by autoclaving for 15 minutes at 121°C. For quality control of SIM medium, the following organisms may be used: E. coli is indole positive, H2S negative, and motility positive; an H2S-producing Salm onella strain may be used to control the H2S reaction and will most likely be motile and indole negative; Shigella spp.are motility negative and H2S negative but are variable for the indole reaction. # Urea medium Urease-positive cultures produce an alkaline reaction in the medium, evidenced by a pinkish-red color (Figure 4-10).Urease-negative organisms do not change the color of the medium, which is a pale yellowish-pink.Shigella spp.are always urease-negative (Table 4-2).P reparation a n d q u a lity con tro l Follow manufacturer's instructions for preparation. Prepare urea agar base as directed on the bottle.Sterilize at 121°C for 15 min.Cool to 50° to 55°C, then add urea concentrate according to manufacturer's directions.Before adding the urea to the agar base, make sure the agar base is cool since the urea is heat labile.Mix and distribute in sterile tubes.Slant the medium so that a deep butt is formed. For quality control of urea medium, the following organisms may be used: P roteus spp.produce urease; E. coli is urease negative. # Xylose lysine desoxycholate agar Xylose lysine desoxycholate agar (XLD) is a selective differential medium suitable for isolation of Shigella and Salm onella from stool specimens.Differentiation of these two species from nonpathogenic bacteria is accomplished by xylose and lactose fermentation, lysine decarboxylation, and hydrogen sulfide production. Shigella colonies on XLD agar are transparent pink or red smooth colonies 1 to 2 mm in diameter (Figure 4-5).S. dysenteriae 1 colonies on XLD agar are frequently very tiny, unlike other Shigella species (Figure 4-4).Coliforms appear yellow (4-6).Salm onella colonies are usually red with black centers but may be yellow with black centers. # P reparation a n d q u a lity con tro l Prepare according to manufacturer's instructions. Mix thoroughly.Heat with agitation just until the medium boils.Do not overheat; overheating when boiling XLD or allowing the medium to cool too long may cause the medium to precipitate.Cool flask under running water until just cool enough to pour.Avoid cooling the medium too long.Pour into petri plates, leaving the lids ajar for about 20 minutes so that the surface of the agar will dry.Plates can be stored at 4°C for up to a week. For quality control of XLD, the following organisms should be adequate for confirmation of selective and inhibitory growth characteristics: S. flexn eri should produce fair to good growth of transparent pink or red smooth colonies that are 1 to 2 mm in diameter; S. dysenteriae 1 may produce very small transparent or red colonies; E. coli should produce poor to fair growth of yellow colonies. Isolates of Vibrio choJerae serogroup O1 are classified into two biotypes, El Tor and classical, on the basis of several phenotypic characteristics.Currently, the El Tor biotype is responsible for virtually all of the cholera cases throughout the world, and classical isolates are not encountered outside of Bangladesh.In addition V choJerae O1 is classified into two serotypes, Inaba and Ogawa, based on agglutination in antiserum.A possible third serotype, Hikojima, has been described, but it is very rare.During an outbreak or epidemic, it is worth docu menting the biotype and serotype of the isolate; however, it is not necessary to know this information to respond appropriately to the epidemic. Within the O1 and O139 serogroups, the ability to produce cholera toxin (CT) is a major determinant of virulence.In general, isolates of V. choJerae O1 or O139 that produce CT are considered fully virulent and capable of causing epidemic cholera (Table 5-1).Most V. choJerae isolated during cholera outbreaks will be toxigenic serogroup O1 or O139.However, some isolates of V choJerae O1 do not produce CT and cannot cause epidemic cholera.When these isolates are encountered, they must be considered within their clinical and epide miologic context.Nontoxigenic isolates may be associated with sporadic diarrheal disease. # A. Historical Background Cholera is thought to have its ancestral home in the Ganges Delta of the Indian subcontinent.In the nineteenth century, pandemic waves of cholera spread to many parts of the world.In 1961, a massive epidemic began in Southeast Asia; this is now recognized as the beginning of the seventh cholera pandemic.This pandemic was caused by the El Tor biotype of toxigenic V. choJerae O1.It spread rapidly through south Asia, the Middle East, and southeastern Europe, reaching Africa by 1970.In January 1991, epidemic cholera appeared in South America in several coastal cities of Peru and spread rapidly to adjoining countries.By the end of 1996, cholera had spread to 21 countries in Latin America, causing over 1 million cases and nearly 12,000 deaths.The number of cholera cases reported elsewhere in the world has also increased in the 1990s.In Africa in the early 1990s, the primary focus of cholera was in southern Africa.However, in the latter part of the decade, the focus moved to west Africa.Overall, more cases were reported from Africa in the 1990s than in a similar time period in previous decades. # Vibrio cholerae serogroup O 139 Vibrio choJerae serogroup O139 appeared in India in late 1992.It quickly spread to Bangladesh and other Asian countries, although the rate of spread has slowed after the initial outbreaks.

Through 1998, 11 countries have officially reported transmission of V choJerae O139 to WHO.Imported cases have been reported from the United States and other countries.At this time, V. choJerae O139 appears to be confined to Asia.The epidemiologic characteristics of the O139 serogroup are similar to those of the O1 serogroup.The isolation and identification characteristics of the O139 serogroup are identical to those of the O1 serogroup except that O139 antiserum is needed for identification.Biotyping tests for V cholerae O1 are not valid for V cholerae O139 or any non-O1/O139 serogroup. # B. Clinical Manifestations Cholera is a secretory diarrheal disease.The enterotoxin produced by V. cholerae O1 and O139 causes a massive outpouring of fluid and electrolytes into the bowel.This rapidly leads to profuse watery diarrhea, loss of circulation and blood volume, metabolic acidosis, potassium depletion, and ultimately vascular collapse and death.In severe cases, purging diarrhea can rapidly cause the loss of 10% or more of the body's weight, with attendant hypovolemic shock and death; however, 75% or more of initial infections with V. cholerae O1 or O139 may be asymptomatic, depending on the infecting dose.Of the 25% of persons with symptomatic infections, most have mild illness.Approximately 5% of patients have moderate illness that requires medical attention but not hospital ization.In only about 2% of patients does the illness progress to life-threatening "cholera gravis."Persons with blood type O are more likely to develop severe cholera than those with other blood types. # C. Treatment Successful treatment of cholera patients depends on rapid replacement of fluid and electrolyte losses.With proper treatment, mortality is less than 1% of reported cases.Fluids and electrolytes can be replaced rapidly through either oral or intravenous routes.Intravenous therapy is required for patients who are in profound shock or cannot drink. Antimicrobial therapy is helpful, although not essential, in treating cholera patients.Antimicrobial agents reduce the duration of illness, the volume of stool, and the duration of shedding of vibrios in the feces.When antimicrobial agents are used, it is essential to choose one to which the organism is susceptible.Antimicrobial agents recommended by WHO for treating cholera patients include tetracycline, doxycycline, furazolidone, trimethoprim-sulfamethoxazole, erythro mycin, or chloramphenicol.Ciprofloxacin and norfloxacin are also effective.Because antimicrobial resistance has been a growing problem in many parts of the world, the susceptibility of V. choJerae O1 strains to antimicrobial agents should be determined at the beginning of an epidemic and be monitored periodically (see Annexes C and E). For V. choJerae, the results of disk diffusion tests for ampicillin, sulfonamides, tetracycline, and trimethoprim-sulfamethoxazole (i.e., percentage of susceptible, intermediate, and resistant) correlate well with the minimum inhibitory concentra tion (MIC) results determined by broth microdilution.Disk diffusion tests should not be used for doxycycline and erythromycin because the results for these drugs are frequently inaccurate for V. choJerae O1 and O139 strains.However, the tetracycline disk test can be used to predict the likely susceptibility of isolates to doxycycline.Additional details on antimicrobial susceptibility testing are given in Chapter 9. # D. Epidemiology When cholera first appears in epidemic form in an unexposed population, it can affect all age groups.In contrast, in areas with high rates of endemic disease, most of the adult population have gained some degree of natural immunity because of illness or repeated asymptomatic infections.In this setting, the disease occurs primarily in young children, who are exposed to the organism for the first time, and in the elderly, who have lower gastric acid production and waning immunity.The poor are at greatest risk because they often lack safe water supplies, are unable to maintain proper hygiene within the home, and may depend on street vendors or other unregulated sources for food and drink. Numerous investigations have linked cholera transmission to drinking water drawn from shallow wells, rivers or streams, and even to bottled water and ice.Food is the other important means of cholera transmission.Seafood has repeat edly been a source of cholera, particularly raw or undercooked shellfish harvested from sewage-contaminated beds or from environments where V. choJerae O1 occurs naturally.Although V. choJerae O1 and O139 are easily killed by drying, sunlight, and acidity, they grow well on a variety of moist alkaline foods from which other competing organisms have been eliminated by previous cooking.Cooked rice is an excellent growth medium, as are lentils, millet, and other cooked grains and legumes with neutral pH. Fruits and veg etables grown in sewage and eaten without cooking or other decontaminating procedures are potential vehicles of cholera transmission.Freezing foods or drinks does not prevent cholera transmission. Person-to-person spread through direct contact, as by shaking hands or touch ing or by taking care of a patient, has not been shown to occur.Outbreaks on crowded hospital wards are likely to be due to contaminated food or water.Likewise, outbreaks following the funeral of a cholera patient have been caused by eating contaminated foods served at the wake, often prepared by the same persons who prepared the body for burial. # E. Cholera Vaccine During the past 15 years, considerable progress has been made in the develop ment of new oral vaccines against cholera.Two oral cholera vaccines, which have been evaluated with volunteers from industrialized countries and in regions with endemic cholera, are commercially available in several countries: a killed whole-cell V. choJerae O1 in combination with purified recombinant B subunit of cholera toxin (WC/rBS); and an attenuated live oral cholera vaccine, containing the genetically manipulated V. choJerae O1 strain CVD 103-HgR. The appear ance of V. choJerae O139 has redirected efforts to develop an effective and practical cholera vaccine.None of the currently available vaccines is effective against this strain. # Chapter 6 Isolation and Identification of Vibrio cholerae Serogroups O1 and O139 Isolation and identification of V choJerae serogroups O1 and O139 can be greatly enhanced when optimal laboratory media and techniques are employed.The methods presented here are intended to be economical and to offer laboratorians some flexibility in choice of protocol and media.Laboratories that do not have sufficient resources to adopt the methods described in this chapter should consider sending the specimens or isolates to other laboratory facilities that routinely perform these procedures. # A. Isolation Methods Before 1992, of the more than 150 serogroups of Vibrio choJerae that have been reported, only the O1 serogroup was associated with epidemic and pandemic cholera.However in late 1992 and early 1993, large outbreaks of cholera due to a newly described serogroup, O139, were reported in India and Bangladesh.This strain, like serogroup O1 V. choJerae, produces cholera enterotoxin.Because the cultural and biochemical characteristics of these two serogroups are identical, the isolation and identification methods described below apply to both O1 and O139.Both serogroups must be identified using O-group-specific antisera.Annex A lists diagnostic supplies necessary for laboratory confirmation and antimicrobial susceptibility testing of V. choJerae. Although V. choJerae will grow on a variety of commonly used agar media, isolation from fecal specimens is more easily accomplished with specialized media.Alkaline peptone water (APW) is recommended as an enrichment broth, and thiosulfate citrate bile salts sucrose agar (TCBS) is the selective agar medium of choice (Figure 6-1).In certain instances (for example, when the patient is in very early stages of illness), it may not be necessary to enrich specimens or use selective plating media.However, enrichment broth and a selective plating medium should always be used with convalescent patients, suspected asymptomatic infections, environmental specimens, and whenever high numbers of competing organisms are likely to be present in the specimen. Refer to Section C, "Media and Reagents for V. choJerae," before preparing any of these media because incorrect preparation can affect the reactions of organisms in these tests.Chapter 11 discusses methods for quality control of selective media and antisera. # Enrichment in alkaline peptone water Enrichment in APW can enhance the isolation of V. choJerae when few organisms are present, as in specimens from convalescent patients and asymp tomatic carriers.Vibrio spp.grow very rapidly in APW, and at 6 to 8 hours will be present in greater numbers than non-Vibrio organisms.APW can be inoculated with liquid stool, fecal suspension, or a rectal swab.The stool inoculum should not exceed 10% of the volume of the broth.Incubate the tube with the cap loosened at 35° to 37°C for 6 to 8 hours.After incubation, subculture to TCBS should be made with one to two loopfuls of APW from the surface and topmost portion of the broth, since vibrios preferentially grow in this area.Do not shake or mix the tube before subculturing.If the broth cannot be plated after 6 to 8 hours of incubation, subculture a loopful at 18 hours to a fresh tube of APW.Subculture this second tube to TCBS agar after 6 to 8 hours of incubation (Figure 6-1). # Isolation from TCBS selective agar TCBS agar is commercially available and easy to prepare, requires no auto claving, and is highly differential and selective (see Section C).Growth on this medium is not suitable for direct testing with V. choJerae antisera. # Inoculation of TCBS Figure 6-1 outlines the procedure for isolation of V. choJerae from fecal specimens.Inoculate the TCBS plate as described in Chapter 4 (Figure 4-2).After 18 to 24 hours' incubation at 35° to 37°C, the amount and type of growth (e.g., sucrose-fermenting or sucrose-nonfermenting) on the TCBS plate should be recorded on data sheets (Figure 6-2).Colonies suspicious for V. choJerae will appear on TCBS agar as yellow, shiny colonies, 2 to 4 mm in diameter (Figure 6-3).The yellow color is caused by the fermentation of sucrose in the medium.Sucrose-nonfermenting organisms, such as V. parahaem oJyticus, produce green to blue-green colonies. # Isolation of suspected V cholerae Carefully select at least one of each type of sucrose-fermenting colony from the TCBS plate to inoculate a heart infusion agar (HIA) slant or another nonselective medium.Do not use nutrient agar because it has no added salt and does not allow optimal growth of V. choJerae.Using an inoculating needle, lightly touch only the very center of the colony.Do not take the whole colony or go through the colony and touch the surface of the plate.This is to avoid picking up contaminants that may be on the surface of the agar.If there is doubt that a particular colony is sufficiently isolated from surrounding colonies, purify the suspicious colony by streaking on another agar plate. Incubate the HIA slants at 35° to 37°C for up to 24 hours; however, there may be sufficient growth at 6 hours for serologic testing to be done.Slide serology with polyvalent O1 and O139 antisera is sufficient for a presumptive identification (see section B below for a description of serologic identification).F igu re 6-3.Growth of V. cholerae on TCBS F igu re 6-4.A positive oxidase test (shown here) results in the developm ent of a dark purple color within 10 seconds.V. cholerae is oxidase positive. # Screening tests for suspected V. cholerae isolates Generally for suspected V cholerae isolates from fecal specimens, screening with biochemical tests prior to testing with O1 and O139 antisera is not necessary.However, if the supply of antisera is limited, the oxidase test may be useful for additional screening of isolates before testing with antisera. # O xidase test Conduct the oxidase test with fresh growth from an HIA slant or any non carbohydrate-containing medium.Do not use growth from TCBS agar because it may yield either false-negative or false-positive results.Place 2 to 3 drops of oxidase reagent (1% N,N,N',N'-tetramethyl-p-phenylenediamine) on a piece of filter paper in a petri dish.Smear the culture across the wet paper with a platinum (not nichrome) loop, a sterile wooden applicator stick or toothpick.In a positive reaction, the bacterial growth becomes dark purple immediately (Figure 6-4).Oxidase-negative organisms will remain colorless or will turn purple after 10 seconds.Color development after 10 seconds should be disregarded.Positive and negative controls should be tested at the same time.Organisms of the genera Vibrio (including V. cholerae, Small, curved rods with darting motility K = alkaline; A = acid b An alkaline reaction (purple) in the butt of the medium indicates that lysine was decarboxylated.An acid reaction (yellow) in the butt of the medium indicates that lysine was not decarboxylated. # Additional biochemical screening tests The string reaction, Kligler iron agar (KIA) or triple sugar iron agar (TSI), lysine iron agar (LIA), Gram stain, and wet mount for motility are other possible tests that may be used for additional screening of isolates before testing with antisera (Table 6-1).The value of these tests should be assessed to determine their usefulness before they are applied routinely.See Section C for instructions on preparation of media and appropriate quality control strains. # S trin g test The string test, using fresh growth from nonselective agar, is useful for ruling out non-Vibrio spp.,particularly A erom onas spp.The string test may be per formed on a glass microscope slide or plastic petri dish by suspending 18-to 24hour growth from HIA or other noninhibitory medium in a drop of 0.5% aqueous solution of sodium deoxycholate.If the result is positive, the bacterial cells will be lysed by the sodium deoxycholate, the suspension will lose turbidity, and DNA will be released from the lysed cells, causing the mixture to become viscous.A mucoid "string" is formed when an inoculating loop is drawn slowly away from the suspension (Figure 6-5).V. cholerae ( # K iig ier iro n ag ar a n d tripie su g a r iro n agar Kligler iron agar (KIA) and triple sugar iron agar (TSI) can be used to rule out P seudom onas spp.and certain Enterobacteriaceae.The reactions of V. cholerae on KIA, which contains glucose and lactose, are similar to those of lactosenonfermenting E nterobacteriaceae (alkaline (red) slant, acid (yellow) butt, no gas, no H2S) (see Table 6-1 and Figure 6-6).However, on TSI, V. cholerae strains produce an acid (yellow) slant and acid (yellow) butt, no gas, and no H2S. KIA or TSI slants are inoculated by stabbing the butt and streaking the surface of the medium.Incubate the slants at 35° to 37°C and examine after 18 to 24 hours.Caps on all tubes of biochemicals should be loosened before incubation, but this is particularly important for KIA or TSI slants.If the caps are too tight and anaerobic conditions exist in the KIA or TSI tube, an inappropriate reaction will occur and the characteristic reactions of V cholerae may not be exhibited. F igure 6-6.R eactions of V. cholerae in Kiigier iron ag ar (left) and triple sugar iron ag ar (right) # L ysin e iro n agar LIA is helpful for screening out A erom onas and certain Vibrio spp.,which, unlike V. cholerae, do not decarboxylate lysine.LIA is inoculated by stabbing the butt and streaking the slant.After incubation for 18 to 24 hours at 35° to 37°C, examine the LIA slants for reactions typical of V. cholerae.Organisms that produce lysine decarboxylase in LIA cause an alkaline reaction (purple color) in the butt of the tube (see Chapter 4, Figure 4-11).Organisms without the enzyme produce a yellow color (acid) in the butt portion of the tube.H2S production is indicated by a blackening of the medium.The LIA reaction for V cholerae is typically an alkaline slant (purple), alkaline butt (purple), no gas, and no H2S (Table 6-1).P roteus and Providencia spp.will often produce a red slant caused by deamination of the lysine. It is important that KIA, TSI, and LIA be prepared so the tubes have a deep butt and a long slant.If the butt is not deep enough, misleading reactions may occur in these media.In LIA, the decarboxylation of lysine occurs only in anaerobic conditions and a false-negative reaction may result from insufficient medium in the tube (Section C). # G ram sta in Examining overnight growth from an HIA slant by Gram stain will demon strate typical small, curved gram-negative rods (Table 6-1 # ).Staining with crystal violet only is a more rapid technique and will still demonstrate the cell morphol ogy typical of Vibrio spp.W et m o u n t Dark-field and phase-contrast microscopy have been used for screening suspected isolates of V. cholerae.With these techniques, saline suspensions are microscopically examined for the presence of organisms with typical small, curved rods and darting ("shooting star") motility (Table 6-1). # B. Serologic Identification of V. cholerae O1 and O139 # Presumptive identification using O1 and O139 antisera For slide agglutination testing with polyvalent O1 or O139 antisera, fresh growth of suspected V. cholerae from a nonselective agar medium should be used.Using growth from TCBS agar may result in false-negative reactions.Usually after 5 to 6 hours of incubation, growth on the surface of the slant is sufficient to perform slide serology with antisera; if not, incubate for a longer period.If the isolate does not agglutinate in O1 antiserum, test in O139 antiserum.If it is positive in the polyvalent O1 or in the O139 antiserum, it may be reported as presumptive V. cholerae O1 or O139.Presumptive V. cholerae O1 isolates should be tested in monovalent Ogawa and Inaba antisera (see below).Once one colony from a plate has been identified as V. cholerae O1 or O139, no further colonies from the same plate need to be tested. # Confirmation of V cholerae O1 using Inaba and Ogawa antisera The O1 serogroup of V. cholerae has been further divided into three serotypes, # Inaba, Ogawa, and Hikojima (very rare).Serotype identification is based on agglutination in monovalent antisera to type-specific O antigens (see Table 6-2).

A positive reaction in either Inaba or Ogawa antiserum is sufficient to confirm the identification of a V. cholerae O1 isolate.Isolates that agglutinate weakly or slowly with serogroup O1 antiserum but do not agglutinate with either Inaba or Ogawa antiserum are not considered to be serogroup O1.Identifying these antigens is valid only with serogroup O1 isolates.For this reason, Inaba and Ogawa antisera should never be used with strains that are negative with poly valent O1 antiserum. Strains of one serotype frequently produce slow or weak agglutination in antiserum to the other serotype, depending on how well the serotype-specific antisera have been absorbed.For this reason, agglutination reactions with Inaba and Ogawa antisera should be examined simultaneously, and the strongest and most rapid reaction should be used to identify the serotype.With adequately absorbed antisera, strains that agglutinate very strongly and equally with both the Ogawa and Inaba antisera are rarely, if ever, encountered.If such reactions are suspected, the strains should be referred to a reference laboratory for further examination and may be referred to as "possible serotype Hikojima." Refer to Chapter 11 for a discussion on quality control of antisera. # Slide agglutination procedures Agglutination tests for V. cholerae somatic O antigens may be carried out in a petri dish or on a clean glass slide.Use an inoculating loop or needle, sterile applicator stick, or toothpick to remove a portion of the growth from the surface of HIA, KIA, TSI, or other nonselective agar medium.Emulsify the growth in two small drops of physiological saline and mix thoroughly.Add a small drop of antiserum to one of the suspensions.Usually approximately equal volumes of antiserum and growth suspension are mixed, but the volume of suspension may be as much as double the volume of the antiserum.To conserve antiserum, volumes as small as 10 microliters (0.01 ml) can be used.An inoculating loop may be used to dispense small amounts of antisera if micropipettors are not available (Figure 4-12).Mix the suspension and antiserum well and then tilt the slide back and forth to observe for agglutination.If the reaction is positive, clumping will appear within 30 seconds to 1 minute.Examine the saline suspension carefully to ensure that it does not show clumping due to autoagglutination.If autoagglutination occurs, the culture is termed "rough" and cannot be serotyped. # Confirmation of V cholerae O139 A suspected V. cholerae isolate that reacts in O139 antiserum but not in polyvalent O1 antiserum should be sent to a reference laboratory.Confirmation of V. cholerae O139 includes testing for production of cholera enterotoxin and verification of the O139 antigen.No serotypes have been identified in the O139 serogroup.When inoculated into APW for quality control, V. cholerae O1 should show good growth at 6 to 8 hours. # C. Media and Reagents for # Kligler iron agar and triple sugar iron agar Prepare according to manufacturer's instructions.Dispense a quantity of medium in appropriate containers such that the volume of medium is sufficient to give a deep butt and a long slant.For example, dispense 6.5 ml of medium into 16 x 125-mm screw-cap tubes (leave caps loose), and after autoclaving, allow the slants to solidify in a manner such that the medium in the butt of the tube is 3 cm deep and the slant is 2 cm long.Tighten caps and store at 4°C for up to 6 months. Each new lot should be quality controlled before use.E. coli should give an acid slant and butt, with production of gas but no H2S. S. flexneri should give an alkaline slant, acid butt, without production of gas or H2S . # Lysine iron agar Prepare medium according to manufacturer's instructions on the bottle.Dis pense a quantity of medium in appropriate containers such that the volume of medium is sufficient to give a deep butt and a long slant.For example, dispense 6.5 ml of medium into 16 x 125-mm screw-cap tubes (leave caps loose), and after autoclaving, allow the slants to solidify in a manner such that the medium in the butt of the tube is about 3 cm deep and the slant is about 2 cm long.When the agar is cooled and solidified, tighten caps and store at 4°C for up to 6 months. Each new lot of dehydrated medium should be quality controlled before use.S. flexn eri should produce an alkaline slant and an acid butt without production of H2S. H2S-producing Salm onella strains should produce an alkaline slant and an alkaline butt with blackening of the medium due to H2S. V. cholerae strains are lysine-positive and will produce an alkaline reaction in the butt of the LIA. # Oxidase reagent -Tetramethyl-p-phenylenediamine dihydrochloride 0.05 g Distilled water 5.0 ml Dissolve the reagent in purified water (do not heat to dissolve).Prepare fresh daily. Positive and negative controls should be tested every time the reagent is prepared.V. cholerae is oxidase positive; E. coli is oxidase negative. # Sodium deoxycholate reagent (0.5%) for string test # Sodium deoxycholate 0.5 g Sterile distilled water 100.0 ml Add sterile distilled water to sodium deoxycholate and mix well.Store at room temperature for up to 6 months. Each new batch should be quality controlled before use.A V. cholerae O1 strain should be used as positive control.E. coli may be used as a negative control. # Thiosulfate citrate bile salts sucrose agar Follow manufacturer's instructions to weigh out and suspend the dehydrated medium.Heat with agitation.Medium should be completely dissolved.Cool agar in a water bath until cool enough to pour (50° to 55°C).Pour into petri plates, leaving lids ajar about 20 minutes so that the surface of the agar will dry.Close lids and store at 4°C for up to 1 week. Each new lot should be quality controlled before use since TCBS is subject to lot-to-lot and brand-to-brand variations in selectivity.V. cholerae O1 should show good growth of yellow colonies.E. coli should have none to poor growth of translucent colonies. # Chapter 7 Epidemiology of Escherichia coliSerotype O157:H7 E scherichia coli O157:H7 is a recently recognized pathogen that causes a dysentery-like illness.The disease is typically a bloody diarrhea, often without prominent fever, that can be complicated by hemolytic uremic syndrome.It is primarily found in developed countries.Only one confirmed outbreak has occurred in a developing country-in Swaziland in 1992 affecting 20,000 persons.Other outbreaks have been thought to occur but have not been confirmed. The major modes of transmission are through undercooked beef, unpasteurized milk, and foods that have come in contact with materials of animal origin.Water borne outbreaks have been reported, as have outbreaks associated with swimming in contaminated lakes. The organism produces toxins similar to those produced by Shigella dysenteriae serotype 1.Treatment with antimicrobial agents has not been demonstrated to be useful in improving the course or outcome of infection with E. coli O157:H7.In fact, treating with some agents may actually worsen the outcome.Since no treatment is recommended, it is not necessary to test the antimicrobial susceptibil ity of isolates of E. coli O157:H7. Laboratories should be familiar with this organism and should periodically look for it in stools from patients with bloody diarrhea.It is not necessary to examine every stool submitted to the laboratory for E. coli O157:H7, but it should be considered in outbreaks of dysentery in which Shigella spp.are not isolated from the stools of patients with bloody diarrhea.Laboratory supplies required for diagnosis of E. coli O157:H7 are listed in Annex H. # Chapter 8 Isolation and Identification of Escherichia coli Serotype O157:H7 Isolation and identification of E scherichia coli serotype O157:H7 can be greatly enhanced when optimal laboratory media and techniques are employed.The methods presented here are intended to be economical and to offer laboratorians some flexibility in choice of protocol and media.Laboratories that do not have sufficient resources to adopt the methods described below should consider sending specimens or isolates to other laboratory facilities that routinely perform these procedures.Laboratory supplies required for diagnosis of E. coli O157:H7 are listed in Annex H. # A. Isolation and Identification Methods E. coli O157:H7 rapidly ferments lactose and is indistinguishable from most other E. coli serotypes on traditional lactose-containing media.However, unlike approximately 80% of other E. coli, nearly all isolates of E. coli O157:H7 ferment D -sorbitol slowly, or not at all.Sorbitol-MacConkey (SMAC) agar was developed to take advantage of this characteristic by substituting the carbohydrate sorbitol for lactose in MacConkey agar, and it is the medium of choice for isolation of E. coli O157:H7.Sorbitol-negative colonies will appear colorless on SMAC (Figure 8-1). F igu re 8-1.E. c o liO 157:H7 colonies are colorless on SMAC.Non-O157 E. coli colonies are pink. Enrichment for E. coli O157:H7 is not usually necessary for isolation of the organism from acutely ill patients. Figure 8-2 illustrates the procedure for recovery of E. coli O157:H7 from fecal specimens.SMAC is inoculated as described in Chapter 4 (Figure 4-2).Incubate 18 to 24 hours at 35° to 37°C.After 18 to 24 hours' incubation, the amount and type of growth (e.g., sorbitol-positive or sorbitol-negative) on SMAC should be recorded on data sheets for each patient specimen (Figure 8-3).Colonies suspicious of E. coli O157:H7 will appear colorless and about 2 to 3 mm in diameter (Figure 8-1). Test sorbitol-negative colonies selected from SMAC with E. coli O157 anti serum or latex reagents (O157 antibody-coated latex and control latex) according to the procedures recommended by the manufacturer.Suspected colonies may be tested with antisera directly from the SMAC plate or subcultured to a nonselective medium (HIA, for example) and tested the next day.This provides more growth on which to perform the agglutination assay (however, some manufacturers of O157 latex reagents recommend testing only colonies taken directly from the plate).If colonies are tested directly from the plate, a colony that is positive in O157 latex reagent should also be transferred to another medium for subsequent testing.Once one colony from a plate has been identified as O157-positive, no further colonies from the same plate need to be tested. If O157 latex reagent is used, it is important to test any positive colonies in the latex control reagent also; this is because some sorbitol-nonfermenting organisms will react nonspecifically with latex.The manufacturers of these kits recommend that strains reacting in both the antigen-specific and control latex reagents be heated and retested.However, in a study that used this procedure, none of the nonspecifically reacting strains were subsequently identified as E. coli O157:H7. Isolates that are O157 positive should be sent to a reference laboratory for confirmation.The reference laboratory should identify isolates biochemically as E. coli because strains of several species cross-react with O157 antiserum.Identification of the H7 flagellar antigen is also required for confirmation.Isolates that are nonmotile or that are negative for the H7 antigen should be tested for production of Shiga toxins to identify pathogenic strains. It is not necessary to test E. coli O157:H7 isolates for susceptibility to antimicrobial agents (see Chapter 7). # B. Preparation and Quality Control of Sorbitol-MacConkey agar Prepare according to the manufacturer's instructions. Sterilize by autoclaving at 121°C for 15 minutes.Cool to 50°C and pour into petri plates.Leave lids ajar for about 20 minutes so that the surface of the agar will dry.Close lids and store at 4°C for up to 1 month.If medium is to be stored for more than a few days, put plates in a sealed plastic bag to prevent drying.Each new lot should be quality controlled before use. E. coli should produce good to excellent growth of pink to red colonies.E. c o liO157:H7 should produce colorless colonies. # Chapter 9 Antimicrobial Susceptibility Testing (Agar Disk Diffusion Method) The disk diffusion method presented in this chapter has been carefully stan dardized by the National Committee for Clinical Laboratory Standards (NCCLS) and if performed precisely according to the protocol below, will provide data that can reliably predict the in vivo effectiveness of the drug in question.However, any deviation from the method may invalidate the results.For this reason, if laboratories lack the resources to perform the disk diffusion test exactly as described, they should forward isolates to other laboratories for susceptibility testing. # A. Considerations for Antimicrobial Susceptibility Testing As antimicrobial resistance increases in many parts of the world, it becomes increasingly important to monitor the antimicrobial susceptibility of Shigella and Vibrio cholerae O1 and O139.However, because antimicrobial therapy for E scherichia coli O157:H7 infection has not been demonstrated to be efficacious or safe, except for cases of cystitis and pyelonephritis, determination of the antimicrobial susceptibility pattern is usually not meaningful. See Chapters 3 and 5 for a discussion of appropriate antimicrobial agents for treatment of dysentery and cholera.Testing Shigella, V. cholerae, and E. coli O157:H7 against certain drugs may yield misleading results when in vitro results do not correlate with in vivo activity.Shigella spp.,for instance, are usually susceptible to aminoglycosides (e.g., gentamicin, kanamycin) in the disk diffusion test, but treatment with these drugs is often not effective.Some special consider ations for susceptibility testing of V cholerae are discussed in section B below.Antimicrobial agents suggested for use in susceptibility testing of Shigella and V cholerae are listed in Table 9-1. # B. Procedure for Agar Disk Diffusion Figure 9-1 summarizes the disk diffusion method of susceptibility testing.Laboratory supplies required for Shigella and V. cholerae disk diffusion testing are listed in Annexes A and B. # Mueller-Hinton susceptibility test agar Mueller-Hinton agar medium is the only susceptibility test medium that has been validated by NCCLS.Mueller-Hinton agar should always be used for disk diffusion susceptibility testing, according to NCCLS and international guidelines.Because the way Mueller-Hinton is prepared can affect disk diffusion test results, it is very important to refer to Section C below for instructions on preparation and quality control of this medium.a If resistant to nalidixic acid, test with ciprofloxacin.b The results from the tetracycline disk are used to predict susceptibility to doxycycline also. # McFarland turbidity standard A McFarland 0.5 standard should be prepared and quality controlled prior to beginning susceptibility testing (see Section C).If tightly sealed to prevent evaporation and stored in the dark, the standard can be stored for up to 6 months.The McFarland standard is used to adjust the turbidity of the inoculum for the susceptibility test. # Preparation of inoculum Each culture to be tested should be streaked onto a noninhibitory agar medium (blood agar, brain heart infusion agar, or tryptone soy agar) to obtain isolated colonies.After incubation at 35°C overnight, select 4 or 5 well-isolated colonies with an inoculating needle or loop, and transfer the growth to a tube of sterile saline (see Section C) or nonselective broth (Mueller-Hinton broth, heart infusion broth, or tryptone soy broth) and vortex thoroughly.The bacterial suspension should then be compared to the 0.5 McFarland standard.This comparison can be made more easily if the tubes are viewed against a sheet of white paper on which sharp black lines are drawn (see Figures 9-2 and 9-3).The turbidity standard should be agitated on a vortex mixer immediately prior to use.If the bacterial suspension does not appear to be the same density as the McFarland 0.5, the turbidity can be reduced by adding sterile saline or broth or increased by adding more bacterial growth. Alternatively, the growth method may be used to prepare the inoculum.Four or five colonies are picked from overnight growth on agar and inoculated into broth (Mueller-Hinton broth, heart infusion broth, or tryptone soy broth).Incubate the broth at 35°C until turbid, and then adjust the turbidity to the proper density. # A g en ts fo r Shigella A g en ts fo r V. cholerae # Inoculation procedure Within 15 minutes after adjusting the turbidity of the inoculum suspension, dip a sterile cotton swab into the suspension.Pressing firmly against the inside wall of the tube just above the fluid level, rotate the swab to remove excess liquid.Streak the swab over the entire surface of the medium three times, rotating the plate approximately 60 degrees after each application to ensure an even distribution of the inoculum (Figure 9-4).Finally, swab all around the edge of the agar surface. F igu re 9-4.The Mueller-Hinton plate should be swabbed over the entire surface of the medium three times, rotating the plate 60 degrees after each application. # Antimicrobial disks The working supply of antimicrobial disks should be stored in the refrigerator (4°C).Upon removal of the disks from the refrigerator, the package containing the cartridges should be left unopened at room temperature for approximately 1 hour to allow the temperature to equilibrate.This reduces the amount of conden sation on the disks.If a disk-dispensing apparatus is used, it should have a tightfitting cover, be stored in the refrigerator, and be allowed to warm to room temperature before using. # Antimicrobial Susceptibility Testing (Agar Disk Diffusion M ethod) Apply the antimicrobial disks to the plates as soon as possible, but no longer than 15 minutes after inoculation.Place the disks individually with sterile forceps or with a mechanical dispensing apparatus, and then gently press down onto the agar.In general, place no more than 12 disks on a 150-mm plate and no more than 4 disks on a 100-mm plate.This prevents overlapping of the zones of inhibition and possible error in measurement.Diffusion of the drug in the disk begins immediately; therefore, once a disk contacts the agar surface, the disk should not be moved. # Recording and interpreting results After the disks are placed on the plate, invert the plate and incubate at 35°C for 16 to 18 hours.

After incubation, measure the diameter of the zones of complete inhibition (including the diameter of the disk) (Figure 9-5) and record it in millimeters (Figures 9-6, 9-7).The measurements can be made with a ruler on the undersurface of the plate without opening the lid.With sulfonamides and trimethoprim-sulfamethoxazole, a slight amount of growth may occur within the inhibition zone.In this instance, slight growth (80% inhibition) should be ignored and the zone diameter should be measured to the margin of heavy growth.The zones of growth inhibition should be compared with the zone-size interpretative table (see Table 9-2), and recorded as susceptible, intermediate, or resistant to each drug tested. Colonies growing within the clear zone of inhibition may represent resistant variants or a mixed inoculum.The distance from the colony(ies) closest to the disk to the center of the disk should be measured and then doubled to obtain a diameter.The diameter of the outer clear zone should be recorded as well and an interpretation recorded for each diameter.The colony(ies) inside the zone should be picked, re-isolated, re-identified, and retested in the disk diffusion test to confirm the previous results.The presence of colonies within a zone of inhibition may predict eventual resistance to that agent. # Quality control To verify that susceptibility test results are accurate, it is important to include at least one control organism (ATCC 25922 is the E. coli control strain used when testing E nterobacteriaceae and V cholerae) with each test.Zone diameters obtained for ATCC 25922 should be compared with NCCLS published limits (see Table 9-2 for diameters of the zones of inhibition for ATCC 25922).If zones produced by the control strain are out of the expected ranges, the laboratorian should consider possible sources of error. Susceptibility tests are affected by variations in media, inoculum size, incuba tion time, temperature, and other factors.The medium used may be a source of error if it fails to conform to NCCLS recommended guidelines.For example, agar containing excessive amounts of thymidine or thymine can reverse the inhibitory effects of sulfonamides and trimethoprim, causing the zones of growth inhibition to be smaller or less distinct.Organisms may appear to be resistant to these drugs F igu re 9-5.R esults of the disk diffusion assay.This Shigella isolate is resistant to trim ethoprim -sulfam ethoxazole and is growing up to the disk (SXT), the zone of which is recorded as 6 mm.when in fact they are not.If the depth of the agar in the plate is not 3 to 4 mm or the pH is not between 7.2 and 7.4, the rate of diffusion of the antimicrobial agents or the activity of the drugs may be affected. If the inoculum is not a pure culture or does not contain a concentration of bacteria that approximates the McFarland standard, the susceptibility test results will be affected.For instance, a resistant organism could appear to be susceptible if the inoculum is too light.Also, if colonies from blood agar medium are used to prepare a suspension by the direct inoculum method, trimethoprim or sulfonamide antagonists may be carried over and produce a haze of growth inside the zones of inhibition surrounding trimethoprim-sulfamethoxazole disks even when testing susceptible isolates. If antimicrobial disks are not stored properly or are used beyond the stated expiration date, their potency may decrease; this will usually be indicated by a decrease in the size of the inhibition zone around the control strain. As mentioned above, testing some bacteria against certain antimicrobial agents may yield misleading results because these in vitro results do not neces sarily correlate with in vivo activity.Examples include narrow-and expandedspectrum cephalosporins and aminoglycosides (e.g., gentamicin) tested against Shigella spp. (see Chapter 3), and erythromycin tested against V. cholerae (see section C below). # C. Special Considerations for Susceptibility Testing of V. cholerae Although the disk diffusion technique is the most commonly used method for antimicrobial susceptibility testing, zone size interpretive criteria for V cholerae O1 and O139 have been established only for ampicillin, chloramphenicol, sulfonamides, tetracycline and trimethoprim-sulfamethoxazole.It has been determined that disk diffusion results are not accurate for V. cholerae when testing erythromycin and doxycycline, and these agents should not be tested by this method.The results from the tetracycline disk should be used to predict suscepti bility to doxycycline.If susceptible to tetracycline, the strain will be susceptible to doxycycline.At this time there is no in vitro method to accurately determine susceptibility to erythromycin. The reliability of disk diffusion results for other antimicrobial agents, including ciprofloxacin, furazolidone and nalidixic acid, has not been validated.Until interpretive criteria have been established for V. cholerae, disk diffusion may be used to screen for resistance to ciprofloxacin, using interpretive criteria for the E nterobacteriaceae as tentative zone size standards.Tentative breakpoints have been proposed for testing furazolidone and nalidixic acid with V. cholerae (see Table 9-2).When screening with the disk diffusion method for these agents, results should be interpreted with caution.If zone sizes for these drugs fall within the intermediate range, the organism should be considered possibly resistant. # D. Preparation and Quality Control of Media and Reagents # Mueller-Hinton agar Follow manufacturer's instructions to prepare medium.After autoclaving, cool medium to 50°C.Measure 60 to 70 ml of medium per plate into 15 x 150-mm plates, or measure 25 to 30 ml per plate into 15 x 100-mm plates.Agar should be poured into flat-bottom glass or plastic petri dishes on a level pouring surface to a uniform depth of 4 mm.Using more or less agar will affect the susceptibility results.Agar deeper than 4 mm may cause false-resistance results, whereas agar less than 4 mm deep may be associated with a false-susceptibility report. Freshly prepared plates may be used the same day or stored in a refrigerator (2° to 8°C) for up to 2 weeks.If plates are not used within 7 days of preparation, they should be wrapped in plastic to minimize evaporation.Just before use, if excess moisture is on the surface, plates should be placed in an incubator (35° to 37°C ) until the moisture evaporates (usually 10 to 30 min).Do not leave lids ajar because the medium is easily contaminated. Each new lot should be quality controlled before use by testing the E. coli ATCC 25922 and/or Staphylococcus aureus ATCC 25923 standard strains.These standard strains are used with every test run for E nterobacteriaceae and gram-positive aerobes, respectively.The pH of each new lot of Mueller-Hinton should be between 7.2 to 7.4.If outside this range, the pH medium should not be adjusted by the addition of acid or base; the batch of plates should be discarded and a new batch of plates prepared.If the pH for every batch is too high or low, the entire lot of dehydrated medium may have to be returned to the manufacturer as unsatisfactory. # Turbidity standards (McFarland) McFarland 0.5 turbidity standards are available from various manufacturers.Alternately, the 0.5 McFarland may be prepared by adding 0.5 ml of a 1.175% (wt/vol) barium chloride dihydrate (BaCl2^2H2O) solution to 99.5 ml of 1% (vol/ vol) sulfuric acid.The turbidity standard is then aliquoted into test tubes identical to those used to prepare the inoculum suspension.Seal the McFarland standard tubes with wax, Parafilm, or some other means to prevent evaporation.McFarland standards may be stored for up to 6 months in the dark at room temperature (22° to 25°C).Discard after 6 months or sooner if any volume is lost.Before each use, shake well, mixing the fine white precipitate of barium sulfate in the tube. The accuracy of the density of a prepared McFarland standard should be checked by using a spectrophotometer with a 1-cm light path; for the 0.5 McFarland standard, the absorbance at a wavelength of 625 nm should be 0.08 to 0.1.Alternately, the accuracy of the McFarland standard may be verified by adjusting a suspension of a control strain (e.g., E. coli ATCC 25922) to the same turbidity, preparing serial 10-fold dilutions, and then performing plate counts (see Figure 9-8).The adjusted suspension should give a count of 108 colony forming units/ml.F igu re 9-8.Procedure for preparation and quality control of the M cFarland 0.5 stan dard # Frozen storage (ultralow freezer, -70°C; or liquid nitrogen freezer, -196°C) Isolates may be stored indefinitely if they are maintained frozen at -70°C or below.Storage at -20°C is not recommended because some organisms will lose viability at this temperature. - give greater assurance that the medium is adequate for recovery of a small number of organisms from a clinical specimen.An example of a protocol for quality control of media is given here: - The control strain is inoculated to nonselective broth (e.g., tryptone soy broth) and grown up overnight. -To prepare a standardized inoculum for testing selective and inhibitory media, make a 1:10 dilution of the overnight nonselective broth culture.If testing nonselective media, prepare an additional 1:10 dilution (to give a 1:100 dilution of the broth). -One tube or plate of each medium should be inoculated with the standardized inoculum of the control strain(s).When testing selective plating media, a nonselective plating medium such as heart infusion agar should be inoculated at the same time for comparison purposes. -Using a loopful of the 1:10 or 1:100 dilution prepared above (use a calibrated loop, if available) inoculate media to be tested, streaking for isolation on plating media.The same loop should be used for all quality control of all media; it is more important to use the same inoculating loop every time than it is to use a calibrated loop. # Sources of quality control strains # B. Quality Control of Reagents As with all other products used in testing, reagents, either purchased or pre pared in the laboratory, should be clearly marked to indicate the date on which they were first opened and the expiration date, if appropriate.Each reagent should be tested to make sure the expected reactions are obtained.If the reagent is a rare, expensive, or difficult-to-obtain product such as diagnostic antiserum, it does not necessarily have to be discarded on the expiration date.If satisfactory sensitivity and specificity can still be verified by normal quality control procedures, the laboratory may indicate on the vial label the date of verification of quality of the reagent.All reagents should be tested for quality at intervals established by each laboratory to ensure that no deterioration has occurred. For quality control of antiserum, two or more control strains (one positive and one negative) should be used to test its agglutination characteristics.The results of all reactions should be recorded.Following is an example of a typical quality control procedure. - Place a drop (about 0.05 ml) of each antiserum on a slide or plate.Also, place a drop of 0.85% saline on each slide or plate to test each antigen for roughness or autoagglutination. -Prepare a densely turbid suspension (McFarland 2 or 3; see Corresponding approxim ate density o f bacteria/m l 0.5 0.5 ml 99.5 ml 1 x 108 1 0.1 ml 9.9 ml 3 x 108 0.2 ml 9.8 ml 6 x lO 8 0.3 ml 9.7 ml 9 x 10s 0.4 ml 9.6 ml 12 x lO 8 0.5 ml 9.5 ml 15 x 10s 0.6 ml 9.4 ml 18 x 108 0.7 ml 9.3 ml 21 x 108 0.8 ml 9.2 ml 24 x lO 8 0.9 ml 9.1 m l 27 x 10s 10 1.0 ml 9.0 ml 30 x lO 8 # M o u th p ip e ttin g Mouth pipetting should be strictly prohibited in the laboratory.Rubber bulbs or mechanical devices should be used. # S h a rp s A high degree of precaution must always be taken with any contaminated sharp items, including needles and syringes, slides, pipettes, capillary tubes, and scalpels.Dispose of sharps in designated containers.To minimize finger sticks, used disposable needles must not be bent, sheared, broken, recapped, removed from disposable syringes, or otherwise manipulated by hand before disposal.Nondisposable sharps, including syringes, should be placed in a labeled discard pan for decontamination before cleaning.Broken glassware should not be handled directly by hand but should be removed by mechanical means such as a brush and dustpan, tongs, or forceps. # A eroso ls Perform all procedures carefully to minimize the creation of splashes or aerosols.Techniques that tend to produce aerosols should be avoided.Cool inoculating wires and loops by holding them still in the air for 5 to 10 seconds before touching colonies or clinical material.Loops containing infectious material should be dried in the hot air above the burner before flaming.Vortexing and centrifugation should be done in closed containers.Gauze should be used to remove the tops on blood specimens and should be placed around the top of blood culture bottles to minimize aerosol production during removal of the needle.Needles should never be cut or removed from the syringe before autoclaving.All body fluids should be centrifuged in carriers with safety caps only. When procedures with a high potential for creating infectious aerosols are conducted or when there is a risk of splashing or spraying the face with infectious or other hazardous materials, laboratory work should be conducted in a safety cabinet or with face protection (goggles, mask, face shield or other splatter guards).Procedures that pose a risk may include centrifuging, grinding, blending, vigorous shaking or mixing, sonic disruption, opening containers of infectious materials whose internal pressures may be different from ambient pressures, inoculating animals intranasally, and harvesting infected tissues from animals or eggs.Face protection should also be used when working with high concentrations or large volumes of infectious agents. # D eco n ta m in a tin g ben ch tops a n d o th er su rfa ces Bench tops should be wiped with a disinfectant (a phenolic disinfectant, 1% sodium hypochlorite, or 70% alcohol) routinely after working with infectious agents or clinical specimens or after spills, splashes, or other contamination by infectious materials.Solutions of disinfectants should be maintained at the work station (see D isinfectants below). # D isposal o f con ta m in ated m a teria ls All discarded plates, tubes, clinical samples or other contaminated materials are to be placed in disposal containers at each bench.Special disposal boxes must be used for sharps such as syringes or broken glass to minimize the risk of injury.Avoid overfilling such containers.Containers of contaminated material should be carefully transported to the autoclave room and autoclaved before disposal. # A u to cla vin g An autoclave must be available for the BSL-2/3 laboratory and must be operated only by personnel who have been properly trained in its use.To verify that each autoclave is working properly, spore strips or other biological indicators designed to test for efficiency of sterilization should be included in autoclave loads on a regular basis.Each autoclave load should be monitored with tempera ture-sensitive tape, thermograph, or other means (e.g., biological indicators). # G eneral la bo rato ry p o licies All areas of the laboratory must be kept clean and orderly.Dirt, dust, crowd ing, or clutter is a safety hazard and is not consistent with acceptable biological research.Floors should be kept clean and free of unnecessary clutter.They should be washed with a germicidal solution on a regular basis and after any spills of infectious material have occurred. # R efrig era to rs a n d freezers Refrigerators and freezers should be regularly inspected for the presence of broken vials or tubes containing infectious agents.Wear gloves and proper attire when removing and discarding broken material.Refrigerators and freezers should be regularly cleaned with a disinfectant and defrosted to prevent possible contami nation and temperature failure. # F ire p reven tio n Keep burners away from lamps and flammable materials.Bulk flammable material must be stored in the safety cabinet.Small amounts of these materials, such as ethyl acetate, ethyl alcohol, and methanol, can be stored in safety contain ers.Turn off burners when not in use.Know the location of fire extinguishers, fire blankets, and showers.Fire safety instructions and evacuation routes should be posted. # B. Special Practices # T ra n sp o rt o f biohazardous m a teria ls Transport of biohazardous materials from one building to another increases the risk of breakage and spills.If transport is necessary, the primary infectious agent container (regardless of size) must be placed in an unbreakable second container that can be sealed (e.g., screw-top tube, plastic bag). # D isin fecta n ts Organisms may have different susceptibilities to various disinfectants.As a surface disinfectant, 70% alcohol is generally effective for the E nterobacteriaceae, but other organisms are more resistant.However, 70% alcohol is not the disinfectant of choice for decontaminating spills.Phenolic disinfectants, although expensive, are usually effective against many organisms.Always read disinfectant labels for manufacturers' recommendations for dilution and for exposure times for efficacy, especially before use on BSL-3 organisms such as M ycobacterium tuberculosis.A good general disinfectant is a 1:100 (1%) dilution of household bleach in water; at this dilution, bleach can be used for wiping surfaces of benches, hoods and other equipment.A 1:10 (10%) dilution of bleach is corro sive and will pit stainless steel and should not be used routinely; however, it may be used to clean up spills of cultured or concentrated infectious material where heavy contamination has occurred.Dilutions of sodium hypochlorite should be made daily from a stock solution. # D econtam ina tio n o f sp ills The following procedure is recommended for decontaminating spills.Isolate the area to prevent anyone from entering.

Wear gloves and protective clothing (gown or lab coat; mask if the spill may contain a respiratory agent or if the agent is unknown).Absorb or cover the spill with disposable towels.Saturate the towels with an appropriately diluted intermediate or high level disinfectant (e.g., a phenolic formulation or household bleach).Place disinfectant-soaked towels over the area and leave them in place for at least 15 minutes before removing and discarding them.Wipe area using clean disinfectant-soaked towels and allow area to air dry.Place all disposable materials used to decontaminate the spill into a biohazard container.Handle the material in the same manner as other infectious waste. # A ccid en ts All injuries or unusual incidents should be reported immediately to the supervi sor.When cuts or puncture wounds from potentially infected needles or glassware occur, the affected area should be promptly washed with disinfectant soap and water.In the event of a centrifuge accident in which safety carriers have not been used, other personnel in the area should be warned immediately and the area isolated to prevent anyone from entering. # C. Protective Clothing and Equipment # L ab oratory coats Protective coats, gowns, smocks, or uniforms designated for laboratory use must be worn while working in the laboratory.This protective clothing should be removed and left in the laboratory before leaving for non-laboratory areas.All protective clothing is either disposed of in the laboratory or laundered by the institution; it should never be taken home by personnel. # G loves Regardless of the type of infectious material, gloves should be worn when performing potentially hazardous procedures (e.g., slide agglutination) in which there is a risk of splashing or skin contamination or when the laboratory worker has cuts or broken skin on his or her hands.Gloves should always be worn when handling clinical specimens, body fluids, and tissues from humans and animals.These tissues should be assumed to be positive for hepatitis B virus, HIV, other bloodborne pathogens, or M ycobacterium tuberculosis.Gloves must be removed when contaminated by splashing or spills or when work with infectious materials is completed.Gloves should not be worn outside the laboratory.Do not use the telephone or open doors with gloves that have been used in laboratory procedures.Dispose of all used gloves by discarding them with other disposable materials and autoclaving.Hands should be washed immediately after removing gloves. # B a rrier p reca u tio n s Clinical specimens, body fluids, and tissues from humans and animals should be assumed to be positive for hepatitis B virus, HIV, other bloodborne pathogens, or M ycobacterium tuberculosis.These materials should be handled in a safety cabinet or using other barrier precautions such as goggles, mask, face shield or other splatter guards whenever there is a potential for creating an aerosol.infectious substances, anyone packaging isolates or infectious specimens should consult the appropriate national regulations and the current edition of D an gerous Goods R e g u la tio n s before packing and shipping infectious substances by any means of transport.D efin itio n o f in fe ctio u s sub stan ces Infectious substances are defined as substances known to contain, or reason ably expected to contain, pathogens.Pathogens are microorganisms (including bacteria, viruses, rickettsia, parasites, fungi) or recombinant microorganisms (hybrid or mutant) that are known or reasonably expected to cause infectious disease in humans or animals.C la ssifica tio n o f clinica l/dia gn ostic specim en s - Specimens (human, animal, food, environmental, etc.)known or reasonably expected to contain pathogens are now to be classified as infectious sub stances.When these specimens are transported/shipped for any purpose, including initial or confirmatory testing for the presence of pathogens, they are to be packaged and shipped as infectious substances (see below). -Specimens that have a relatively low probability of containing pathogens are to be classified as clinical/diagnostic specimens.When these specimens are transported/shipped for the purpose of routine screening tests or initial diagnosis for other than the presence of pathogens, they are to be packaged and shipped as clinical/diagnostic specimens. -Those specimens known not to contain pathogens are to be packaged and shipped as nonrestricted, i.e., packaging and shipping is not regulated.They are to be packaged in watertight primary containers and leakproof secondary containers.Unless it has been specifically determined, i.e., by testing, that a clinical/ diagnostic specimen does not contain a pathogen(s), it is considered to fall within the categories either of those specimens known or reasonably expected to contain pathogens or those specimens that have a relatively low probability of containing pathogens. # G u id elin es fo r packaging and la beling in fectio u s sub stan ces Persons who ship infectious agents or diagnostic specimens must comply with all local and international regulations pertaining to the packaging and handling of these items.They must ensure that specimens arrive at their destination in good condition and that they present no hazard to persons or animals during shipment.The inner packaging must include the following: - An inner watertight primary container that is glass, metal, or plastic and has a leakproof seal.Petri plates should not be shipped. -A watertight, impact-resistant secondary container - Absorbent material between the primary container and the secondary container.If multiple primary containers are placed in a single secondary packaging, they must be wrapped individually to ensure that contact between them is prevented.The absorbing material, such as cotton wool, must be sufficient to absorb the entire contents of all primary containers. -An itemized list of contents between the secondary packaging and the outer packaging Multiple primary receptacles placed in a single secondary packaging must be wrapped individually, or for infectious substances transported in liquid nitrogen, separated and supported to ensure that contact between them is prevented.The absorbing material must be sufficient to absorb the entire contents of all primary receptacles.The outer packaging must meet the following requirements: - Be of sufficient strength to adequately protect and contain the contents - Be at least 100 mm (4 inches) in its smallest overall external dimension - Be durably and legibly marked on the outside with the address and tele phone number of the consignee.A biohazard warning label must be affixed to the outside of the outer container, and must bear the inscription, "Infec tious substance.In case of damage or leakage immediately notify public health authority."Packaging for infectious substances must be marked with United Nations specification markings denoting that the packaging has been tested and certified for shipping infectious substances.Figure 13-1 illustrates these packaging recommendations.G uidelines fo r p a cka g in g a n d la b elin g clinica l/dia gn ostic specim en s n o t fo r m icrob iolog ic exam in ation Clinical specimens with a low probability of containing an infectious agent that are not being transported for examination for the presence of pathogens must be packaged as follows: - Be "triple packaged" as described above for infectious agents - Be in packaging that will not leak after a 4-foot drop test - Have a "Clinical Specimens" label affixed to the outside of the outer container - If being shipped by air, bear the following statement, "Contents not re stricted, packed in compliance with IATA packing instruction 650."Figure 13-2 illustrates these packaging recommendations.S u p p lies need ed b y each n a tio n a l referen ce labo rato ry fo r con firm ation 5 x 100 sterile cotton or polyester swabs 5 x 500 g Cary-Blair medium 5 x 500 g TCBS medium 5 x 25 g sodium desoxycholate Glass slides for serologic testing and string test 5 x 5 g A^ALrALftetramethyl-D-phenylenediamine dihydrochloride (oxidase reagent) Filter paper Sterile wooden sticks or platinum inoculating loops 5 x 500 g nonselective agar- (e.g., tryptone soy agar, heart infusion agar) 20 x 2 ml polyvalent V. cholerae O1 diagnostic antiserum 5 x 2 ml V. cholerae O139 diagnostic antiserum 5 x 2 ml V. cholerae O1 serotype Ogawa diagnostic antiserum 5 x 2 ml V. cholerae O1 serotype Inaba diagnostic antiserum 5 x 500 g Bacto-peptone medium 5 x 500 g NaCl NaOH pH paper or pH meter 5 x 500 petri dishes (9 cm) 5 x 1000 test tubes (e.g., 13 x 100 mm or 16 x 125 mm) # National Reference Laboratory S u p p lies n eed ed b y each n a tio n a l referen ce labo rato ry fo r con firm ation 500 sterile cotton or polyester swabs 5 x 500 g Cary-Blair medium or other transport medium 5 x 500 g XLD medium 5 x 500 g MacConkey medium 3 x 500 g Kligler iron agar 3 x 500 g motility agar 3 x 500 g nonselective agar (e.g., tryptone soy agar, heart infusion agar) Diagnostic antisera: 20 x 2 ml monovalent S. dysenteriae serotype 1 (not Group A polyvalent) 10 x 2 ml polyvalent S. flexn eri (Group B) 5 x 2 ml polyvalent S. sonnei (Group D) Glass slides for serologic testing 5 x 500 disposable petri dishes (9 cm) 5 x 1000 disposable test tubes (e.g., 13 x 100 mm or 16 x 125 mm) A n tim icro b ia l su scep tib ility te st su p p lies fo r 100 Shigella iso lates 2 x 500 g Mueller-Hinton Agar 200 disposable petri dishes ( 9 National Reference Laboratory (Materials to confirm 500 isolates) - Heart infusion agar (HIA) or other nonselective medium - Petri dishes - Tubes for transport (HIA used as transport medium for isolates) # Reference level The regional laboratory sends isolates to a national reference laboratory for confirmation and antimicrobial susceptibility testing.Each reference laboratory will need sufficient materials to confirm at least 500 isolates sent from the regional level throughout the year.The basic materials needed are as follows: - TCBS medium # Referral to international reference laboratories As part of the laboratory-based surveillance process, isolates should periodi cally be sent to an international reference laboratory for confirmation of the antimicrobial susceptibility patterns.This is especially important if strains exhibit a new or unusual antimicrobial susceptibility pattern.Arrangements can be made through WHO for sending such specimens to an international reference laboratory and to provide for the rapid feedback of the results. # Feedback of Results R eg io n a l la bo rato ry to district, co n firm a tio n o f outbreak When the regional laboratory confirms the presence of V. cholerae O1 in stool specimens received from the district, it should contact the district as quickly as possible to inform the health authorities that V. cholerae O1 has been identified from the district. # R eferen ce laboratories to reg io n a l laboratories The reference laboratory should regularly communicate the results of the studies carried out on isolates submitted from the regional laboratory.The results should be sent to the regional laboratory and to the Ministry of Health.This includes the results of isolates sent both for confirmation of outbreaks and for the routine surveillance for V. cholerae carried out every 3 months.These results can serve as an internal quality control for the regional laboratories.In addition, every 3 months summaries of the results from all national reference laboratories should be distributed to the regional laboratories and appropriate persons in the Ministry of Health for further distribution to all relevant parties.The international reference laboratory should provide timely feedback of results to the national reference laboratory that is coordinating the shipping of the specimens.These results will be shared with the other reference laboratories and will serve as an external quality control for identification of V. cholerae O1 and O139 and for determining the antimicrobial susceptibility of the these strains. # Additional components for network This system could be expanded to include other bacterial pathogens, such as those causing dysentery.For instance, periodic surveillance of isolates from patients presenting with bloody diarrhea could be done to determine the prevalence of various organisms causing dysentery and their antimicrobial susceptibility patterns. Interna tion a l reference laboratory to reference laboratory

recommends that employee exposure to sulfuric acid (H2S04) at the workplace be controlled by requiring compliance with the following sections.The standard is designed to protect the health and safety of workers for up to a 40-hour work week over a working lifetime; compliance with the standard should therefore prevent adverse effects of sulfuric acid on the health and safety of workers.The standard is measurable by techniques that are valid, reproducible, and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard.The standard will be subject to review and will be revised as necessary. Section 1 -Environmental (Workplace Air) # (a) Concentration Occupational exposure to sulfuric acid mist shall be controlled so that workers shall not be exposed to a concentration greater than one milligram per cubic meter of air (1 mg/cu m) determined as a time-weighted average (TWA) exposure for up to a 10-hour work day, 40-hour work week. # (b) Sampling and Analysis Procedures for sampling, calibration of equipment, and analysis of environmental samples shall be as provided in Appendix I or by any method shown to be equivalent in accuracy, precision, and sensitivity to the method specified. (c) Exposure "Exposure to sulfuric acid" means exposure to a concentration of liquid, mist, or special dry powder of sulfuric acid, or to sulfur trioxide associated with oleum (fuming sulfuric acid) equal to or above one-half the recommended environmental standard- Exposures at lower environmental concentrations will not require adherence to the following sections except for work practices, equipment, and clothing which may be necessary to guard against the occurrence of forseeable accidents such as from spray or splash.Procedures for identification of exposure areas can be accomplished by time-weighted average (TWA) determinations by the method described in Appendix I or by any method shown to be equivalent in accuracy, precision, and sensitivity. Section 2 -Medical (a) Comprehensive preplacement and annual medical examinations shall be provided for all workers subject to "exposure to sulfuric acid." The examination shall be directed toward, but not limited to, the teeth, eyes, skin, and the cardiopulmonary system.Particular attention shall be focused on dental erosion and complaints of mucous membrane irritation and cough.An evaluation of the advisability of a worker's using negativeor positive-pressure respirators shall also be made. (b) Initial examinations for presently employed workers shall be offered within 6 months of the promulgation of a standard incorporating these recommendations and annually thereafter.Avoid breathing mist. In case of contact, immediately flush skin or eyes with plenty of water for at least 15 minutes; for eyes, get medical attention. Use protective clothing and equipment as instructed. Do not add water to acid. # UNAUTHORIZED PERSONS KEEP OUT (b) Areas where oleum (fuming sulfuric acid) is used, handled, or stored shall be posted with a sign reading: OLEUM Fuming Sulfuric Acid Danger!Causes Severe Burns Do not get in eyes, on skin, on clothing. Avoid breathing mist or gas. In case of contact, immediately flush skin or eyes with plenty of water for at least 15 minutes; for eyes, get medical attention. Use protective clothing and equipment as instructed. Do not add water to acid. # UNAUTHORIZED PERSONS KEEP OUT (c) Areas where bags of dry sulfuric acid are handled or stored shall be posted with a sign reading: SULFURIC ACID Dry Sulfuric Acid Avoid contamination with foreign matter. Do not rebag contaminated material. Place broken and torn bags and contents in slipover bags. Dispose of bags as instructed. Sweep up and promptly dispose of all spilled material as instructed. In case of fire avoid use of water directly on bags. Use protective clothing and equipment as instructed. UNAUTHORIZED PERSONS KEEP OUT These signs shall be printed both in English and in the predominant primary language of non-English-speaking workers, if any. # Section 4 -Protective Clothing and Personal Protective Equipment Engineering controls shall be used to maintain sulfuric acid concentrations below the prescribed limit.Administrative controls may also be used to reduce exposure.Requirements for personal protective equipment shall be as approved under provisions of 29 CFR 1910 (37 FR 22102, Subpart I, October 18, 1972). (a) Skin Protection (1) Skin contact with sulfuric acid will produce burns the site of contact.Impervious protective clothing, such as rubber gloves, aprons, suits, hoods, and boots shall be provided by the employer and used by the employee as appropriate to the severity and likelihood of body contact with liquid acid. (2) Sulfuric acid-wetted clothing, unless impervious, shall be removed promptly. (3) Protective clothing should be changed at least twice a week or more frequently if required. # (b) Eye Protection Eye protective equipment shall be provided by the employer and used by the employee where eye contact with liquid sulfuric acid is likely. (1) Selection, use, and maintenance of eye protective equipment shall be in accordance with provisions of the American National Standard Practice for Occupational and Educational Eye and Face Protection, ANSI Z87. . (2) Chemical safety goggles-cup-type, cover-cup-type, or rubber-framed goggles, equipped with approved impact-resistant glass or plastic lenses, shall be worn whenever there is danger of sulfuric acid eye contact. (3) Face shields-full length, 8-inch minimum plastic shields with forehead protection may be worn in place of, or in addition to, goggles.If there is danger of material striking the eyes from underneath, or around the sides of the face shield, chemical safety goggles should be worn as added protection. # (c) Respiratory Protection This subsection shall apply whenever a variance from the standard recommended in Section 1 (a) is granted under provisions of the Occupational Safety and Health Act, or in the interim period during the application for a variance.When the limits of exposure to sulfuric acid prescribed in subsection (a) of Section 1 cannot be met by controlling the concentration of sulfuric acid in the work environment, an employer must utilize, as provided in this subsection, a program of respiratory protection to effect the required protection of every worker exposed. Respirators shall also be provided and used for nonroutine operations (occasional brief exposures above the TWA of 1 mg/cu m and for emergencies); however, for these instances, a variance is not required, but the requirements set forth below continue to apply.Appropriate respirators as described in Table 1-1 shall only be used pursuant to the following requirements: (1) For the purpose of determining the type of respirator to be used, the employer shall measure the atmospheric concentration of sulfuric acid in the workplace when the initial application for variance is made and thereafter whenever process, worksite, or climate changes occur which are likely to increase the sulfuric acid concentration.This requirement shall not apply when only atmosphere-supplying positive pressure respirators are used.The employer shall ensure through proper respirator selection, fit, use, and maintenance that no worker is being exposed to sulfuric acid in excess of the standard. The respirator and cartridge or canister used shall be of the appropriate class, as determined on the basis of exposure to sulfuric acid. # Greater than lOOx Respirator Type (for both sulfuric acid mist and sulfur trioxide unless specified) (1) Type C supplied air respirator, demand type (negative pressure), with quarter, half, or full facepiece; if eye irritation noted, full facepiece must be worn. Sulfur trioxide only-Chemical cartridge respirator for sulfur dioxide with quarter, half, or full facepiece; if eye irritation noted, full facepiece must be worn.Use mist filter when sulfuric acid mist is present, Sulfuric acid mist only-Air purifying mist respirator with cartridge and half mask facepiece; if eye irritation noted, full facepiece must be worn. (1) Gas mask with chin style canister for acid gases and acid mists. (2) Gas mask with front or back mounted chest type canister for acid gases and acid mists. (3) Type C supplied air respirator, demand (negative pressure); pressure-demand; or continuous flow type with full facepiece. (4) Self-contained breathing apparatus in demand mode (negative pressure) with full facepiece. (1) Self-contained breathing apparatus in pressure-demand mode (positive pressure) with full facepiece. (2) Combination supplied air respirator, pressure-demand type, with auxiliary selfcontained air supply with full facepiece. (for both sulfuric acid mist and sulfur trioxide unless specified) (1) Self-contained breathing apparatus in pressure-demand mode (positive pressure) with full facepiece. (2) Combination supplied air respirator, pressure-demand type, with auxiliary self-contained air supply with full facepiece. (1) Self-contained breathing apparatus in demand or pressure-demand mode (negative or positive pressure). (2) Gas mask with acid gas chest canister, and mouthpiece respirator for acid gases and acid mists.shall be adopted and enforced. The employer shall provide respirators in accordance with If acid is to be diluted with water, the acid shall be added to the water except that in special cases when water must be added to acid, suitable precautions shall be taken. # (b) Emergency, Cleanup, and Inspection (1) Procedures for emergencies shall be established to meet foreseeable events.The irritant and corrosive properties of sulfuric acid demand that corrective measures be instituted as soon as possible. In the event of spills or leaks, sulfuric acid shall be neutralized with soda ash (sodium carbonate), washing soda, or suitable material and washed down with copious amounts of water.The contaminated area shall be immediately zoned off and ventilated thoroughly. Where there is the possibility of sulfuric acid contact on the eyes or skin, safety showers, eye-wash fountains, and cleansing facilities shall be installed and maintained to provide prompt, immediate access by the workers.The safety showers should have quickacting valves and deluge-type heads.Inspections and tests shall be conducted at least every 30 days to ensure proper operation. (4) Appropriate respirators shall be immediately available for wear during evacuation. (5) Each shipment of sulfuric acid shall be inspected for leakage upon arrival or upon transfer or filling operations.Pipelines, equipment, and containers shall be examined periodically for leaks at least every 3 months. # (c) Exhaust Systems and Enclosure (1) Exhaust ventilation and enclosure processes shall be used wherever practicable to control workplace concentrations.Systems shall be designed and maintained to prevent the accumulation or recirculation of sulfuric acid into the workplace. (2) Ventilation, enclosure, surface active agents, chips, etc, shall be used where operations or processes result in the evolution of sulfuric acid so as to protect employees from airborne concentrations in excess of the requirements of Section 1 (a) of the Standard.It is also necessary to remove hazardous concentrations of toxic gases such as arsine or hydrogen selenide which may result from the interaction of hydrogen with impurities present either in sulfuric acid or in metals with which the acid comes in contact. # (d) Storage ( From the health hazard standpoint, sulfuric acid must be handled with utmost care because of its highly corrosive action on the skin, eyes, and respiratory tract.The importance of good work practices is emphasized herein, along with the necessary documentation from which the proposed environmental standard is recommended.In addition, it is recognized that a great potential hazard exists, particularly by inhalation, from the use of oleum (fuming sulfuric acid). These criteria were not designed for the population-at-large and any extrapolation beyond general occupational exposures is not warranted. # III.BIOLOGIC EFFECTS OF EXPOSURE # Extent of Exposure Sulfuric acid is produced by the oxidation of sulfur dioxide. Approximately 99% of all production is now by the contact process.It is one of the most widely used chemical compounds. Sulfuric acid is a colorless to cloudy liquid.Fuming sulfuric acid (oleum) has a sharp, penetrating odor.Concentrated sulfuric acid has an extremely irritant, corrosive, and destructive action on all living matter, including human tissues, not by virtue of its acidity (in concentrated form it is only slightly ionized) but because of its affinity for water.The affinity is so strong that it will remove the elements of water from even anhydrous organic matter such as carbohydrates, resulting in charring or carbonization with the liberation of heat.In sulfuric acid splashing accidents, the heat liberated by dilution of the concentrated acid with water used to flush the affected areas, can add thermal burn to chemical injury of the body. Oleum, or fuming sulfuric acid, is a solution of sulfuric anhydride (sulfur trioxide) in anhydrous sulfuric acid.The "fumes" of oleum are initially composed of sulfur trioxide which will combine with water, either present in the air or on the mucous membranes of exposed persons, to form sulfuric acid.Effectively then, exposure to sulfur trioxide is equivalent to exposure to sulfuric acid, the site of effect in the respiratory tract being largely determined by droplet size. The more important strengths, properties, and characteristics of sulfuric acid and oleum are presented in Table X-l. Sulfuric acid mist, the airborne form of sulfuric acid, is an aerosol of droplets of varying diameter of aqueous sulfuric acid solution, the concentration of which will initially depend upon the concentrations of the liquid acid from which the mist is generated.However, the concentration of droplets may change as the highly hygroscopic droplets pick up more water from the atmosphere, growing in size in the process. Sulfate is one of the normal anions in the body ; however, the occupational hazard results not from the sulfate ion, but it is related either to the hygroscopic characteristics of the acid or to its oxidizing potential. Among the common processes which result in the evolution of sulfuric acid mist are pickling, anodizing, and plate-forming and charging in battery manufacturing.Exposures to the mist may result whenever sulfuric acid is heated in the open air or when gas bubbles are released from a liquid surface containing the acid.together with its low cost, make it useful for many purposes.Among these are the pickling of steel, the manufacture of halogen acids, removal of water vapor from gases, alkylation operations in the petroleum and petrochemical industries, acidulation and neutralization processes, and the manufacture of organic sulfonates used in household detergents and lubricants.The single largest use of sulfuric acid is in the manufacture of phosphate fertilizers. Sulfuric acid production in the United States in 1970 was almost 30 million tons. A small amount of sulfuric acid is available in a "dry" powdered form, composed of 80% by weight of 1.835 specific gravity sulfuric acid and 20% inert absorbent material (synthetic hydrated silicate).The particle size of the powder is approximately 0.02 to 0.07 pm.In use, the powder is dissolved in water and filtered, yielding a clear acid in strengths up to 60%. NIOSH estimates that 200,000 persons in the work force have potential exposure to sulfuric acid. # Historical Reports Alfred Nobel, prior to the establishment of the Nobel awards, is said to have commented that the economic progress of a country might be measured in terms of how much sulfuric acid is consumed through manufacturing productivity.In view of the 200 years history of the use of sulfuric acid in industry and the wide variety of industries in which it has been used, there is a remarkable dearth of reports in the early literature concerning adverse health effects of sulfuric acid in any form, including mist.Possibly the effects of concentrated sulfuric acid splashed on the skin or eyes are too well known for published comment. Greenwald in 1954 reviewed occupational and experimental observations of exposure to sulfuric acid mist in conjunction with his review of the effects of sulfur dioxide exposure upon man and animals. Dorsch in 1913 presented the only historical report of adverse health effects in workers to sulfuric acid mist.He noted coughing and sneezing among exposed persons in a lead-sulfuric acid battery room of a telephone exchange.Dorsch also made the following observations on himself and his colleagues: below 0.5 mg/cu m (expressed as S02) , hardly noticeable "annoyance"; between 0.5 and 2 mg/cu m, slight, from 3 to 4 mg/cu m, distinct; and from 6 to 8 mg/cu m, strong "annoyance" or "nuisance."He also personally experienced nosebleeds on occasions when exposed in the 3.12 to 8.3 mg/cu m range (again expressed as S02) .Values would be approximately 50% greater if they were calculated as sulfuric acid. Although there is evidence, both circumstantial and direct, that sulfuric acid aerosol was a significant atmospheric pollutant in some instances of "smog" episodes in the population-at-large, many other factors have undoubtedly also been present. # Effects on Humans (a) Observed Effects Concentrated sulfuric acid, by virtue of its great affinity and strong exothermic reaction with water, will effectively remove the elements of water from many organic materials with which it comes in contact, thus it can burn and char the skin. It is even more rapidly injurious to the mucous membranes, and exceedingly dangerous to the eyes.Dilute sulfuric acid, while it does not possess this charring property, irritates the skin and mucous membranes by virtue of its acidity and can cause dermatitis. Splash injuries to the eyes are in practice the most serious adverse health effect of sulfuric acid in industry, because contact with concentrated acid of any magnitude is capable of causing irreparable corneal damage resulting in blindness. At the same time, acid burns of the eyelids and surrounding parts of the face will produce cicatrization with disfigurement. As liquid sulfuric acid becomes progressively more dilute with water, the intensity of its dehydration/charring action gradually diminishes and it then behaves as a strong mineral acid by virtue of its complete ionization.Oleum, or fuming sulfuric acid, may be regarded as sulfuric acid of above 100% concentration, because it contains sulfur trioxide (sulfuric anhydride) in solution.As oleum combines with water, more sulfuric acid is formed until all the sulfur trioxide is consumed.Only thereafter does the sulfuric acid start to become diluted. The effects of exposure to mist of sulfuric acid in the human can be considered under two distinct headings: irritant effects on the mucous membranes, including those of the eyes, but principally the respiratory tract epithelium, and the chemical corrosive effects upon the teeth.

Exposure to sulfuric acid at the mist concentrations encountered in certain industries (about 0.8 to 17 mg/cu m and sometimes higher) causes first, etching of the dental enamel, amd then erosion of enamel and dentine with loss of tooth substance.The damage is limited to the parts of the teeth which are exposed to direct impingement of acid mist droplets upon the surface. This phenomenon does not seem to influence dental caries or other dental and periodontal lesions.The teeth affected are mostly the central and lateral incisors, and, to a much less extent, both the upper and lower canines.The observed effects are largely influenced by the degree of mouth-breathing and by the resting position of the lips, which effectively shield the teeth from the acid.In severe cases, which usually develop after many years of exposure, the loss of tooth substance may cause considerable cosmetic disfigurement as well as functional loss due to nonapposition of the cutting teeth.Denuding of the dentine may make the teeth sensitive to temperature extremes. Inhalation of sulfuric acid in high enough concentration causes an irritation or tickling of the nose and throat, sneezing, and coughing which is somewhat likened to the effects of breathing dusty air.At levels below those detectable by the foregoing subjective effects, sulfuric acid causes a reflex increase in the rate, and diminution of the depth, of respiration, with reflex bronchoconstriction resulting in increased pulmonary air flow resistance. Exposure to higher concentrations or for longer periods may result in bronchitic symptoms, and rhinorrhea, lacrimation, and epistaxis. Over the course of many years, exposure to sulfuric acid has also been claimed to result in conjunctivitis, frequent respiratory infections, emphysema, and digestive disturbances. However, other substances, including dusts, have also been associated with the effects noted.A single overexposure to sulfuric acid may lead acutely to laryngeal, tracheobronchial, and even pulmonary edema, and chronically to pulmonary fibrosis, residual bronchiectasis, and pulmonary emphysema. Dilute sulfuric acid, as with sulfuric acid mist, is absorbed as sulfate and hydrogen ions through mucous membranes, ultimately into the bloodstream.The sulfate ion is quite stable in the body and one of the normal minor anions of the plasma.Some sulfate (6 to 8%) from the plasma pool is conjugated in the liver with such metabolites as phenol, cresol, indole, and skatole and excreted in the urine as "ethereal sulfates."Such urinary excretion of the ethereal sulfates constitutes a detoxicating mechanism.The inorganic sulfate (85 to 90%) is excreted as compounds of sulfuric acid with Na, K, Ca, and NH3.The remainder, neutral sulfur (4 to 6%), is excreted in compounds such as sulfur-containing amino acids, thiosulfates , and thiocyanates. There is some evidence that acclimatization to the subjective effects of inhalation of sulfuric acid mist may occur in many persons who are occupationally exposed, to the extent that they may be able to tolerate 3 or 4 times the exposure levels which are intolerable to the unacclimated. On the other hand, there is also limited, inadequate evidence that sensitization to the effects of sulfuric acid mist may occur. Possibly both phenomena occur, and in the industrial situation, self-selection may take place.Individuals becoming acclimatized would most likely remain in an occupation involving exposure to sulfuric acid mist, whereas those with either an idiosyncratic hypersusceptibility or an acquired hypersensitivity leave such employment. Bushtueva failed to find any evidence of potentiation between sulfuric acid aerosol at 0.3 mg/cu m and 0.7 mg/cu m and sulfur dioxide at 0.65 and 3 mg/cu m, respectively, to effects on the light sensitivity of the dark adapted eye in 3 women subjects.The simultaneous administration of 0.3 mg/cu m sulfuric acid and 0.65 mg/cu m sulfur dioxide failed to produce an effect which differed from unexposed control determinations.The combination of 0.7 mg/cu m sulfuric acid and 3 mg/cu m sulfur dioxide produced simple physiological summation of effects as compared with effects produced by each substance separately.Similarly, the percent prolongation of the time required to produce a reflex optical stimulus (optical chronaxy) was also reported to be simply additive for a combination of 0.73 mg/cu m sulfuric acid and 1.5 mg/cu m sulfur dioxide. On the other hand, Amdur in 1954 demonstrated potentiation between sulfuric acid and sulfur dioxide in guinea pigs with respect to growth, lung changes, and respiratory alterations (see Animal Toxicity). # (b) Human Experimental In the past two decades a certain amount of human as well as animal experimental work has been performed with sulfuric acid aerosols, some of it at exposure levels relevant to the occupational situation, that is, in the 0.35 to 40 mg/cu m range. In 1952, Amdur and her associates reported exposing by mask a group of 15 normal subjects, men and women, to levels of 0.35 to 5 mg/cu m sulfuric acid aerosol (1.0 ym mean particle size), for periods of 5 to 15 minutes and determined subjective sensations, percent The increase in rate of respiration was always accompanied by some decrease in depth and also by a decrease in maximum inspiratory and expiratory flow rates.Retention of sulfuric acid in the respiratory tract averaged 77% over a 0.4 to 1.0 mg/cu m exposure concentration range. Morando, in 1956 reported surprisingly similar information to that given by Amdur et al which indicated that Morando was probably presenting data as exemplary of the effects resulting from exposures to low concentrations of sulfuric acid in humans under experimental conditions. In 1957, Sim and Pattle exposed healthy male volunteers by mask to 10 N acid mist concentrations ranging from 3 to 39 mg/cu m (1 ym median diameter) at 62% relative humidity.The subjects were also exposed in a chamber to 4 N acid mist of from 11.5 to 38 mg/cu m (1.5 ym median diameter) at 91% relative humidity.Mask exposures were of 10 minutes' duration and chamber exposures were up to 60 minutes in duration.In general, the sulfuric acid was much more irritating at higher humidity.The irritant effect of 20.8 mg sulfuric acid/cu m at high humidity (and larger particle size) was greater than that of 39.4 mg sulfuric acid/cu m at lower humidity (and smaller particle size).Under the conditions of high humidity, increases in airway resistance of from 43 to 150% above preexposure levels were measured and increases under the lower humidity conditions (62%) ranged from 35.5 to 100%. A study on pulmonary airway resistance by Toyama and Nakamura in 1964 reported interaction between hydrogen peroxide aerosols and sulfur dioxide.The interaction product was reported as sulfuric acid aerosol.Nine healthy male volunteers were exposed, through mouth breathing, to reported concentrations of from 0.01 to 0.1 mg/cu m sulfuric acid of 1.8 ym "count median diameter" (CMD) for a period of 5 minutes.Fifteen similar subjects were reportedly exposed to from 0.8 to 1.4 mg/cu m sulfuric acid of 4.6 ym CMD.Both exposures followed in sequence 5 minutes' exposure to similar aerosols of hydrogen peroxide alone, and 5 minutes' exposure to 1 to 60 ppm sulfur dioxide alone.The sulfuric acid exposures represented simultaneous administration of predetermined amounts of the hydrogen peroxide and sulfur dioxide. Airway resistance was measured by an airflow interruption technique. Airway resistance was not statistically different from controls by inhalation of hydrogen peroxide aerosol alone, it was increased following inhalation of sulfur dioxide alone to an extent partly dependent upon concentration, and the airway resistance was increased more on exposure to sulfuric acid mist (hydrogen peroxide and sulfur dioxide together).The mean increase in airway resistance was 36.5% above preexposure baseline in the 15 subjects exposed to the higher sulfuric acid concentration and larger droplets (4.6 pm CMD).The mean increase in airway resistance in the 9 subjects exposed to the lower concentration and smaller droplets was 17.9%.. Considerable individual variation existed in sensitivity to change in airway resistance. Futhermore, no data were given concerning how much unreacted sulfur dioxide or hydrogen peroxide was present during the sulfuric acid exposure phases of the study. Bushtueva in 1957 rhythm in all subjects.The particle size of the mists and the ambient humidity were not given. Bushtueva also studied sensory and central nervous system responses to sulfuric acid mist with and without sulfur dioxide in female volunteer subjects.The effects studied were optical chronaxy (in 1 subject) and dark adaptation (in 3 subjects).A sulfuric acid concentration of 0.73 mg/cu m was reported to elicit a threshold response, an approximately 19% prolongation of chronaxy, whereas 0.6 mg/cu m sulfuric acid was subthreshold.Similarly, 0.7 mg/cu m sulfuric acid produced an average 24% increase above control levels in sensitivity to light during the dark adaptation studies.A sulfuric acid concentration of 0.3 mg/cu m was below the sensitivity thresholds of the test subjects. Sulfuric acid aerosols given in combination with sulfur dioxide resulted in simple addition of physiological effects (see Effects on Humans). # Epidemiologic Studies Very few epidemiologic studies of health effects resulting from sulfuric acid exposure have been carried out in industry.In recent years, there have been some community studies of morbidity and mortality associated with "smog" episodes, but since sulfuric acid is only one of the significant constituents of most smogs, the results of such studies have little meaning to the industrial sulfuric acid exposure situation. In 1970, Williams Both exposed and control workers showed a statistically significant decrease in mean FVC and FEV 1 during both Monday and Friday shifts. These decreases were somewhat larger in the exposed than in the control groups but the author considered this difference to be insignificant and attributed the decrease in both groups to circadian (presumably day-night) variation.It was suggested that the absence of statistically significant differences in FVC and FEV 1 between the exposed and control groups could have been due to the several minutes which elapsed between exposure to acid mist and observations of ventilatory capacity in the medical department.It was concluded from the study that an excess of spells of respiratory disease, especially bronchitis, occurred in the forming group.It seemed likely that there were one or more factors present in the forming operation which was specifically associated with bronchitis and other respiratory disease in susceptible individuals.It was also suggested by Williams that the absence of any considerable lower respiratory tract disease observed in this study might be due to the large size of the mist particles or droplets, thus preventing their reaching the deep lung. Although the mist particle size was not measured in this plant, it was found in the forming department of another similar factory to have a mass median diameter (MMD) of 14 ym with only 4% of the particles being less than 4 urn in diameter.The mean concentration of sulfuric acid in the air of this other forming department was 2.7 mg/cu m. These data on particle size were cited by Williams apparently as having some bearing by analogy to the conditions present in his own study.As an additional factor to particle size, the high solubility of sulfuric acid would suggest rapid absorption in the upper respiratory air passages with little effect being expected on the lower portions of the respiratory tract.In the absence of comparative data such as ambient relative humidity, temperature, and air movement, the comparisons may be uncertain. In Egypt, El-Sadik and his associates An additional 117 workers from other parts of the plant free from sulfuric acid mist were studied as controls.The prevalence and graded severity of dental erosion and decayed, missing, and filling rates were compared in the three groups: high level sulfuric acid exposure (forming), low level exposure (charring), and unexposed controls.Etching of the dental enamel (a change in surface texture without loss of tooth substance) was found most commonly in the highest exposed group, less so in the lower exposed group, and was absent from the controls.The lowest grade of dental erosion defined, loss not exceeding 2 mm of incisal enamel, along with etching, was most prevalent in the high exposed group (55 out of 63, 87%), less so in the lower exposed group (7 out of 15, 47%), and absent in the controls.The differences were highly significant (p less than 0.01).The two higher grades of erosion, loss of 2 to 5 mm of tooth crown and loss of more than 5 mm of tooth crown, were present in the high exposed group only.Additionally, of 7 men transferred from the forming department of another factory, 6 showed advanced stages of erosion and the seventh had dentures.This small group had a mean length of exposure of 5 years, which was far less than that at the main factory. It was established that dental etching and erosion occurred only on the anterior teeth (central and lateral incisors, and to a much smaller extent, the canines) to the extent that these teeth were directly exposed to the impingement of acid droplets, as left uncovered by the lips in their customary position.Six workers from the high exposed group were unaffected by the acid.This was postulated to be due either to resistance of the enamel or to the individuals seldom parting their lips, thus preventing acid mist from reaching the teeth.Also, it seems that time-on-the-job could have been a factor; the employment duration was not given for these workers. In a comprehensive study of the problem of dental erosion in all those industries which involve exposure to any significant concentration of acid spray or mist, ten Bruggen Cate in 1968 reported on 555 "acid workers" over a two-year observation period in Britain.The study was initiated in response to a memorandum to the Industrial Injuries Advisory Council from the British Dental Association which concluded that industrial dental erosion was a hazard which existed, and that in the majority of cases severe dental damage resulting in disfigurement occurred.Of the total workers studied, 101 workers were exposed essentially to sulfuric acid alone, the other workers being exposed primarily to hydrochloric, nitric, hydrofluoric, chromic, and phosphoric acids in a wide variety of industries (48 firms) and processes.All control workers came from acid-free departments of the firms participating in the survey and all controls were found to be free from industrial dental erosion.All 555 workers studied had natural teeth, 38% having been excluded because their teeth had been extracted and descriptions of the conditions of their teeth prior to removal were unreliable.The classification of dental erosion used previously by Malcolm and Paul proved unsatisfactory because it was necessary to subtract the remaining tooth substance from assumed dimensions of the original crown in order to estimate tooth loss.A classification was therefore selected ranging from etching, loss of enamel only (Grade 1), loss of enamel with involvement of dentine (Grade 2), further exposure of secondary dentine (Grade 3), to loss resulting in pulpal exposure (Grade 4).Interestingly, no Grade 4 erosion was observed.It was suggested that pain would lead to early treatment of such an erosion, in most cases resulting in extraction. Further, pain was very rarely reported, and when present,_was described as a hypersensitivity to cold.Only 5 cases reported pain for which erosion was considered to be the cause.In the storage battery industry involving almost exclusively exposure to sulfuric acid mist, nearly 20% of the forming workers showed Grade 2 or Grade 3 erosion at the first examination.Erosion was less in the charging departments, yet some of these workers had been employed for only short periods and showed progressive erosion at subsequent examinations.Erosion was also present in other acid-using industries, although the prevalence was consistently less than that observed among battery, particularly formation, workers.Functional disability and disfigurement occurred although little evidence was seen of treatment to restore function or appearance to acid-eroded natural teeth.This was believed due to the fact that many workers were not interested in the level of dental treatment required or were not aware that treatment was possible.Additionally, it was concluded that acid environments had no influence on the incidence of caries. # Animal Toxicity Treon et al in 1950 reported a comparative mortality study in guinea pigs, rabbits, rats, and mice exposed to high concentrations of sulfuric acid aerosol (87 to 1,600 mg/cu m) in which about 95% of the particles were below 2 ym in diameter.Guinea pigs succumbed after having been exposed for a brief period to 87 mg/cu m. Animals of other species survived after being exposed at this concentration for 2.75 hours, and much higher concentrations were required to produce death.Some mice died following exposure to 549 mg/cu m for 3.5 hours, exposure to 699 mg/cu m was lethal to rats, while higher concentrations were required to cause death in rabbits.Deaths occurred almost uniformly when groups of mice, rabbits, and rats were exposed to a concentration of 383 mg/cu m for 7 hours on each of five successive days.All mice, rats, and rabbits, however, survived exposure for the same duration to 203 mg/cu m. Therefore, the order of increasing sensitivity established was rabbits, rats, mice, and guinea pigs.Concentration rather than duration was more critical in the mortality of guinea pigs.Lesions produced included degenerative changes in the epithelium of the respiratory tract, pulmonary hyperemia and edema, and focal pulmonary hemorrhages.The lungs of all animals exposed showed areas of atelectasis and emphysema. Amdur et al found the 8-hour LC50 (concentration lethal to 50% of the animals) of sulfuric acid aerosol of mass median diameter (MMD) of 1 ym to be 18 mg/cu m for 1-to 2-month old guinea pigs and 50 mg/cu m for 18-month old animals.The cause of death in the animals dying within 2 hours appeared to be asphyxia caused by bronchoconstriction and laryngeal spasm.Animals dying after longer exposures showed gross capillary engorgement and hemorrhage.When the exposure times were extended to 72 hours, there was no mortality at 8 mg/cu m; thickening of alveolar walls and areas of consolidation were found.

Longer exposures at higher concentrations did not increase mortality beyond that observed at 8 hours at a given concentration, but the above-mentioned lung changes were much more marked.It was postulated that the toxicity of sulfuric acid aerosol for the guinea pig has two aspects: it promotes laryngeal spasm and bronchospasm which may be lethal depending on the concentration and, in additon, it causes parenchymal lung damage, dependent upon the total dose represented by the product of concentration and time. Thomas et al reported exposing guinea pigs for longer periods (18 to 140 days) to mean concentrations mostly from 1 to 4 mg/cu m and with 3 different particle sizes, 0.6, 0.9, and 4 ym. Of the 3 particle sizes used, 0.9 ym produced the greatest effects including slight lung edema and rare capillary hemorrhages.There was some increase in desquamated epithelial cells in the minor bronchi. Slight edema of the larynx and trachea and a decrease in mucus in the major bronchi were seen with the 4-ym particles.It was concluded that the guinea pig can tolerate levels of 2 mg/cu m for more than 3 months of continuous exposure, with only minor pathological effects. Bushtueva reported exposing guinea pigs to 2 mg/cu m sulfuric acid aerosol of unspecified particle size for 5 days and found edema and thickening of the alveolar walls.One-to 2-weeks following exposures to 2 mg/cu m, a slight catarrhal reaction in the tracheal and bronchial mucosa with interstitial proliferative processes was observed accompanied by round lymphoid cell infiltration around blood vessels and bronchi.These changes seemed to progress with prolonged exposure up to 2 and 3 months. Amdur studied the effects on airway resistance in guinea pigs of sulfuric acid aerosol of 0.8-, 2.5-, and 7-ym MMD in concentrations ranging from 2 to 40 mg/cu m. The largest particles, 7 ym, even at a concentration as high as 30 mg/cu m, caused only a slight increase in airway resistance.Such particles would probably not penetrate beyond the nasal passages.The 0.8-ym particles produced a significant increase in resistance, even at 1.9 mg/cu m concentration.At 40 mg/cu m, the 2.5-um particles produced the greatest increase in resistance, but at concentrations below 2.0 mg/cu m, the 0.8-ym particles produced the greater effect.In general, it was concluded that large particles which reached the middle respiratory tract (trachea and bronchi) probably acted by producing mucosal swelling, secretion, and exudation of fluid which lead to obstruction of major airways, whereas the smaller particles produced simple reflex bronchoconstriction. Lewis et al studied the effects of sulfuric acid mist, alone In a later report, Lewis et al studied the effects in beagles of exposure to 0.9 mg/cu m sulfuric acid alone and in combination with 13.4 mg/cu m sulfur dioxide on certain hematological indices, organ weights at autopsy, and lung function indices similar to those studied earlier. Exposure to sulfuric acid, with or \tfithout concomitant sulfur dioxide, for 225 or 620 days had no demonstrable effect on the white cell count or on erythropoiesis. Statistically significant decreases in both lung and heart weights in the dogs exposed to sulfuric acid aerosol were observed as compared with total body weight.It was hypothesized that this might either be an effect of elevated blood sulfate bathing those organs, or a neural or humoral response to injury to the lung.The effect of sulfuric acid exposure on lung function, as in the earlier series of experiments, was most marked in decreasing diffusion capacity.In the opinion of the authors their findings indicated that continuous chronic inhalation of 0.9 mg/cu m sulfuric acid mist had a deleterious effect, in beagles, on both the conducting airways and the lung parenchyma. In 1954, Amdur reported the effects of a combination of sulfuric acid mist at 8 mg/cu m and sulfur dioxide at 89 ppm on growth, lung pathology, and respiratory response.In 8 guinea pigs exposed for 8 hours, weight had decreased the day following exposure and growth was slower to resume than was observed for either agent administered separately.Two guinea pigs were exposed 72 hours following the initial exposure to the same concentrations for another 8 hours.In these reexposed animals, growth ceased entirely during the period of observation following reexposure.Pathologic lung changes were also more extensive than that observed for either agent alone, consisting of large areas of complete consolidation and hepatization involving entire lobes in all cases.In the reexposed animals, extensive hemorrhage and consolidation were present.It was commented that the general ill health of the animals was very likely related to the presence of the extensive lung damage.Labored breathing was very pronounced, continuing for 24 to 48 hours after exposure.In contrast, there were no noticeable respiratory effects in guinea pigs exposed to 8 mg/cu m sulfuric acid mist alone.Restlessness and annoyance initially appeared in animals exposed to 89 ppm sulfur dioxide alone, but that disappeared after approximately 5-to 10-minutes exposure.It was therefore concluded that the effects on growth, lung changes, and respiration were much more marked than would have been predicted from the use of either agent alone. # Correlation of Exposure and Effect Because of the widespread use of sulfuric acid in industry, reports appear frequently of accidental skin or eye contact with the acid.The vast majority of cases where exposures through surface contact with the acid occur, either from splash or spray, can be attributed to some type of equipment malfunction.Because of the sudden and frequently unanticipated occurrences of acute occupational exposures, concentrations are difficult to establish.The case report presented by Goldman and Hill emphasizes the severe damage caused to a worker when sprayed in the face with liquid oleum resulting from a burst valve.Even with use of a safety shower, exposure was sufficient to cause second and third degree burns of the face and body and pulmonary edema due to sulfuric acid inhalation.Chronic after-effects were manifested as pulmonary fibrosis, residual bronchitis, and pulmonary emphysema.In addition, burning and charring of the skin were sufficient to cause marked scarring and disfigurement. The epidemiologic studies concerning the health effects resulting from sulfuric acid exposure are difficult to correlate with environmental concentrations, either because environmental sampling was not performed, because data were unavailable for inclusion in the studies, or because sampling and analytical procedures made environmental results very questionable (see Environmental Data).The 1970 study by Williams for lead-acid battery workers indicated that forming process workers and ex-workers had more spells of sickness absence due to respiratory disease than was expected from a calculated absence rate for all men.Pasting and assembly workers (controls) had fewer spells than expected.Statistically significant decreases were noted in mean forced vital capacity (FVC) and forced expiratory volume at one second (FEV 1), but the differences were attributed to possibly circadian (presumably day-night) variation.However, the FVC and FEV 1 decreases were somewhat larger in the exposed than in the control groups.No environmental measurements were made expressly for this study ; however, estimates from other studies conducted in the same plant indicated environmental sulfuric acid levels to vary from 3 to 16.6 mg/cu m, taken on a single day and reported in the dental erosion study by Malcolm and Paul. The second estimate, 1.4 mg/cu m (range, 0.2 to 5.6 mg/cu m), was reported by Anfield and Warner 6 years after the end of Williams' sickness absence study.Williams concluded that an excess of spells of respiratory disease, especially bronchitis, occurred in the forming group workers manufacturing the lead-acid batteries. El-Sadik et al reported environmental concentrations of 25 to 35 mg/cu m of sulfuric acid in one storage battery plant and 12.6 to 13.5 mg/cu m in another (see Environmental Data).No significant difference was found in the incidence of chronic bronchitis or chronic asthmatic bronchitis between 33 exposed workers and 20 controls.Changes in vital capacity and FEV 1 were similar to those observed by Williams and there was a greater group mean decrease in FEV 1 in the exposed group than in the controls.The authors suggested that the decreased FEV 1 might be due to the inhalation of sulfuric acid mist.In addition, the sulfuric acid exposed workers showed a nearly 40% higher occurrence of dental erosion and dental discoloration than was noted in the controls. The studies on dental erosion reported by Malcolm and Paul in 1961 and by ten Bruggen Cate in 1968 demonstrated a high incidence of dental damage among forming process workers and among charging workers, with dental erosion being absent in all of the controls (p less than 0.01). Airborne acid concentrations varied from 3.0 to 16.6 mg/cu m in the forming process and from less than 0.8 to 2.5 mg/cu m in the charging process. A positive relationship was also observed between the onset and advance of dental erosion and the length of service.In addition, functional disability and disfigurement occurred, although there appeared to be no influence of acid environments on the incidence of dental caries. Human experimental exposure studies have included changes in respiratory airway resistance and changes studied by measurement of sensory and central nervous system responses from light sensitivity in the dark adapted eye or from reflex optical stimulation. In addition, determinations have been made on the lower limits of detection of sulfuric acid. Bushtueva reported erratic changes in respiratory amplitude and an increase in respiratory rate at sulfuric acid concentrations of 1.8 to 2 mg/cu m. Very slight changes were noted at 1.0 to 1.1 mg/cu m and no effects were obtained at concentrations below 1 mg/cu m. Amdur et al reported an increased respiratory rate in all subjects tested at 0.35, 0.40, and 0.50 mg/cu m. At 1.0 mg/cu m, forced expiration was noted and at 2 mg/cu m the increased rate was more rapid and marked. Effects were even more marked and varied at 5 mg/cu m. Morando reported similar results at 0.52 to 0.7 mg/cu m. Bushtueva reported prolongation of optical chronaxy at 0.73 mg/cu m sulfuric acid (0.6 mg/cu m was subthreshold) and an increase in sensitivity to light during dark adaptation at 0.7 mg/cu m (0.3 mg/cu m was subthreshold).The subjective limit of detection to sulfuric acid has been reported to be between about 0.5 and 0.7 mg/cu m by a number of investigators. Sulfuric acid exposures are lethal to mice, rabbits, and rats at about 400 mg/cu m of air for exposure periods of 7 hours a day for 5 days. Guinea pigs are much more susceptible, however, 87 mg/cu m being lethal after only brief exposure periods accompanied by degenerative changes of the respiratory epithelium, pulmonary edema, and hemorrhages. The lungs of all animals exposed showed areas of atelectasis and emphysema. Amdur et al reported the 8-hour LC50 to be 18 mg/cu m for young guinea pigs (1 to 2 months old) and 50 mg/cu m for 18 month old animals. Sulfuric acid exposures of 8 mg/cu m for 72 hours produced no mortality. Further, no changes in respiratory effects were noted in guinea pigs exposed at 8 mg/cu m sulfuric acid. At exposure levels of 2 mg/cu m, Thomas et al reported minor pathological changes in guinea pigs after more than 3 months and Bushtueva reported edema and thickening of alveolar walls after 5 days' exposure.Lewis et al considered that the continuous chronic inhalation (225 days) of 0.9 mg/cu m sulfuric acid had a deleterious effect on beagles on both the conducting airways and the lung parenchyma. Particle (droplet) size seems to interplay along with temperature and humidity to influence the toxic effects of sulfuric acid in the respiratory tract.Amdur found that 2.5 um particles produced a marked increase in pulmonary flow resistance at a concentration of 40 mg/cu m. However, median particle sizes of about 0.8 pm were more effective at concentrations below 2.0 mg/cu m" It was concluded that large particles probably exerted their effects on the middle respiratory tract (trachea and bronchi) whereas the smaller particles produced simple reflex bronchoconstriction. Thomas et al found similar results in guinea pigs with particle sizes of 0.6, 0.9, and 4 pm.The animal mortality studies of Treon et al and Amdur et al were performed with median particle sizes of sulfuric acid mist less than 2 ym.In contrast, the human experimental study of Toyama and Nakamura reported a greater mean increase in pulmonary airway resistance (36.5%) in subjects exposed to 0.8 to 1.4 mg/cu m sulfuric acid of 4.6 ym particle size.A 17.9% increase in airway resistance was found for a reported sulfuric acid concentration of from 0.01 to 0.1 mg/cu m of air at 1.8 ym particle size.These results are difficult to evaluate because of the method by which the sulfuric acid was generated.An interactive effect was indicated between hydrogen peroxide and sulfur dioxide rather than to sulfuric acid alone. A comment given by Williams in his epidemiologic study may be pertinent at this point to reflect particle sizes in an occupational situation.Although mist particle size was not measured in the Williams study, a forming process department of another similar factory was reported to demonstrate acid mist having a mass median diameter of 14 V>m with only 4% of the particles being less than 4 ym in diameter. The interaction of sulfuric acid with other gases and aerosols has been reported.Amdur reported that a combination of sulfuric acid mist at 8 mg/cu m in guinea pigs (which produced no noticeable respiratory effects when administered alone) and 89 ppm sulfur dioxide produced effects on growth, lung changes, and respiration which were more marked than would have been predicted from the use of either agent alone.Bushtueva, however, reported that in humans 0.7 mg/cu m sulfuric acid (which was a threshold concentration) and 3 mg/cu m sulfur dioxide produced simple physiological summation of effects as measured by light sensitization to the dark adapted eye.Similar additive effects were noted for optical chronaxy at 0.73 mg/cu m sulfuric acid and 1.5 mg/cu m sulfur dioxide.Lewis et al reported a statistically significant reduction in mean diffusion capacity in beagles exposed 21 hours a day for 225 days to a combination of 0.835 mg/cu m sulfuric acid and 5.1 ppm sulfur dioxide.The reduction was greater than that which would have been expected by either agent alone.Further studies by Lewis et al showed statistically significant decreases in both lung and heart weights as compared with total body weight to exposures at 0.9 mg/cu m sulfuric acid and 13.4 mg/cu m sulfur dioxide. The human study on sulfuric acid exposure reported by Toyama and Nakamura appears to resemble more closely a combination study between hydrogen peroxide and sulfur dioxide rather than sulfuric acid because of the manner in which the substances were administered. Humidity also seems to play a role in influencing the effects of sulfuric acid exposure.Sim and Pattle reported a greater increase in pulmonary airway resistance in humans exposed to 20.8 mg/cu m sulfuric acid at 91% humidity as compared with 39.4 mg/cu m at 62% relative humidity.The lower dose under conditions of high humidity was also more irritating to the respiratory tract than the higher dose under the less humid conditions. # IV.ENVIRONMENTAL DATA Environmental Concentrations Data on occupational environmental concentrations of sulfuric acid are very meager, possibly because the corrosive action of the acid on the skin and eyes is so commonly recognized from splash and spray that environmental levels have been overlooked.The few data that are available have generally been collected only on a single day; therefore, it is extremely difficult to relate the reported environmental information to actual conditions.At best, only rough estimates of environmental concentrations, especially ranges, can be made.Occupational environmental levels reported by Malcolm and Paul, El-Sadik et al, and Anfield and Warner are as meaningful as could be obtained. Malcolm and Paul's study concerned dental erosion in workers. Reported acid mist concentrations in forming process areas to a mixture of dilute sulfuric acid (specific gravity 1.020 to 1.100) varied from 3.0 to 16.6 mg/cu m of air.Measurements were made on a dry day with low relative humidity.Forming tanks contained a foaming agent on the top of the acid which coalesced acid-containing gas bubbles, thus reducing acid mist escaping into the air.In addition, impervious sheets were used to cover the tanks which condensed the spray and permitted it to run back into the tanks.It was stated that the amount of acid present in the air on a cold humid day often exceeded 16 mg/cu m. In the charging process, the acid specific gravities were mostly about 1.265, higher than those in the forming process, and airborne acid levels varied from less than 0.8 to 2.5 mg/cu m. The method of analysis was not given; however, the standard error of the method was reported to be ±25%.These same environmental data were the only ones referred to in the epidemiologic study on dental erosion reported by ten Bruggen Cate in 1968. El-Sadik et al reported environmental sulfuric acid concentrations, again in the manufacture of storage batteries.In a simple laboratory experiment conducted in an exhaust hood with a beaker of 15% w/v sulfuric acid solution and a filter sampler located "a few inches" above the beaker, Anfield and Warner demonstrated that although heating and agitation of fluid with an air bubbler would increase airborne sulfuric acid concentrations, processes involving the evolution of hydrogen produced enormously high acid levels Early collection methods for sulfuric acid in air involved the use of water or alkaline solutions in a scrubber or impinger followed by some form of acid-based titration. Such methods also absorbed sulfate salts and possibly acid gases.Sulfate measurements using filtration or impaction techniques have been used in air pollution studies by titration for total acidity or by a related procedure of sulfate analysis through the use of a barium sulfate turbidimetric determination.

The use of selective filters to separate sulfuric acid (with sulfates) from sulfur dioxide has also been reported. In 1969, Scaringelli and Rehme reported a method for measuring sulfuric acid aerosol in microgram quantities which had application for community air measurements.The method successfully separated sulfuric acid from sulfur dioxide and other sulfates by filter collection with controlled temperature (400 C) in a nitrogen atmosphere, followed by conversion to sulfur dioxide with hot copper which could then by determined by spectrophotometric, coulometric, or flame photometric technics. The method, although satisfactory for sulfuric acid isolation, required controlled heat, a rather special setup of apparatus, and a zirconium oxide combustion tube, thus entailing a rather complicated preparation procedure prior to the analytical determination.Dubois et al devised a microseparation of sulfuric acid from other airborne sulfates by the microdiffusion of sulfuric acid at 200 C into sodium hydroxide absorbing solution using glass petri dishes.Subsequently, following the preliminary separation, the isolated sulfuric acid was then measured by a method specific for sulfate. Because gravimetric determinations with sulfate were both time-consuming and tedious, and turbidimetric procedures were often unreliable and difficult to reproduce, direct titration methods for sulfate were devised which were rapid, accurate, and widely applicable.In 1952, the American Conference of Governmental Industrial Hygienists (ACGIH) adopted 1.0 mg/cu m as their recommended Threshold Limit Value (TLV) for sulfuric acid mist. This decision was based upon human experimental work reported by Amdur et al in which it was found that concentrations below 1 mg/cu m could not be detected by odor, taste, or irritation by unacclimated persons.The threshold for odor and irritation was 1 mg/cu m in 2 persons and 3 mg/cu m in all subjects. The ACGIH TLV has remained unchanged at 1.0 mg/cu m. In the latest documentation of TLV's, the ACGIH Committee reviewed 8 published reports from which the TLV of 1.0 mg/cu m was recommended to prevent irritation of respiratory passages and injury to the teeth. In a report presented by the Czechoslovak Committee of MAC, the majority of members of the Committee agreed on a MAC of 1 mg/cu m of air as a mean concentration and a peak MAC of 2 mg/cu m although it was recognized that slight irritation, though not necessarily unpleasant, might be experienced at 1 mg/cu m. The report of Amdur et al was not sufficiently convincing to influence the opinion of the Committee at that time (1969).It was also commented that a great effort was necessary under the conditions of sulfuric acid production to adhere to their recommendations of 1 mg/cu m. The same standard exists in Soviet Russia, Hungary, and Poland.In the # Basis for Recommended Environmental Standard Although subjective responses such as throat tickling and scratching have been reported at sulfuric acid concentrations of less than 1 mg/cu m, other investigators have reported no subjective responses until a level of 1 mg/cu m was reached. Concentrations of about 5 mg/cu m may be very objectionable, usually causing cough, with marked alterations in respiration. Overexposure to sulfuric acid by splash or spray has resulted in pulmonary edema and chronic pulmonary fibrosis, residual bronchiectasis, and pulmonary emphysema. Very few reports are available of occupational sulfuric acid concen trations especially reports from which exposure-effect relationships may be obtained.Environmental concentrations in the lead-acid battery industry have been reported ranging from 3 to 16.6 mg/cu m of air in which relatively dilute sulfuric acid is used in forming processes.In addition, charging processes in the same industry have produced measured airborne sulfuric acid levels at about 0.8 to 2.5 mg/cu m. Other studies have reported mean concentrations of 1.4 mg/cu m (range, 0.2 to 5.6 mg/cu m) and findings ranging from 12.5 to as high as 35 mg/cu m. These figures serve more to illustrate general circumstances for which many -unknown variables exist rather than quantitative levels in attempts to derive exposure-effeet relationships. The published epidemiologic studies provide valuable information on the signs and symptoms resulting from occupational exposure to sulfuric acid. In studying sickness absence and ventilatory capacity in 461 lead-acid battery workers, Williams concluded that an excess of spells of respiratory disease, especially bronchitis, occurred in forming process workers.Variation was noted in the number of spells of sickness absence which was contributed by different individuals; therefore, no tests of statistical significance were made.It was suggested that the increased number of spells of respiratory disease was due to an increased incidence of spells in attacked men rather than by an increased proportion of men attacked.It was also believed likely that one or more factors might have been present in the forming operation which was specifically associated with bronchitis and other respiratory disease. Interestingly, the same forming operation used for this study was also the source of considerable dental erosion reported by Malcolm and Paul in 1961.It was suggested by Williams that the absence of lower respiratory tract disease observed in his study, where marked dental erosion had been earlier reported, might have been due to the large size of sulfuric acid mist particles or droplets, thus preventing their reaching the deep lung. Williams found no significant difference in the prevalence of chronic bronchitis and/or chronic asthmatic bronchitis between 33 exposed workers and 20 controls; however, there was a greater group mean decrease in pulmonary function (FEV 1) in the exposed group than in the controls which the authors stated might be due to the inhalation of sulfuric acid mist.The consistent findings of dental erosion among sulfuric acid workers reported in 2 separate studies indicates the problem to be one of definite health impairment.The consistent relationship that was observed compared their environmental findings (see Table X -4) with those of ten Bruggen Cate on tooth erosion incidence and stated that their 1.4 mg/cu m finding likely underestimated the dental risk to which workers had been exposed during their earlier years.A more realistic value of environmental acid concentration was suggested as being somewhere between 1.4 mg/cu m and that reported by Malcolm and Paul, 3 to 16.6 mg/cu m. Even though dental erosion produced functional disability and disfigurement, workers were able to compensate by using the canine teeth in place of the anterior teeth which could not be brought together.Because of the many uncertainties present in the reported environmental sulfuric acid levels, it is not possible to estimate an exposure level to sulfuric acid mist which would eliminate the occurence of dental etching and erosion. Experimental studies have shown that sulfuric acid produces mucous membrane irritation and reflex bronchoconstriction with increased airway resistance.Most animal experimental work has been conducted in guinea pigs, considered to be the most sensitive of the standard laboratory animals to the respiratory effects of sulfuric acid. At concentrations considered important for the evaluation of environmental standards, exposure of guinea pigs to 2 mg/cu m sulfuric acid for 1 hour produced increases in pulmonary airway resistance from reflex bronchoconstriction. Bushtueva found edema and thickening of the alveolar walls of guinea pigs also exposed to 2 mg/cu m, but for 5 days continuous exposure.Thomas et al reported minor unspecified pathological changes for continuous exposure periods greater than 3 months.Similarly, continuous exposure of dogs to 0.9 mg/cu m sulfuric acid for 225 days produced decreased lung function as measured by diffusion capacity and changes in lung parenchyma. However, effects produced by continuous exposure are difficult to evaluate in terms of intermittent exposures which are more representative of the occupational experience.In humans, Bushtueva noted respiratory changes in amplitude and rhythm at sulfuric acid exposures of 1.8 to 2 mg/cu m. Slight changes at 1.0 to 1.1 mg/cu m, and no alterations in respiratory patterns, were noted at concentrations less than 1 mg/cu m. In another study, measurements of sensory and central nervous responses from light sensitivity in the dark adapted eye or from reflex optical stimulation produced effects at 0.7 mg/cu m sulfuric acid.Both of these studies are regarded as screening observations because results were observed in only 2 subjects.Furthermore, whether such optical changes, or for that matter, minimal respiratory changes represent undesirable effects is debatable.The increased respiratory effects reported by Amdur to occur in subjects exposed to sulfuric acid concentrations as low as 0.35 mg/cu m are again uncertain as to their meaning.The findings were reported many years ago and have not been recently confirmed at the levels reported.In humans, a strong cortical influence exists to regulate respiration, and mechanical procedures, especially the use of a face mask, could influence the results markedly. In summary, the minimal changes reported in respiratory rate and on optical response to sulfuric acid concentrations below about 2 mg/cu m, remain unconvincing and unconfirmed. The interaction of sulfuric acid with other gases and aerosols has been reported to produce effects on growth, lung changes, and respiration which were more marked than would have been predicted from either agent alone. Bushtueva found the effects of sulfuric acid combined with sulfur dioxide exposure to be merely additive as measured by reflex optical responses.In dogs, statistically significant reductions in mean diffusion capacity were also found between combinations of sulfuric acid and sulfur dioxide. Although Toyama and Nakamura reported increases in mean pulmonary airway resistance in humans to very low concentrations of sulfuric acid (0.01 to 0.1 mg/cu m), their method of producing sulfuric acid from the reaction between hydrogen peroxide and sulfur dioxide indicated a combination effect between the 2 substances rather than to sulfuric acid alone.Although sulfuric acid was identified, no data were given concerning the amount of unreacted sulfur dioxide or hydrogen peroxide which was present with the sulfuric acid.Other investigations of particle (droplet) size, as well as temperature effects and humidity, emphasize a strong interplay between these factors, thus making interpretations of exposure-effect extremely difficult.The problems encountered in interpreting results from a combination of only 2 substances emphasizes the difficulty encountered when considering particle size, temperature, humidity, and multiple substance interrelationships. It is concluded that the existing federal standard of 1 ppm TWA should be retained.It is believed that adherence to the present environmental federal standard in conjunction with a strong program of work practices to prevent skin and eye contact from sulfuric acid will prevent the irritant effects of sulfuric acid in workers. # VI.WORK PRACTICES The corrosive, oxidizing, and sulfonating properties of sulfuric acid are such as to require that it be handled at all times with proper care.The work practices specified in the recommended standard are primarily for the purpose of preventing or minimizing sulfuric acid contact with the respiratory tract, skin, or eyes.These practices incorporate basic principles described in standard guides such as the Chemical Safety Data Sheet SD-20, and the Chemical Hazards Bulletin on Sulfuric Acid. Sulfuric acid itself is not flammable; however, it can cause ignition when in contact with other combustible materials.It reacts with some metals to release hydrogen gas, which is potentially explosive.As the gas is released from the liquid surface, it may also entrain acid droplets which may be inhaled or burn the skin.Released hydrogen will also react with arsenic, selenium, or cyanides which may be present as impurities either in the acid or in metals, producing highly toxic arsine, hydrogen selenide, or hydrogen cyanide. Sulfuric acid generates heat when mixed with water.Adding water to the acid can be extremely dangerous; therefore, when mixing is necessary, the acid should be added to the water; in special cases when water must be added to acid, suitable precautions should be taken. Workers should not expose themselves unnecessarily to sulfuric acid mist or fumes.Because of its irritant properties, an individual is usually conscious of the presence of acid mist in the environment, especially when the acid occurs at high concentrations.Should a situation arise where it is essential to remain in an environment where high airborne acid levels exist, such as for repairs or in an emergency, the individual should be especially aware of the need for proper protective equipment. This should include impervious clothing, gloves, rubber shoes, goggles, face shields, and respiratory devices as appropriate to prevent acid contact with the skin, eyes, or respiratory tract. Should an emergency make it necessary to enter a tank or closed space, reliance should never be placed on a canister-type gas mask.Only self-contained breathing apparatus in pressure-demand mode or a combination supplied air respirator, pressure-demand type, with auxiliary self-contained air supply should be used in such situations. Employees should be trained at appropriate regular intervals in the proper techniques for handling, moving, and emptying carboys, drums, tank trucks, railroad cars, and barges of sulfuric acid.They should also be trained in the emergency procedures to be followed in case of accidents involving sulfuric acid. All of the prescribed practices apply to oleum, which is a more hazardous form of sulfuric acid. VIII. characterize the exposure from each job or specific operation in each production area.times the standard are expected, smaller air volumes may be collected, but never less than 10 liters. A minimum of 3 samples shall be taken for each operation (more samples if the concentrations are close to the standard) and averaged on a time-weighted basis.At least one blank filter with cassette shall be provided which has been subjected to the same handling as the samples but through which no air has been sampled.One additional blank filter with cassette shall be supplied with every 10 samples obtained. # Shipping The cassette with samples are collected, along with the appropriate number of blanks, and shipped to the analytical laboratory in a suitable container to prevent damage in transit. # Calibration of Sampling Trains Since the accuracy of an analysis can be no greater than the accuracy of the volume of air which is measured, the accurate calibration of a sampling pump is essential to the correct interpretation of the pump's indication.The frequency of calibration is dependent on the use, care, and handling to which the pump is subjected.In addition, pumps should be recalibrated if they have been misused or if they have just been repaired or received from a manufacturer.If the pump received hard usage, more frequent calibration may be necessary. Ordinarily, pumps should be calibrated in the laboratory both before they are used in the field and after they have been used to collect a large number of field samples.The accuracy of calibration is dependent on the type of instrument used as a reference.The choice of calibration instrument will depend largely upon where the calibration is to be performed.For laboratory testing, primary standards such as a spirometer or soapbubble meter are recommended, although other standard calibrating instruments such as a wet test meter or dry gas meter can be used.The actual setup will be the same for all instruments.Instructions for calibration with the soapbubble meter follow.If another calibration device is selected, equivalent procedures should be used. # (a) Flowmeter Calibration Test Method The calibration setup for personal sampling pumps with the sampling system of a cassette with filter is shown in Figure X-l. # Range and Sensitivity The method is sensitive to 0.1 mg sulfuric acid/cu m of air, assuming a 100-liter air sample.The upper limit is the amount of sulfuric acid retained by the filter and is at least 0.5 mg of sulfuric acid. # (c) Interferences Soluble particulate sulfates in the air sample would give erroneously high sulfuric acid values. Metal ion interferences can be eliminated by passing the solution through an ion exchange resin. Concentrations of phosphate and sulfite ions greater than any sulfate ion concentration cause appreciable interference.Phosphate can be removed by precipitation with magnesium carbonate.Sulfite is corrected for by titration with standard iodine. # (d) Accuracy and Precision At 1 mg/cu m, the accuracy is at least 10% with a relative standard deviation of 4%.At 10 mg/cu m, the accuracy and relative standard deviation can be improved to about 1%. # (e) Advantages and Disadvantages The samples are easily collected, stable, and conveniently shipped to the laboratory for analysis. The analysis is relatively rapid and simple. A disadvantage is the possible error due to airborne soluble particulate sulfate salts. (f) # Apparatus (1) Personal sampling pump with flowmeter capable of sampling at a rate of 1 to 2 liters/minute. (2) 37 mm mixed cellulose ester filter, 0.8 ym nominal pore size. (3) Necessary glassware. (4) A buret of 10-ml capacity graduated in 0.05 ml subdivisions. (5) A daylight fluorescent lamp aids in identifying the endpoint. (5) Hydrochloric acid, 4 N-add 300 ml concentrated HC1 to 600 ml of distilled water.This is needed only to regenerate the column if the ion exchange procedure is used. (6) Perchloric acid, 1.8%-dilute 25 ml of reagent grade perchloric acid (70-72%) to 1 liter of distilled water. (2) Ion exchange procedure (used to purify standard sulfate solution)-when about two-thirds of the capacity of the resin has been exhausted (deterioration in sharpness of the end point), regenerate the resin by passing 30 ml of 4 N hydrochloric acid through the column.After thorough washing with distilled water, the column is ready for use.Since small volumes of sample solution are passed through the ion exchange column, care must be taken not to dilute the sample with the water that remains on the resin.One way this can be accomplished is by forcing air through the resin with a squeeze bulb to remove most of the distilled water from the ion exchange resin.One or two ml of sample is passed through the column and is discarded after air is again forced through the resin.The remainder of the sample is then passed through the ion exchange column and an aliquot is titrated according to the general procedure in (i)(3) below. The column is flushed with distilled water between samples to prevent contamination from the previous sample.

If anhydrous sodium sulfate is used to standardize the barium perchlorate, it must first be ion-exchanged since sodium obscures the endpoint.A 5-ml aliquot of the 0.5 mg/ml sulfate solution is ample for standardization when using a 10-ml buret. # (k) Calculations The analytical results are calculated on the basis of the (1) The name, address, and telephone number of the manufacturer or supplier of the product. The trade name and synonyms for a mixture of chemicals, a basic structural material, or for a process material; and the trade name and synonyms, chemical name and synonyms, chemical family, and formula for a single chemical. (c) Section II.Hazardous Ingredients. (1) Chemical or widely recognized common name of all hazardous ingredients. (1) Toxic level for total compound or mixture, relevant symptoms of exposure, skin and eye irritation properties, principal routes of absorption, effects of chronic (long-term) exposure, and emergency and first-aid procedures. (g) Section VI.Reactivity Data. (1) Chemical stability, incompatibility, hazardous decomposition products, and hazardous polymerization. (h) Section VII.Spill or Leak Procedures. (1) Detailed procedures to be followed with emphasis on precautions to be taken in cleaning up and safe disposal of materials leaked or spilled.This includes proper labeling and disposal of containers holding residues, contaminated absorbents, etc. (i) Section VIII.Special Protection Information. (1) Requirements for personal protective equipment, such as respirators, eye protection, clothing, and ventilation, such as local exhaust (at site of product use or application) , general, or other special types. (j) Section IX.Special Precautions. (1) Any other general precautionary information such as personal protective equipment for exposure to the thermal decomposition products listed in Section VI, and to particulates formed by abrading a dry coating, such as by a power sanding disc. (k) The signature of the responsible person filling out the data sheet, his address, and the date on which it is filled out. In addition to attacking many metals, the acid in its concentrated form is a strong oxidizing agent and may cause ignition on contact with organic materials and such products as nitrates, carbides, chlorates, etc.It also reacts exothermically with water.Yes Derived from

Explosive devices and high-velocity firearms are the terrorists' weapons of choice.The devastation wrought in two European capitals, Madrid and London, demonstrate the impact that can be achieved by detonating explosives among densely packed civilians.In an instant, an explosion can wreak havoc-producing numerous casualties with complex, technically challenging injuries not commonly seen after natural disasters such as floods, tornadoes, or hurricanes.Because many patients self-evacuate after a terrorist attack, and prehospital care may be difficult to coordinate, hospitals near the scene can expect to receive a large influx-or surge-of victims after a terrorist strike.This rapid surge of victims typically occurs within minutes, exemplified by the Madrid bombings where the closest hospital received 272 patients in 2.5 hours.Such a surge differs dramatically from the gradual influx of patients after an outbreak of infectious disease or an environmental emergency such as a heat wave, which can last several days to weeks afterwards.In addition, injuries to workers involved in recovery procedures can lead to a secondary wave in surge.The key question is this: Can hospitals meet the challenge?Health care and public health specialists anticipate profound problems in adequately caring for the resulting surge of victims.Our current health care system, especially the emergency care system, is already severely strained by its routine volume of daily care.Further, the health care system, emergency departments, and intensive care units (ICUs) of acute care hospitals are chronically overcrowded and resource-constrained.Without immediate federal assistance, many, if not most, communities would have difficulty caring for a surge of victims because each hospital and emergency medical service differs dramatically in capacity, training, and level of coordination.Indeed, a terrorist bombing in the United States would be a "predictable surprise."To address the challenges posed by such an event, CDC's National Center for Injury Prevention and Control (CDC's Injury Center) convened an expert panel in October 2005 and January 2006.The panel included experts in the areas of emergency medical services, emergency medicine, trauma surgery, burn surgery, pediatrics, otolaryngology, intensive care medicine, hospital medicine, radiology, pharmacology, nursing, hospital administration, laboratory medicine (blood bank), and public health.The panel was charged with identifying creative strategies that could be adopted in a timely manner to address surge issues from terrorism.The panel focused on recommending strategies for rapid management of large numbers of bombing casualties.They examined the related challenges that would confront not only the general emergency medical response and health care system, but would also affect select medical disciplines.Though developed in the context of a surge of injuries from a terrorist bombing, the recommendations in this report may improve the response to and management of a surge of patients from any cause, including biological, chemical, or nuclear.This document, which is the result of the expert panel meetings, reflects the opinions and recommendations of the experts.It includes a description of system-wide and discipline-# specific challenges as well as recommended solutions to address these challenges.The proposed solutions for the discipline-specific challenges have been incorporated into easy to use templates that can assist various disciplines in managing surge needs for injuries.The needs and resources of each community must be considered to effectively plan for a surge of patients into an already overburdened health care system.Admittedly, community resources are not specific to handling casualties of explosives, but the likelihood of this threat and the sudden demand it would place on the health care system make it imperative to manage deficiencies in surge capacity now-not when crisis strikes-and to do so in an aggressive, but thoughtful manner. # Background Current patterns in terrorist activity increase the potential for civilian casualties from explosions.Recent events in Egypt, India, Iraq, Israel, Spain, and the United Kingdom clearly indicate that bombings targeting civilian populations are an ever-present danger worldwide.The U.S. Department of State reported 7,000 terrorist bombings worldwide between 1968 and 1999.1 From 2001 through 200, more than 500 international terrorist bombings caused more than 4,600 deaths, 1-excluding the attacks of September 11, 2001, which essentially used planes as flying bombs. The U.S. Federal Bureau of Investigation confirmed 24 incidents of terrorist bombings in the United States between 1980 and 2001.4 More than 21,000 bombing incidents (actual, accidental, attempted) occurred in the U. S. between 1988 and 1998.5 In 2005 alone, according to reports compiled from the Terrorist Attack Archives, Terrorism Research Center, 758 terrorist events were staged in 45 countries, and more than half (N = 99) were bombings.These events resulted in 8,019 injured persons and ,049 deaths.6 Despite justifiable concerns about the dangers of chemical, biologic, or nuclear attacks, bombings with conventional explosives remain the terrorists' method of choice.Explosions, particularly in confined spaces, can inflict multi-system injuries on numerous patients and produce unique management challenges to health providers.Unlike the gradual influx of patients after events such as infectious diseases, the surge of patients after an explosion typically occurs within minutes of the event and overwhelms nearby hospital resources.7,8 The potential for large numbers of casualties and an immediate surge of patients may stress and limit the ability of emergency medical services (EMS) systems, hospitals, and other health care facilities to care for the onslaught of critically injured victims. The ongoing and increasing threat of terrorist activities, combined with documented evidence of decreasing emergency care capacity, requires preemptive action.Health care and public health systems, individual hospitals and health care personnel must collaborate to ensure that strategies are in place to effectively receive, evaluate, and treat large numbers of injured patients; to rapidly identify and stabilize the most critically injured; to evaluate these efforts; and to strategically plan for future incidents. The Role of the National Center for Injury Prevention and Control (CDC's Injury Center) Centers for Disease Control and Prevention (CDC) The mission of CDC's Injury Center, is to prevent premature death and disability and to reduce the human suffering and medical cost caused by injuries.This mission supports CDC's strategic goal to protect people in all communities from terrorist threats.As a means to prevent injuries and minimize the consequences of injury, the Injury Center uses the public health approach-a systematic process to define the injury problem, identify risk and protective factors, develop and test prevention interventions and strategies, and ensure widespread adoption of effective interventions and strategies. Many agencies have addressed issues of surge capacity for events such as biological attacks-most notably, CDC's public health and laboratory surge programs and the Health Resources and Services Administration's (HRSA) hospital preparedness program.To date, little effort has been directed toward increasing surge capacity in response to terrorist bombings.After in-depth discussions with HRSA, the Department of Homeland Security, the Federal Emergency Management Agency (FEMA), the National Highway Traffic Safety Administration (NHTSA), and CDC's Coordinating Office for Terrorism Preparedness and Emergency Response, the Injury Center learned that CDC could play a unique role in identifying surge capacity issues related to terrorist bombings and proposing solutions.Furthermore, any solutions to enhance surge capacity in preparation for terrorist bombings directly apply to surge issues for other manmade or natural disasters. To this end, CDC's Injury Center convened an expert panel in October 2005 and January 2006.The expert panel was charged with identifying creative strategies that could be adopted in a timely manner to address surge issues from terrorism; in essence, identifying both system-wide and discipline-specific concerns and recommending feasible and affordable strategies for rapidly managing large numbers of bombing casualties.This document is the result of those meetings, reflects the opinions and recommendations of this expert panel, and includes its recommendations.These recommendations were designed for emergency medical, health care, and public health systems, with the caveat that immediate steps be taken to ensure an effective response.To kick off the process, the expert panel set objectives: - Increase collaboration between CDC and federal agencies, external partners, and other experts on issues of surge capacity for injuries from conventional weapons. -Identify factors that limit rapid assessment and treatment of injured patients in the field and at hospitals (including triage, availability of radiology, and access to operating theatres) and develop mechanisms to address these factors; and - Develop a strategy and identify mechanisms to widely disseminate and implement findings from the expert panel (e.g., Web, print publications, and training curricula). The panel represented a broad spectrum of medical care and administrative disciplines required to care for victims of a bombing.Panel members included personnel from emergency medical services; physicians specializing in emergency medicine, trauma surgery, burn surgery, pediatrics, otolaryngology, intensive care medicine, hospital medicine, and radiology; experts in pharmacology, nursing, hospital administration, and blood banking; and experts in public health.Expert panel members are listed in the acknowledgements section of this report. # The Evolution of Terrorism At the heart of, and as an impetus for, this meeting is the fact that terrorist attacks remain an ever-present threat.Terrorist events continue to occur globally and on an alarming scale.Bombings-the perpetrators' method of choice-remain a real and constant threat, averaging two terrorist attacks per day worldwide in 2005.6 In the past thirty years, terrorism has evolved from mostly secular, nationalist movements to diverse, multinational, global organizations.12 These organizations have different motivations and tactics, and their bombings are increasingly lethal, 1 as witnessed in Madrid (March 2004), London (July 2005), and Mumbai (July 2006), terrorist efforts reveal an ever-increasing degree of sophistication, coordination, and capacity for harm. # Lessons Learned in Madrid In an effort to provide a framework to the meetings and subsequent discussions, the panel was presented with the example of the March 2004 Madrid bombings at the beginning of the first meeting.The Madrid experience provides a real-life scenario of what U.S. health care providers and systems must be prepared to confront: a complex, coordinated attack with thousands injured and a rapid surge of patients into surrounding hospitals.On March 11, 2004, between 079 and 0742 hours, ten terrorist bombs detonated on four crowded commuter trains, killing 177 people instantly and injuring more than 2,000.Three hundred and twelve patients were evaluated and treated at Gregario Maranon University General Hospital (GMUGH), 272 of them arriving between 0759 and 100 hours.The Madrid response entailed multiple logistical and operational challenges, including field triage and transportation of injured persons; inpatient discharge; evacuation of emergency departments (EDs) and intensive care units (ICUs), and multiple surgical procedures and tests (hundreds of radiographs, computerized tomography (CT) scans, and ultrasounds).By 2100 hours that same day, 1,40 casualties had been treated at multiple hospitals; of these, 966 had been transported to 15 public community hospitals.14 Panel members were asked to describe how their discipline would respond to the Madrid example. Terrorist Bombings in the United States: A "Predictable Surprise" The reality of persistent, complex, global terrorist bombings, such as Madrid, make terrorist bombings in the U. S. a "predictable surprise."The expert panel reviewed the characteristics of "predictable surprises" listed below early in the course of the meeting process, to provide background on common problems that could hinder effective surge response, and in an effort to identify concerns and issues that needed to be addressed within their recommendations. The following characteristics of "predictable surprises" outlined by Bazerman and Watkins 15 apply to terrorist bombings and the U. S.: # A shared trait of predictable surprises is that leaders knew a problem existed and that the problem would not solve itself. Reports of bombings occur almost daily.When-not if-terrorism returns to the U. S., our EMS and hospital systems will be ill-equipped to manage the consequences. # Predictable surprises can be expected when organizational members recognize that a problem is getting worse over time. Terrorist events show no signs of abating.Between 2001 and 200, more than 500 international terrorist bombings resulted in more than 4,600 deaths, as reported by the U.S. Department of State.1-In 2005 alone, 758 worldwide terrorist events occurred, of which 99 were bombings.These events occurred in 45 countries and resulted in 8,019 persons injured and ,049 deaths.6 # Fixing the problem would incur significant costs in the present, while the benefits of action would be delayed and ambiguous. A central issue in preparing for terrorist bombings in the U.S. is to proactively educate health care providers in the clinical management of bombing injuries.Education is expensive.Even if health care providers are initially trained to care for bombing-related injuries, unless these terrorist events become a more frequent and unfortunate reality, education must be repeated regularly to assure currency of knowledge and clinical competency.Another issue concerns the rapid push of clinical information immediately after an event.The mechanisms and capability to do this need to be developed and may be costly.Finally, many EMS systems and hospitals do not have capacity to care for patients beyond their usual volume; and some do not have capacity to care for the volume they now have, as evidenced by frequent ambulance diversions and lengthy delays for ambulances to offload patients at hospital EDs.The cost of increasing facility capacity in the EMS and hospital systems may be substantial.Although increasing capacity will have immediate impact on daily operations in EMS and hospitals, the benefits of education and better systems for disseminating information will not be fully recognized until used in response to a terrorist attack or other disaster. # Decision makers often fail to prepare for predictable surprises because the natural human tendency is to maintain the status quo. Outside the military, our country's health care providers have little experience with terrorist bombings-particularly those capable of producing many potentially survivable injuries.Injury is the leading cause of death in the United States for persons between the ages of 1 and 44; 16 thus, many civilian health care providers, especially those in trauma systems, have vast experience in injury care, including incidents with multiple casualties.However, we have learned from the experiences of our military and international colleagues that clinical management of casualties from terrorist bombings differs considerably from that seen daily in trauma centers (e.g., blunt and penetrating trauma).To assume we can provide the same level of care for large numbers of victims from terrorist bombings as we do for victims of a bus crash is self-deceiving-a natural reaction is to maintain the status quo.Relying on traditional disaster management and trauma life support training is far easier and less expensive than learning and practicing new skills. # A small vocal minority benefits from inaction, and is motivated to subvert the actions of leaders for their personal benefit. No matter what the motivation, some people benefit from inaction. # Leaders can expect little credit for the prevention of predictable surprises. Advocating for and acquiring resources for terrorist bombing preparedness and response is challenging-especially when so many competing preparedness and response needs must also be met.With limited resources and the need for near-term results, leaders who prepare for events that may not occur can expect little credit for being proactive. # Surge Capacity Challenges # System-wide Challenges The threat of terrorism exists at a time when our hospitals and EDs are struggling to care for the patients who present during routine operations each day.Hospitals and emergency health care systems are stressed and face enormous challenges.Ambulances are routinely diverted from one facility to another.According to a 200 report from the National Center for Health Statistics, 4% of U.S. EDs diverted ambulances from primary destinations; diversions occurred more frequently in metropolitan areas (50% of metro hospitals).16 Emergency departments routinely operate above capacity.Sometimes, paramedics are forced to wait for extended periods before their patients can be transferred to hospital staff.Patients are evaluated and treated in ED hallways and held for hours, or even days, awaiting placement in an inpatient bed as hospitals struggle with high occupancy.In 200, there were 11.9 million visits to EDs in the U. S., representing a 26% increase from 199's 90.million visits.During this same period, the number of U.S. EDs decreased 14%.17 The problem became worse in the 1990s when our nation lost 10,000 staffed inpatient medical surgical beds and 7,800 ICU beds.18 Reductions in hospitals with EDs, regionalization of surgical care, increases in non-emergency patient visits to EDs, diversion of EMS, and personnel shortages have led to unprecedented crowding in EDs. The Institute of Medicine recently released a three-part report highlighting the challenges facing our nation's emergency care system. This is the context in which we confront the growing threat of international terrorism.Hospitals are wholly unequipped to handle a sudden surge of highly complex injuries. If a large-scale event (manmade or natural) occurs, health care systems and hospitals must be able to treat an immediate and potentially large influx of patients.A recent CDC publication determined that about three fourths of hospitals had disaster plans that addressed explosives, but few (one fifth) had actually conducted a drill involving imagined use of explosives.27 Issues affect the spectrum of injury care from prehospital through rehabilitation and also affect personnel from fire chiefs, trauma surgeons, and nursing supervisors to emergency medical technicians.Many problematic areas stand between the current reality of emergency care in the United States and the effective management of a Madrid-like event: # Organization and Leadership Effective preparedness and response demand an established, functional leadership structure with clear organizational responsibilities.In many instances, particularly at a local operational level, such preparation has not occurred.Consequently, confusion over who has responsibility for specific actions will occur, increasing the potential for redundant efforts or gaps in decision-making. # Alterations in Standards of Care Altering the standards of medical care provided in order to do the greatest good for the community is a concept and practice that is fraught with ethical, societal, and legal issues, making it difficult to surmount.

# Education Disaster preparedness and response education is not included in most medical or nursing school curricula; and, with the exception of emergency medicine, preparedness and response is not a requirement in residency training programs.Thus, most health care providers are not prepared to handle clinical care during a disaster.As standard curriculum, emergency medical technician (EMT) paramedics are required to complete a module on "medical incident command."Yet EMT Intermediates and EMT-Basics do not always receive this essential training.A well linked educational process for those involved in mass casualty disaster preparation and response is not yet available. # Communications Effective and timely communications are essential to functional command and control; admittedly, communication failure (prehospital, hospital, and public) is a recurrent theme during and immediately after a disaster. # Transportation Coordinated transportation service is vital and often, timely and effective use of mutual aid transport units to transport or transfer patients to tertiary care is challenging.Additionally, there is currently no comprehensive plan for disaster response which effectively integrates civilian with military medical transport resources. # Infrastructure and Capacity Communities differ in their capabilities and infrastructure to handle disasters in the prehospital and hospital arenas.Regardless of a community's capabilities and the level of coordination between resources, those injured from an explosion will rapidly seek care from or will be transported to the nearest hospital, 28 and may not seek care at the facilities designated by existing response plans.Thus all communities need plans that have been successfully and repeatedly drilled.Additionally, facilities vary in capabilities and staffing.Any facility, whether it offers tertiary (i.e., specialty) care or community, rural, or alternate care, will undoubtedly face problems in several areas: - Personnel Shortages of qualified personnel, including nurses and specialized technicians, exist throughout our health care system.During a mass casualty event, these shortages could manifest to catastrophic levels.Some staff may not respond during a bombing or other disaster event for various reasons, including fear for personal safety, family issues, or injury.Estimating available staff may be difficult because many work at multiple facilities.Conversely, the screening, managing, and credentialing of well-intentioned volunteers during a disaster can be challenging, if not impossible. - Equipment and supplies Shortages of essential equipment and supplies often occur in the aftermath of a large-scale terrorist bombing or natural disaster.Moreover, most facilities in a given region use the same suppliers for back-up stock and equipment (e.g., pharmaceuticals, general medical supplies, ventilators). # Information technology (data management/data systems) Oftentimes, software systems involving EMS services, hospitals, and health departments are incompatible.To maximize patient outcomes and allow family members to quickly locate loved ones, a data management system must have the ability to track patients from the scene to the hospital, track patients throughout the facility, and track transfers to other facilities. # Cost Preparation and incident mitigation requires a commitment of resources. Training prehospital providers, stockpiling key equipment such as stretchers and reserving capacity in the blood supply will be expensive. # Interoperability An effective medical response to a terrorist bombing demands that the response system components (personnel, organizations, and command structures) are interoperable.Yet services, agencies, and systems are not integrated for maximum efficiency (i.e., equipment; preparation; communications; and incident command, both prehospital and hospital). # Potential Bottlenecks Despite the impact of these events on multiple areas of clinical care, there are some areas whose response and capability may impact patients across the spectrum of care: - Radiology Given the nature of injuries related to terrorist bombings, the most victims will undergo multiple radiology studies.In Madrid, 50 radiology studies and interventions were performed the day of the bombing.14 The numbers of patients requiring studies may lead to a bottleneck, and hinder the institution's ability to streamline care.However, to date, professional radiology societies have not focused on surge capacity for bombing victims and the potential for radiology to become a bottleneck.Instead, they have focused exclusively on detection and treatment of radiation emergencies and disasters. # Critical Care If a terrorist bombing increases the demand for critical care/ICU services which, in turn, exceeds reserve ICU capacity, hospitals would have limited ability to divert or transfer patients to other hospitals and will need a plan in place to provide emergency mass critical care. # Pharmacy Ensuring an adequate supply of required pharmaceuticals throughout the institution, and community, is essential, and may prove challenging.This may be complicated by the fact, as noted above, that many facilities in a given region use the same suppliers for back-up stock and supply. # Triage Our current planning and preparedness activities assume that prehospital providers will be dispatched in coordinated fashion, will arrive on the scene to triage patients, and will transport them to the appropriate facilities, thereby preventing any component of the system from being overwhelmed.In many disasters, however, most victims self-transport or are transported by other laypersons.Victims do not wait for an organized field triage system to come into effect; consequently, the system or facilities are overwhelmed.28 # Legal Issues Multiple legal issues impact the response to a terrorist bombing or other major disaster, and may impact effective, coordinated medical care that optimally utilizes all of a community's resources.Examples include credentialing of providers; altered standards of care; standards for clinical documentation; the Emergency Medical Treatment and Active Labor Act (EMTALA), the Health Insurance Portability and Accountability Act (HIPAA), or Clinical Laboratory Improvement Amendments (CLIA). # Discipline-specific Challenges Each of the aforementioned problems has an impact on the spectrum of care; however, unique examples exist for many disciplines.The expert panel also identified the following discipline-specific challenges and provided feasible and affordable strategies for effectively addressing surge capacity. (The proposed solutions are provided in a template format at the end of this document.) # Emergency Medical Service Response As initial responders, EMS providers and personnel must confront several issues, including: - Personal protection Currently, there is no unified approach to protect rescuers or stage a response.When do appropriate concerns for scene safety and the potential for secondary explosive devices hinder the initial response? - Decontamination Though treatment will be delayed, decontamination may be imperative.Uniform policies and protocols for decontamination of personnel and patients need to be established for all scenarios (e.g., weather, bombing). # Incident command Interoperability between prehospital and hospital command structures is a challenge.This challenge manifests not only in the technical aspects of radio interoperability, but also in the interdisciplinary aspects of communications plans.A unified incident command structure must be incorporated into health care and EMS practice; further, EMS must be designated as part of the field response command structure. # Field triage Although multiple triage systems are used across the country, there is no agreed-upon methodology for field triage during a disaster. # Destination decisions Determining the appropriate destination in the aftermath of an event may be difficult, especially if the initial scene "size-up" has not been performed. - Hospital evacuations Whenever EMS transfers patients from hospitals to free up acute care beds, normal hospital functions are adversely affected. # Sustainability of operations Providing personnel with needed support (e.g., physical, emotional) and maintaining facilities, equipment and supplies in the aftermath of an event is an ongoing challenge. # Emergency Department Response The emergency department (ED) is a central portal to any hospital; as such, the ED is where initial information about a disaster is communicated.The challenge is to determine the magnitude of the event and initiate the appropriate institutional response.This response must be in concert with the assessed magnitude, including decisions to declare an institutional disaster, to declare an institutional lock-down, and to determine if recipient victim decontamination is needed.To determine the extent of the response, the quality and quantity of information from the field and between the regional emergency operations center and hospital is critical.Frequently, information challenges and communications are a source of failure. In a large-scale event, each hospital must have the capability to increase staffing, rapidly assess its available bed status, and make occupied beds available-especially in the ED, operating theatres, and critical care units.To free up beds, hospitals should cancel elective surgeries and admissions, open traditionally non-patient hospital areas for patient care (e.g., classrooms, offices, etc), and begin early discharge for inpatients as appropriate. During a mass casualty event, transfer of patients to an alternative care site may be delayed due to the time, personnel, and equipment needed to set up that site.However, development of an alternative site will, over time, free up non-critical care beds. # Key issues follow: - Ascertaining the validity and scope of the event.Notification is essential to activate and implement an appropriate response; information/updates must be consistent and frequent. - Incident command.A Hospital Incident Command System (HICS) must be implemented within the ED, hospital, and community.HICS is a widely used emergency management system known for providing a chain of command that can mobilize at a moments notice, provide accountability of position functions, allow flexible responses to emergencies, improve documentation of facility actions, provide a common language to facilitate outside assistance, and develop prioritized response checklists for senior leadership.Each hospital should be part of a regional unified command structure. - Discharging patients from the ED.To free up resources, patients should be discharged, or transferred to other areas for care. # Surgical and Intensive Care Unit Response Multiple factors affect trauma surgery and its preparedness and response to a bombing event or natural disaster. # Changes in surgical practice The recent increased interest in disaster response capabilities is in contrast to the general surgery community's decreased interest in managing emergency surgery.Thus, the knowledge base and skill set to manage a Madrid-type scenario is being concentrated at fewer hospitals.Many hospitals with the capacity to handle surge, as it relates to beds and staffing, have little technical capability to manage a surge of patients from a bombing. # Time of day As in the Madrid bombings, the time of the event is critical for trauma centers and community hospitals.However, disaster planning often does not consider time of day.At 0200 hours, for example, a community hospital may not have operating theatre capability. # Limited ICU beds Overcrowding may require decisions to delay surgeries, identify beds in other areas of the hospital, and/or transfer patients to another facility. # Loss of excess capacity/Capacity on a given day The U.S. health care system has systematically and deliberately eliminated capacity because unused capacity is an additional expense. # Education More surgeons, especially those in trauma centers, need further education on the planning and response process.The U.S. military in Iraq has successfully demonstrated concepts in surgical surge capacity management that should be translated immediately to civilian medicine.Further, Iraq's experience with damage-control (emergency) surgery has shown that more patients' lives can be saved through temporizing damage-control surgery than if patients received time-consuming definitive surgery. Additionally, after a terrorist attack, critical care and ICU services will be needed to treat the seriously ill or injured casualties.The emergency mass critical care plan should address hemodynamic resuscitation and support using intravenous fluids and vasopressors; administration of antibiotic and other disease-specific countermeasures; prophylactic interventions to reduce adverse consequences of critical illness; and basic modes of mechanical ventilation, and should include: 1.Interventions that improve survival; without which death is likely; 2.Interventions that do not require extraordinarily expensive equipment; and .Interventions that do not consume extensive staff or hospital resources. If ventilators are unavailable to treat all patients in need, minimally skilled individuals could use an endotracheal tube to manually ventilate the patient.Critical care areas should be equipped to measure, at a minimum, oxygen saturation, temperature, blood pressure, and urine output.When critical care/ICUs are full, hospitals can create additional capacity in non-ICU rooms concentrated on specific wards or floors.Patient care areas that already contain equipment similar to ICU's (endoscopy and surgical suites) are good alternatives, but these ad hoc critical care areas will increase capacity only slightly and require cessation of services normally provided. When a hospital cannot meet increased demand for critical care services using its existing critical care practitioners, a two-tiered staffing model comprising noncritical care physicians and nurses may be substituted.Members of the Working Group on Emergency Mass Critical Care (Center for Bioterrorism at the University of Pittsburgh) and the Society of Critical Care Medicine concluded that a critical care physician can supervise up to four noncritical care physicians who can each manage up to six critically-ill patients.They also concluded that a critical care nurse could supervise up to three noncritical care nurses with each caring for up to two patients.In this model, a hospital's critical care staff is multiplied to where one critical care physician could oversee the care of up to 24 critically-ill patients, and one critical care nurse could oversee the care of up to six critically-ill patients.29 Additionally, many of our nation's leading children's hospitals with large Pediatric Intensive Care Units (PICUs) operate at maximum capacity.If a mass casualty involving children and infants were to occur, the PICUs' response and ability to provide intensive care would be severely constrained. The emotional issues surrounding the care for a dying or dead child compounds this issue as paramedics, physicians, and others generally do not want to pronounce children dead at the scene.Thus, they will transport a child who has been pulseless and apneic for an hour, and still hopelessly receiving CPR, to the ED and ultimately to the PICU where the child will be declared deceased.Such considerations affect field triage and care in a mass casualty situation.Finally, PICUs have a chronic shortage of trained, available, and experienced staff. # Radiology Response # Blood Bank Response In the last 0 years, the United States has experienced only five disasters in which more than 100 units of blood were used.If a large-scale terrorist bombing took place, large amounts of blood would be needed only if many victims were seriously injured. The blood banking community has formed an interorganizational task force to address blood needs in the event of a disaster.The AABB (formerly known as the American Association of Blood Banks) Interorganizational Task Force on Domestic Disasters and Acts of Terrorism (AABB Interorganizational Task Force) unites national blood organizations representing virtually all the nation's blood centers (AABB, America's Blood Centers, and American Red Cross) and hospital and supplier associations with liaisons from the Department of Health and Human Services, Food and Drug Administration, CDC, and Armed Services Blood Program to coordinate efforts in preparation for and response to disasters affecting the blood supply.Potential issues with our nation's blood supply follow: - Disruption of the blood supply system Lack of blood will probably not be a problem, but disruption or interference of the blood supply system could wreak havoc.During times of disaster, including terrorist attacks, Americans will search for ways to help.Potential donors will descend on hospitals and blood centers and quickly overburden the system.Blood collection, processing, and testing are highly regulated procedures in a technical system that requires trained staff.On September 11, 2001, New York and New Jersey used 224 units of blood, while Washington and Virginia used 4-totaling 258 units, all of which were on the shelf before the disaster occurred.0 Across the nation, more than a half million potential donor's volunteered blood. In the event of a disaster, the AABB Interorganizational Task Force will inform the American public if blood donations are needed and tell them how and where to donate.In most instances, the appropriate message is that additional blood is not needed immediately after the disaster, but that individuals should contact their local blood centers to schedule a donation in the upcoming weeks. # Transportation of blood Even when blood products are not shelved at the surge capacity site, the products can be available in hours.In fact, blood can be transported to a disaster location faster than donations can be processed.There are some issues with transporting blood; for example, authorization may be required to transport blood around the state or country.In addition, blood centers may have difficulty obtaining diesel and unleaded fuel to power generators or to operate staff vehicles that transport blood.Federal, state, and local emergency preparedness offices need to make blood products a priority for obtaining transportation and fuel. # Local organization In a disaster, blood needs to be placed exactly where it is needed-at the hospitals serving the large influx of patients.Few hospitals regularly collect blood; fewer still are capable of handling an influx of donors while caring for disaster patients.In some metropolitan areas, hospitals may be served almost entirely by one blood center; in other areas, hospitals might get blood regularly from several sources.Planned and coordinated efforts are needed during a disaster to know which blood centers will service the hospitals at surge capacity.Within an hour of a disaster, the AABB Interorganizational Task Force will convene a conference call of national blood organizations, HHS, and local affected blood centers to determine local needs for blood and actions necessary to meet those needs.The Task Force will meet again hours or days later to coordinate subsequent blood-related efforts. # Staff who can administer blood Most hospitals aim for a three-day supply of blood.If blood is not stored at the hospital; typically, the blood can be readily accessed.For a hospital to consume a three-day blood supply in three hours is highly unlikely.Instead, the hospital may have too few trained staff to administer blood.Several documents are available to assist blood centers, hospital blood banks, and transfusion services prepare for and respond to disasters and acts of terrorism that could affect the blood supply.

1- # Hospitalists' Reponse By the end of this decade, there will be more hospitalists (physicians or internists caring for hospital patients) than other medical subspecialties; currently, half the hospitals with 200 or more beds employ hospitalists.Although they may not be directly involved in the care of casualties from a terrorist event, hospitalists will be vital in rapidly discharging inpatients, accepting transfers from ICUs, and freeing bed space for victims. # Administration Response When an institution is stressed clinically, it will also be stressed administratively.Hospitals face formidable challenges in the post-911 era.Shrinking revenue margins put pressure on budgets and complicate investment decisions to purchase items for contingency operations.Unlike nations with publicly funded health systems, the U.S. health care industry must support its contingency investment needs by pooling a mix of private funding with local, state, and federal resources.As a result, every hospital has some capability, but the clinical and administrative capabilities of each vary widely. The United States has 4,919 community hospitals, of which 221 are major teaching hospitals.The major teaching hospitals are components of academic medical centers, often include a Level 1 trauma center, and may coordinate local EMS transport.These 221 hospitals are the focal points of graduate medical education, technology, and tertiary services.Should an incident occur, these hospitals will be expected to serve the local community, through either direct clinical care or system coordination.Maintaining these hospitals in the face of falling revenue margins strains the ability of any organization to support infrastructure for "response capability." The rest of the hospital industry is similarly stressed.Total staffed beds in the United States have dropped to just below 956,000.Outsourcing outpatient services and procedures to non-hospital settings further reduces revenue.Less money means less opportunity to invest in hospital infrastructure, which gradually erodes sophisticated diagnostic services in hospitals and complicates our nation's health care industry from responding in traditional ways, let alone under extraordinary circumstances. Within each community, leadership from the health care industry is a key element in an effective response.Hospital executives recognize that major events will activate political and law enforcement leadership and that they must be proactive and form professional and collegial contacts with community leaders.Similarly, hospitals must be linked to provide mutual aid and assist patient transfers.Businesses function on increasingly narrow inventory levels, and hospitals in the same community usually rely on the same suppliers.In a crisis, suppliers will resort to rationing inventory.Regional and multistate mutual aid plans should be developed; but in catastrophic events, help from those outside the affected zone may take days to arrive, underscoring the need to identify resources to support three days of operations before reordering supplies. Hospital responses to mass casualty events are often chaotic.In part, this is due to lack of training and experience, but the disorganized response is compounded by not having an appropriate command structure such as the HICS.Use of an appropriate incident command system does not guarantee a successful response, but without one, failure is almost certain.Hospital personnel need to understand the concept of regional unified command and be willing to participate appropriately during a disaster. When a situation demands swift action, hospital administrators have to focus on many areas simultaneously.Using a step-by-step approach, administrators can bring some order to chaos and, in fact, improve response times and save lives.Administrators should focus on the critical areas listed below: - Control of the external environment The external environment will change rapidly during a large event. Maintaining control of hospital grounds (e.g., facility security and traffic) is essential.Clearing beds to accommodate incoming casualties, redirecting nonemergency patients to other resources, and managing overall comings and goings of staff will require effective control of the external environment, including media control. # Implementation of Hospital Incident Command System In a fast-paced disaster like the Madrid bombings, it is of crucial importance to have identified the appropriate decision-makers beforehand for the HICS.In a crisis, there is little time for meetings or discussion about the appropriate use of support functions and personnel. # Personnel Issues There should be a balance between the individual needs of staff and the organization as a whole to assure adequate coverage for short-and long-term medical responses.Decisions must be made early about when staff can go home to check on family members or what to do if staffers leave in the middle of the response.A method to request additional staff on short notice coupled with defining an individual institution's surge capacity can assist in finding the right mix of clinical and nonclinical support to handle the increased workload. # Memorandums of Understanding or Agreement Prescripted agreements to share supplies, personnel, or equipment should be written and drilled to support local, regional, and state partners in time of need. - Logistics and supplies Coordination with key suppliers and maintenance of inventories throughout the health system will make ramping up the level of effort easier.Depending on the event, some areas (i.e., obstetrics, outpatient surgery, and various clinics) may not be directly affected and could provide supplies.Effective logistics management would also include patient transportation to and from appropriate care settings.Although the housing of evacuees is a municipal function, knowing the locations of designated Red Cross shelters throughout the vicinity and transportation resources for low-acuity patients and their family members will hasten discharge planning and improve patient flow in the ED. - Alternate care sites A hospital is most effective when it can mobilize quickly and expand care to the city's walking wounded.Triage systems are typically used to prioritize patients so that low-priority patients can be directed from the main hospital, thus allowing ambulances and hospital staff to focus on high-priority patients (i.e., burns, dehydration, multiple injuries).Alternate sites may allow large health systems to facilitate triage and direct patients and families to appropriate sources of care. # Credentialing The Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) emergency credentialing system does work, but it must be tested within an organization before it is needed.State Emergency Systems for Advance Registration of Volunteer Health Professionals (ESAR-VHP) reflect JCAHO requirements and provide a standardized set of verified credentials for volunteers who may be called to assist hospitals during emergency situations.Many aspects of staff credentialing and privileging can be streamlined, but the formal enrollment cannot be circumvented.In most hospitals, formal enrollment provides access to entering orders, prescribing modalities, writing prescriptions, ordering laboratory tests, and documenting care using automated systems.No matter whether credentialing is handled by human resources or a professional staffing office, the design of the system should support the use of volunteers in nonclinical activities. # Patient tracking Tracking patient movement is a critical function during any mass casualty situation.Successful tracking begins at the point a patient enters the health care system.When more time is spent identifying and tracking patients, the prospect of reimbursement for related costs is better.The ability to track patients, identify their supply consumption, and monitor bed use enables senior management to proactively meet the needs of health care providers on the frontline.Many patient tracking systems exist, and if at all possible, the system should allow automated tracking for exercises and real disasters. This list is not all encompassing for every facility.The staff of any health care organization should periodically evaluate areas like plant management, social work resources, safety, materials management, biomedical equipment and repair, service procurement, and patient admittance to help prepare for the unexpected.Often, disaster preparedness is focused solely on the transfer of care between provider and patient and not on the infrastructure to support the effort. # Surge Capacity Solutions Addressing System-wide Challenges How do we address acute events that stress our overburdened system?Apparently, we must prepare for the predictable surprise-a bombing-which is the most common form of terrorist attack.The United States has a basic, functional capability to respond to the surge of patients following a terrorist event such as a bombing; however, several critical areas must be addressed for effective surge capacity to occur.To address the system specific challenges related to surge capacity that are highlighted above, the expert panel outlined the following recommendations for each challenge. # Organization and Leadership Leadership is important for successful preparedness and response at all levels-field, hospital, city, state, and federal-and it is mandatory in the planning and response phases. # Alterations in Standards of Care Culturally, the United States may need to revise its stance on health care.Instead of doing the greatest good for the individual, we may need to do the greatest good for the community (i.e., save the most victims).There is, however, no universally accepted methodology of doing this, and the process is fraught with ethical, societal, medical, and legal issues.A protocol is needed to determine when and how to deviate from the norm without the civilian health care provider or facility experiencing repercussions.An altered protocol would improve the civilian sector's ability to manage patient assessment, treatment, flow, and outcomes for the greatest number of patients.It is clear that changing standards of care will require efforts to preserve quality of care, a formal process in each community to determine when and how to transition from standard operating procedures to an altered standard of care, and determining who will have the authority to order the transition.In August 2004, the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services (HHS) convened a panel of experts to examine the complex issues surrounding alterations in clinical care.Their findings are published in the monograph Altered Standards of Care in Mass Casualty Events.4 The rationale for suspending standards of care in an emergency is that more patients will survive a terrorist attack if key interventions are provided to the greatest numbers of casualties likely to benefit from receiving care.Hospitals and EMS systems at surge capacity will require autonomy to suspend regular standards of care and shift to emergency critical care practices. - Although care can be altered at the institutional level, if all hospitals affected by a crisis switch to emergency critical care practice standards at the same time, more patients will receive effective care. - The ethical, political, legal, regulatory, and logistical implications of suspending standards of care and triaging patients to limited resources will require the participation of state and federal government.Legislation will be required to suspend standards of medical practice during an emergency without practitioners and hospitals incurring legal liability. - A mechanism is needed to address issues associated with change from routine to altered (emergency) standards of care/sufficiency of care. - Community education before, during, and after an event is necessary for acceptance and understanding. # Education Educational efforts must include an all-hazards approach that addresses the most likely, predictable terrorist event: a bombing.The education given to care providers should reflect the potential severity of the event.Training must be standardized across all levels of providers so that there is consistency among the disciplines. Training should address clinical care and systems issues. # Communications Communication plans should include interoperable, redundant regional emergency communications systems, ideally with multi-frequency bands, and trunked systems with the capability to pool user groups (for example, among hospitals) via the incident command structure.If a catastrophic incident results in massive power failure, emergency backup systems, such as mobile satellite telephones, will be needed along with other conventional methods of communication.Communication plans also should address command and control structures and disaster crisis counseling. Informatics and data systems link information for real-time impact (i.e., which hospitals have beds, where patients can be diverted, how to find loved ones, and how to access survival data).Without patient tracking and informatics, no one will be able to evaluate what works and what does not work in a given situation. # Transportation The military is probably the only group with the capability to transport patients on a large scale; however, not on short order, as it may take hours to arrange a single transfer.Regional, statewide, and national plans and agreements should address the roles of National Guard and active-duty military personnel for providing large scale air medical resources on relatively short notice.There may also be a need to integrate private and public transportation resources with military resources. # Infrastructure and Capacity Given the wide variability that exists nationwide, basic strategies and solutions must be developed to enable our hospital and medical system infrastructures to respond more effectively to mass casualty events. # Potential Bottlenecks - Radiology Perhaps a minimalist approach to using radiology makes sense-identifying and standardizing a baseline that could be used in many facilities.By identifying and addressing critical life threats and major problems through "tiered" reports-initial "wet" interpretations that are made and left with/on the patient and acted on when resources become available and final reports and interpretations are completed-both patient flow and care may be greatly improved. # Critical Care Plans must be in place to provide for emergency mass critical care, including basic modes of mechanical ventilation, hemodynamic resuscitation and support using intravenous fluids and vasopressors, administration of antibiotics and other disease-specific countermeasures, and prophylactic interventions to reduce adverse consequences of critical illness.If an event exceeds a locality's critical care/ICU capacity, hospitals must be able to activate emergency mass critical care practices, suspending usual standards of care and defining patients and interventions of highest priority. # Pharmacy Pharmacies must be prepared, and the role of pharmaceutical systems in the overall response falls into two areas: - Selection of the proper pharmaceuticals for stockpiling, and - Proper stockpiling of "CHEMPACKS." # Triage Preparedness and response plans must recognized that there are no evidence based standards for mass casualty events, including those that result from terrorist bombings, and that field triage often does not occur for the majority of injured victims.Response plans must account for the self referral of patients to nearby hospitals, and the impact this phenomena may have on the care of the critically injured. # Legal Issues Issues related to EMTALA, HIPAA, and provider credentialing must be addressed on both a national and local level, to ensure that the emergency medical system and individual providers can respond in a timely and effective manner. Addressing Discipline-specific Challenges Our nation's health care system has a chronic problem with managing surge capacity.Providers and administrators struggle daily to provide the full spectrum of injury care for victims of trauma, placing our preparedness for terrorism in a precarious position. This section contains nine templates developed by the expert panel to help various disciplines address issues of surge capacity.Though developed in the context of a surge of injuries from a terrorist bombing, the recommendations in this section may improve the response to and management of a surge of patients from any cause, including biological, chemical, or nuclear.Most, but not all, of these disciplines (e.g., "Drugs and Pharmaceutical Supplies" and "Nursing Care") have been discussed in the preceding sections.However these issues represent a significant concern for systems planners and therefore, the expert panel felt they must be included in the solutions section.Because many disciplines will be affected simultaneously, it is difficult, if not impossible, to identify a longitudinal timeline.For this reason, the templates are listed in a general order of flow through the system.Along with providing general information (i.e., purpose, background, goals), each template provides basic, and in most cases, low-cost strategies that can be implemented rapidly to avoid problems associated with managing surge capacity.The templates emphasize the importance of practicing and evaluating plans. The templates are intended as guides only, as needs, preferences, and capabilities vary among communities.Furthermore, templates propose solutions that assume communities are already actively engaged in disaster planning and preparedness activities; therefore, it is expected that a significant portion of the personnel and resource costs would be absorbed by these ongoing activities.Exact costs should be determined by local communities and institutions therein. # Managing Surge Needs for Injuries: Emergency Medical Service Response # PURPOSE To provide guidance for local emergency medical service (EMS) response and to operationalize additional EMS-related resources needed in a community within four hours of an explosion.These resources are intended to treat 00 injured patients for up to 72 hours. # GOAL To mobilize the appropriate number and type of EMS resources to adequately evaluate injuries, initiate triage, begin transporting 00 injured patients, and to establish ongoing EMS operations for up to 72 hours. This document is a resource guide.Local needs, preferences, and capabilities of affected communities may vary. # REQUIRED RESOURCES 1.Personnel must be: - Appropriately equipped and knowledgeable about chemical, biological, radiological, nuclear, and explosives (CBRNE) detection, personal protection, and decontamination. - Educated in the care of blast-related injuries for adult and pediatric patients. - Prepared to institute triage. - Prepared to institute and participate in unified incident command. 2.A communications system that is interoperable with public safety disciplines (fire, law enforcement, EMS, and emergency management) and with receiving hospitals and local public health officials. .Rapid access to sufficient ambulance resources to transport critically injured patients. 4.Rapid access to sufficient alternative resources (e.g., buses) to transport noncritical, injured persons. Have the necessary material and the capability to detect CBRNE agents to assist with decontamination plans.Fire, EMS, law enforcement, emergency management, hospitals, and public health should collaborate to develop and complete written plans within six months, as listed below.Within one year, other agencies listed in these plans (including mutual aid agencies, etc.)must be included in ongoing planning and evaluation. - Plan for mobilizing 50 ambulances within 10 minutes after the blast.At least 75% of these resources should arrive at staging areas in the first hour with all arriving in the first 90 minutes.This should be accomplished using 9-1-1 EMS resources, mutual aid agreements with other EMS providers, or mutual aid agreements with nonemergency transport providers.

- Plan describing each agency's role in the command structure.This should include how critical functions of command, staging, triage, and treatment will be accomplished in the first 10 minutes of a response; how additional ICS elements will be filled over the first hour; and how the ICS structure will be formally filled by officials trained in advanced ICS (ICS-700 or equivalent) by the end of the first hour. -Plan describing how alternative transport for 200 ambulatory patients will be initiated in the first 10 minutes after an explosion. -Plan describing the details of interdisciplinary communications (primary and alternatives).Representatives from fire prevention, EMS, law enforcement, emergency management, hospitals, and public health must be included in this plan. -Plan for decontaminating and protecting personnel that addresses the following: - -How sites can be activated and staffed with at least one transport ambulance, sufficient law enforcement personnel for security, and adequate support staff to record arrivals.-How gross and technical decontamination could be accomplished at affected site(s). -How medical care at secondary triage sites could be converted to treatment areas (e.g., provision of medical supplies, additional medical personnel, and other logistical concerns). - Plan to establish criteria for determination of death at the scene, particularly in a mass casualty situation, and appropriately manage the deceased. # EVALUATION 1.Plan and conduct a community-wide drill.Afterwards, evaluate it by assessing overall operations and EMS resources such as personnel, ambulances, and PPE.Evaluate compliance with NIMS. 2.Assess and refine plan. # Managing Surge Needs for Injuries: Emergency Department Response # PURPOSE To activate additional emergency department resources needed within four hours of an explosion.These resources should treat 00 injured patients for up to 72 hours. # BACKGROUND INJURY PREVENTION The experiences of the Madrid terrorist bombings were used as a model to help # GOAL To establish policies, procedures, didactic training, and drills to improve institutional preparedness for treating 00 injured patients for up to 72 hours. # RESOURCES REQUIRED There should be adequate medical, nursing, and support staff to provide initial triage, and to evaluate and stabilize 00 persons. This document is a resource guide.Local needs, preferences, and capabilities of affected communities may vary. # ASSUMPTIONS 1.Developed packets for each patient containing disaster bands (those from blood banks work best), manual charting forms, and manual lab and radiology order forms.These packets should be prepared in advance and stored in the ED. 2.Established procedures for obtaining additional personnel, equipment, supplies and beds; establish a mechanism for notifying and activating backup personnel. .Established procedures for triage, patient emergency identification of patients and discharge, and quick documentation. 4.Established temporary disaster log to document basic information. # ACTION STEPS 1.Implement and drill a hospital emergency incident command system (such as Hospital Incident Command System or "HICS"); include clinical care providers in the training and drill. If hospital personnel (e.g., practitioners, administrators, nurses) have not trained or drilled in a hospital incident command system, learned about the National Incident Management System (NIMS), or do not understand the function of a Hospital Incident Command Center, this information should be included in training sessions. 2.Instruct clinical staff, especially surgeons and emergency physicians, about the unique aspects of blast-related injuries and care following an attack with a radiation dispersal device (RDD). .Establish an institutional lockdown process and drill on a regular basis; include radiation detection and decontamination of arriving patients. 4.Update the institutional call-down list and perform a functional call-down exercise. 5.Identify potential institutional surge staffing from employees with clinical training, but not currently tasked with clinical jobs. 6.Identify patient care supplies for a surge situation, such as additional IV equipment, bandages/dressings, gowns, gloves, masks, other operating room supplies, etc. 7.Develop a regional Unified Command Structure that includes local emergency management and area hospitals.This should be achieved under the guidance and leadership of the local emergency managers. 8.Identify non-patient care areas in the institution that could be converted to patient care to expand bed surge capacity. 9.Establish and drill a procedure for early patient discharge to increase bed capacity.This procedure should include evaluation of ICU patients for potential movement to a non-ICU bed and evaluation of all patients for potential early discharge or transfer to an alternative care site (internal or external to the institution). # EVALUATION When appropriate, evaluation drills have been incorporated into the "Action Steps" listed above.The institutional disaster preparedness plan should be updated based on each drill experience. Managing Surge Needs for Injuries: # Surgical and Intensive Care Unit Response # PURPOSE To mobilize and assign operating rooms and related assets for life-and limb-saving surgical care to the most critically injured of 00 patients from explosions (care extends to patients from the community with acute surgical illness for up to 72 hours after a bombing). # INJURY PREVENTION Emergency Medical # BACKGROUND Service Response The Madrid terrorist bombings were used as a model to help develop solutions for # GOAL Within two hours of a blast event, establish incident command for the operating rooms and surgical support areas for up to 72 hours. # RESOURCES REQUIRED Resources needed for communicating within the organization and with the community (e.g., satellite phone, walkie-talkie). This document is a resource guide.Local needs, preferences, and capabilities of affected communities may vary. # ASSUMPTIONS 1.Operating room (OR) assets are a critical component of surge capacity after an explosion and must be mobilized quickly. 2.The OR capacity of any institution or community (i.e., number of operating rooms) is fixed because of structural requirements. .One or more surgeons, anesthesiologists, and critical care specialists will be in the hospital or available immediately after an event. 4.Other surgeons, anesthesiologists, and critical care specialists can be available within two hours of an event to provide direct patient care in the ORs and related areas. 5.The ORs, post-anesthesia care units (PACU), and intensive care units will already be in use.6.Casualties of the blast and patients already in the hospital system or in other treatment centers in the community will occupy one or more of these three areas within the next 72 hours. 7.If these areas are not made available in a timely manner, patients will suffer greater harm. 8.Some patients could be moved to different care sites. 9.Federal resources cannot be expected to arrive sooner than 72 hours from the time of an explosion. # ACTION STEPS The near-term (six months) solutions listed below include estimated hours for each task.1.Identify medical leadership within surgery and anesthesiology for disaster planning. - Leadership should collaborate in the design, implementation, and refinement of an incident command system for an operating room.Initially, leadership in surgery and anesthesiology should meet with representatives from critical care, emergency medicine, administration, and others involved with the institution's disaster planning.These discussions will be facilitated by appointing a hospital disaster committee. 2.Select individuals for incident command roles. - Specify the authority, processes, and responsibilities of the OR incident command and a call schedule identifying individuals available to fill their roles 24 hours a day, beginning within two hours of the event, and extending for 72 hours. -Although individuals from several disciplines and departments in the operating room and related areas may assist the incident command, final decision-making authority should rest with one person-an "Operating Room Czar."The OR Czar would have authority to cancel scheduled OR cases, rearrange OR schedules, identify patients that could be transferred, call in and deploy OR teams, and prioritize patients for beds in the OR, PACU, and ICUs.The OR Czar would report to hospital incident command. -Candidates for this role should be able to assess the medical needs of a variety of patients requiring OR services.They must be physicians, and would most likely be surgeons.An individual serving in this role should not have primary patient care responsibility at the same time (i.e., be part of a surgical team). -Communication systems linking surgery, nursing, anesthesiology, critical care, emergency department, and hospital administration should be specified. -The OR incident command system must account for personnel availability at different times of the day and week and provide for transfer of incident command responsibility as the incident evolves over 72 hours. -The circumstances under which the OR incident command begins and ends should be specified. -Methods for data collection, testing, monitoring, and improving the system should be specified. .Assure that individuals who might assume an incident command role are knowledgeable about incident command, operations of other hospital components, and community disaster response.Determine when individuals should be present onsite.Review triage decisions, quality, quantity, and appropriateness of information obtained from and given to others, including hospital incident command, emergency medicine, and other community assets. 2.Refine and conduct further planning based on drill experience. immediate ("wet") readings of plain films and special studies.This will assist in rapid evaluation and treatment of patients.The plan should also optimize and streamline radiology study protocols for use during a mass casualty event. Enhanced radiology patient throughput will be essential in the initial evaluation and treatment of blast-injuries.Each radiology department must develop a plan to ensure rapid turnaround of patient studies and their results. 2.When disaster patients arrive, a radiology ultrasound technician should be available in the emergency department to support the performance of an immediate FAST (Focused Abdominal Sonography for Trauma) exam.If this is not possible, the emergency physicians and trauma surgeons should be trained to conduct one. .Conduct an imaging equipment survey; evaluate the status of the equipment for multiple traumas, making sure there are adequate amounts of portable equipment available and update if needed. Radiology equipment is expensive and usually requires planning in advance for acquisition and installation.However, by evaluating how available equipment could be put to maximum use during a mass casualty event can improve patient throughput. 4.Establish a protocol for augmenting patient movement and monitoring in the radiology department.Afterwards, review the availability of patient monitoring personnel and equipment to enhance departmental throughput, especially for studies such as CT scans. # EVALUATION Where appropriate, evaluation drills have been incorporated into the "Action Steps" listed above.The institutional disaster preparedness plan should be updated based on each drill experience. -Facilities currently maintain about a three-day supply of blood products-which may need to be expanded to a seven-day supply.-Typically, fewer casualties require blood products than the total number of victims. -Local communities have limited sources of blood products. -If faced with a surge in demand, blood products will likely be transported from blood centers outside the local area. -After a disaster, the public usually responds by volunteering to donate larger quantities of blood products than are needed. -An influx of blood donors could tax collecting and processing efforts. -When resources (personnel, equipment, and supplies) are unnecessarily applied to collecting and processing unneeded products, these resources cannot process and distribute available and urgently needed products to those in urgent need. -The media must continuously provide the community with reliable information about the need and supply of blood products. - There are limited personnel with the training, education, and skills to process and administer blood products within treating facilities. -Additional qualified laboratory personnel may be needed to process requests for blood products.-Additional nursing personnel may be needed to administer blood products. - There may be limited methods of transporting or transferring blood products from supplier to destination during a disaster. -Commercial transport (air and ground) may be limited. -Blood needs are considered by federal, state, and local governments to be a critical element of the public health infrastructure in times of emergency. -The AABB Interorganizational Task Force on Domestic Disasters and Acts of Terrorism, formed in January 2002, has developed a process to educate the community about donations and how to collect, process, and move blood products at the time of a disaster. -This multi-organizational task force includes federal and national organizations. -Published references include a Disaster Operations Handbook and a hospital supplement that addresses these issues.They include a flow chart outlining the process for involving the AABB and appropriate national and federal organizations that provide blood products during a disaster. # ACTION STEPS - Work with AABB to distribute documents to hospitals and blood collection organizations/facilities. - Identify resources (personnel, equipment, supplies) to meet local needs for collection, processing, distribution, and transfusion of blood products.This effort must include local media to provide consistent messages to the community about blood products, supply, and needs. (Note: Individual hospitals and collection organizations incorporate the AABB process into their local disaster response plans.) - Work with other organizations and government agencies (local, regional, state, federal) to make sure blood products are considered critical elements of the public health infrastructure in the event of a disaster/emergency. # EVALUATION - Ensure that survey hospitals and collection organizations incorporate AABB processes into local disaster response plans after 4 to 6 months. - Request that hospitals and collection organizations participate in a local or regional exercise requiring administration of blood products within four hours of an event for up to 72 hours. -Include activation and response of the AABB system, and local, regional, and state resources in the exercise. # GOAL To organize and support response to influx of 00 patients injured from an explosion for a 72-hour period. # RESOURCES REQUIRED The workload associated with an administrative response will require access to multiple facilities to support the needs of patients, staff, and the general public.Administrators will manage communications, acquire political support, work with and respond to media, handle public inquiries, manage internal systems and departments. This document is a resource guide.Local needs, preferences, and capabilities of the affected communities may vary. # ASSUMPTIONS - Health care systems and hospitals should function as an integrated system for the best use of resources. - A medical response to a mass casualty event must be comprehensive, community based, and coordinated. - Legal and regulatory issues need to be included in the hospital emergency preparedness plan: Emergency Medical Treatment and Active Labor Act # ACTION STEPS The solutions listed below include estimated hours for each task. # Control of the External Environment The external environment will change rapidly during a large-scale, mass casualty event. The hospital must be secured and campus traffic must be controlled.Such control of the external environment includes clearing beds to accommodate incoming casualties, redirecting non-emergency patients to other resources, and managing the comings and goings of staff.Managing media relations can be challenging when trying to provide safe and effective care.The institution's security and public affairs offices must work together and be in place before the media arrives. # Activation of Hospital Incident Command System (HICS) HICS, a widely used emergency management system, is known for providing a chain of command with the ability to effectively manage an incident, provide accountability of position functions, allow for a flexible response to specific emergencies, improve documentation of facility actions, provide a common language to facilitate outside assistance, and develop prioritized response checklists for senior leadership.Identifying the appropriate people to make decisions is pivotal in a fast-paced disaster, such as in the Madrid bombings.There is little time for meetings and discussion about the appropriate use of support functions and personnel.Staff should be trained and drilled regularly to ingrain the difference between incident structure and normal operations. # Logistics and Supplies Coordinating with key suppliers and maintaining current inventories throughout the health system will make stocking efforts easier.When resources are limited, providers must be prepared to respond to care needs with whatever is available. Logistics include, but are not limited to, patient transportation.For example, housing evacuees and the walking wounded and their families is a function of the emergency management program.Knowing the locations of designated shelters throughout the vicinity and transportation resources for low-acuity patients and their families will hasten discharge planning and patient flow in acute care facilities. # Alternate Care Sites A hospital's ability to mobilize emergency care units and to extend care to the city's walking wounded adds to its effectiveness.Triage systems are used to prioritize patients so that low-priority patients can be directed from the main hospital, allowing ambulances and hospital staff to focus on high-priority trauma patients in need of medical assistance.Alternate sites, like the ones used during Hurricanes Katrina and Rita, allow large health systems to facilitate triage and direct patients to appropriate sources of care. # Credentialing The Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) emergency credentialing system must be tested within an organization before it is really needed.State Emergency Systems for Advance Registration of Volunteer Health Professionals (ESAR-VHP) reflect JCAHO requirements and provide a standardized set of verified credentials for volunteers who may be called to assist hospitals during emergency situations. .Identify gaps between drugs on hand and goal. 4.Identify potential sources of drugs in the community besides prehospital and hospital supplies (e.g., locally developed stockpiles, community pharmacies, drug wholesalers/ warehouses, physicians' offices via medical society).Identifying additional sources should include daily, routine needs of the community. 5.Develop relationships with leadership from additional sources; ask for "snapshot" inventory of drugs, and establish "mutual aid" agreements to rapidly acquire drugs. 6.Assess drugs available in the community by adding prehospital + hospital + community pharmacies + drug wholesalers/warehouses + physicians' offices (through medical society). 7.If the drug supply is low, develop a plan for intercommunity mutual aid or rationing. 8.Develop a plan to rapidly acquire drugs from additional sources and deliver products to points of care.This plan should include communications between point(s) of care and additional sources, mutual aid agreements with additional community sources, transport of drugs, and reimbursement. # EVALUATION 1.Plan, conduct, and evaluate a community-wide drill.

The evaluation should include measuring quantity and names of drugs and pharmaceutical supplies acquired, distributed and administered; times when drill started, time drugs were acquired from distribution points, duration of transport, time of distribution to points of care, and time of administration to patients. 2.Refine plan based on drill experience. - Develop criteria and policy to discharge patients who can go home or be quickly transferred to long-term care. -Make sure each department has a procedure for mass casualty care.These procedures need to be reviewed and be accessible to the command center.-Departments need to determine procedures for what will be done immediately (0-120 minutes), intermediately (2-4 hours) and long term (4-24 hours). -Notify all departments of incident and of emergency plan activation. - Request that policies be approved by a centralized committee that oversees the emergency operations and plan. - Update call lists.Every department should have a current list that identifies staff by their proximity to the hospital. - Make staff aware of where to park, where to report, how to respond, etc. - Maintain a centralized data base with staff competency skills like ACLS (Advanced Cardiac Life Support®), TNCC (Trauma Nurse Core Course), ENPC (Emergency Nurse Pediatric Course), and PALS.Identify who is competent to care for critically ill patients. - Add on-call staff to the disaster call list. - Maintain names of retired or unemployed staff in a hospital or health system database. - Include Medical Reserve Corp information/lists in the emergency response plan. - Prepare badges in advance for credentialed professional staff. - Credential volunteers in advance.Community agencies typically manage volunteers. - Set up a system so that the hospital can verify credentials (i.e., State ESAR-VHP). - Ensure that staff is assigned to tasks with which they are most familiar and perform daily; do not change routine procedures. # EVALUATION Hospitals/health systems should plan and execute a drill with EMS at least once a year.The drill should include objectives to accommodate 00 patients with beds, staffing, and resources. Critique the completed drill, write a report, and share the findings with participants.Hospital administrators should analyze the report and make recommendations to the disaster plan.Any deficiencies should be tested in the next drill. Planning a drill is expensive.Exercises must be done in conjunction with state or county/ city emergency management agency staff with the resources to conduct them. Worldwide bombings occur almost daily and are escalating in complexity and sophistication.As noted throughout this report, we know the U.S. health care system will be overwhelmed by a terrorist bombing.The proposed solutions outlined in this report, provide strategies that can be put in place now-before a crisis strikes-to address the system wide and discipline-specific surge capacity challenges to providing an effective response.

depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Summary Early childhood home visitation programs are those in which parents and children are visited in their home during the child's first 2 years of life by trained personnel who provide some combination of the following: information, support, or training regarding child health, development, and care.Home visitation has been used for a wide range of objectives, including improvement of the home environment, family development, and prevention of child behavior problems.The Task Force on Community Preventive Services (the Task Force) conducted a systematic review of scientific evidence concerning the effectiveness of early childhood home visitation for preventing several forms of violence: violence by the visited child against self or others; violence against the child (i.e., maltreatment ); other violence by the visited parent; and intimate partner violence.On the basis of strong evidence of effectiveness, the Task Force recommends early childhood home visitation for the prevention of child abuse and neglect.The Task Force found insufficient evidence to determine the effectiveness of early childhood home visitation in preventing violence by visited children, violence by visited parents (other than child abuse and neglect), or intimate partner violence in visited families. (Note that insufficient evidence to determine effectiveness should not be interpreted as evidence of ineffectiveness.)No studies of home visitation evaluated suicide as an outcome.This report provides additional information regarding the findings, briefly describes how the reviews were conducted, and provides information that can help in applying the recommended intervention locally. # Background Juvenile violence, child maltreatment, and intimate partner violence are substantial problems in the United States.In the last 25 years, juveniles aged <18 years have been involved as offenders in at least 25% of serious violent victimizations in the United States.Rates of homicide victimization among youth aged <15 years are five times higher in the United States than they are in 25 other industrialized nations for which data are available, and rates of firearm-related homicide are approximately 16 times higher in the United States than in those same nations (1,2).In 1994, 33% of juvenile homicides involved a juvenile offender.Since 1976 or earlier, the peak rate of homicide in the United States has occurred among persons aged 18-24 years.In 1999, suicide was the sixth leading cause of death among persons aged 5-14 years and the third leading cause of death among those aged 15-24 years. In 1999, 4.1% of children (aged <18 years) were reported to be victims of maltreatment.Of those reports, 33.8% were investigated by child protective services and not confirmed; however, additional cases of maltreatment were not reported, further complicating this picture (2)(3)(4).Child maltreatment can include physical, sexual, or emotional abuse; physical, emotional, or educational neglect; or a combination of abuse and neglect.Not only is child maltreatment a form of violence in itself, it also contributes to adverse consequences among maltreated children, including early pregnancy, drug abuse, school failure, mental illness, and suicidal behavior (5).Children who have been physically abused are more likely to perpetrate aggressive behavior and violence later in their lives, even when other risk factors for violence are taken into account (6,7).Because abuse and neglect are both associated with poverty and single-parent households, many home visitation programs in the United States are directed to poorer, minority, and singleparent families.Given that 12% of 4 million U.S. births in 1999 were to teenage mothers, 33% were to single mothers, and 22% of mothers had less than a high school education, the population at risk is substantial (8). Intimate partner violence victimizes men as well as women in the United States, but women are three times as likely to be victims as are men (9).During her lifetime, one of four women in the United States will be the victim of partner violence: 7.7% will be victims of rape and 22.1% will be victims of other physical assault.Violent victimization of women, including threats of rape and sexual assault, is greatest among women aged 16-19 years.Such violence can also have severe physical and mental health consequences for victims (10). Early childhood home visitation has been used for a wide range of public health goals for both visited children and their parents, including not only violence reduction and other health outcomes but also health-related outcomes such as educational achievement, problem-solving skills, and greater access to social services and other resources (11,12).Home visitation programs are common in Europe, where they are most often made available to all childbearing families, regardless of estimated risk of child-related health or social problems (13).This # Introduction The independent, nonfederal Task Force on Community Preventive Services (the Task Force) is developing the Guide to Community Preventive Services (the Community Guide) with the support of the U.S. Department of Health and Human Services (DHHS) in collaboration with public and private partners.Although CDC provides staff support to the Task Force for development of the Community Guide, the recommendations presented in this report were developed by the Task Force and are not necessarily the recommendations of DHHS or CDC. This report is one in a series of topics included in the Community Guide, a resource that includes multiple systematic reviews, each focusing on a preventive health topic.A short overview of the process used by the Task Force to select and review evidence and summarize its findings is included in this report.A full report on the findings and supporting evidence (including discussions of applicability, additional benefits, potential harms, and existing barriers to implementation), costs and cost-benefit of the intervention, and remaining research questions will be published in the American Journal of Preventive Medicine. # Methods The Community Guide uses systematic reviews to evaluate the evidence of intervention effectiveness, and the Task Force bases its recommendations on the findings of these reviews.Recommendations regarding interventions reflect the strength of the evidence of effectiveness (i.e., sufficient or strong evidence of effectiveness) (14).- Other types of evidence can also affect a recommendation.For example, evidence of harms resulting from an intervention might lead to a recommendation that the intervention not be used if adverse effects outweigh improved outcomes.When interventions are determined - At the June 2002 meeting of the Task Force on Community Preventive Services, new terminology was adopted to reflect the findings of the Task Force.Instead of being referred to as "strongly recommended" and "recommended," such interventions are now referred to as "recommended (strong evidence of effectiveness)" and "recommended (sufficient evidence of effectiveness)," respectively.Similarly, the finding previously referred to as "insufficient evidence" is now more fully stated: "insufficient evidence to determine effectiveness."These changes were made to improve the clarity and the intent of the findings. to be effective, their costs and cost effectiveness are evaluated, insofar as relevant information is available (15).The instrument used to systematically abstract the economic data is available at / econ-abs-form.pdf.Although the option exists, the Task Force has not yet used economic information to modify recommendations.A finding of insufficient evidence to determine effectiveness should not be interpreted as evidence of ineffectiveness but rather as an indicator that additional research is needed before the effectiveness of the intervention can be determined. In contrast, sufficient or strong evidence of harmful effect(s) or of ineffectiveness leads to a recommendation that the intervention not be used. The Community Guide's methods for conducting systematic reviews and linking evidence to recommendations have been described elsewhere (14).In brief, for each Community Guide topic, a multidisciplinary team conducts a review by performing the following actions: - developing an approach to organizing, grouping, and selecting the interventions for review; - systematically searching for and retrieving evidence; - assessing the quality of and summarizing the strength of the body of evidence of effectiveness; - assessing cost and cost-effectiveness evidence, identifying applicability and barriers to implementation (if the effectiveness of the intervention has been established); - summarizing information regarding evidence of other effects; and - identifying and summarizing research gaps.For the systematic review of violence prevention intervention programs, early childhood home visitation was identified as a high-priority intervention by a group of consultants † representing diverse experience.They generated a comprehensive list of strategies and created a priority list of interventions for review based on 1) the potential to reduce violence in the U.S. population; 2) the potential benefits of expanding use of seemingly effective, but underused interventions and reducing use of seemingly ineffective, but overutilized interventions; 3) current interest among violence prevention audiences; and 4) diversity among intervention types. Home visitation programs, reviewed in this article, might be useful in reaching several objectives of Healthy People 2010 (16), the disease prevention and health promotion agenda for the United States.These objectives identify major preventable threats to health and focus the efforts of public health systems, legislators, and law enforcement officials in addressing those threats.Many of the Healthy People objectives in Chapter 15, "Injury and Violence Prevention," relate to home visitation and its proposed effects on violence-related outcomes (Box). To be included in the review of effectiveness, studies had to 1) be primary investigations of the intervention selected for evaluation rather than, for example, guidelines or reviews; 2) provide information on at least one outcome of interest from the list of violent outcomes preselected by the team; 3) be conducted in Established Market Economies; § and 4) compare outcomes in groups of persons exposed to the intervention with outcomes in groups of persons not exposed or less exposed to the intervention (whether the comparison was concurrent between groups or before-and-after within the same group).The search covered any research published before July 2001. The purpose of this review was to assess the effectiveness of home visitation programs in preventing violence.Home visitation programs have focused on diverse aspects of child and family development.In this review, home visitation was defined as a program that includes visitation of parents and children in their home by trained personnel who convey information, offer support, provide training, or perform a combination of these activities.Visits must occur during at least part of the child's first 2 years of life but may be initiated during pregnancy and may continue after the child's second birthday.Participation may be voluntary or mandated.Visitors may be nurses, social workers, other professionals, paraprofessionals, or community peers. Home visitation programs are commonly targeted to specific population groups: low-income; minority; young; less educated; first-time mothers; substance abusers; children at risk for abuse or neglect; and low birthweight, premature, disabled, or developmentally compromised infants.Visitation programs include (but are not limited to) one or more of the following components: training of parent(s) on prenatal and infant care, training on parenting, child abuse and neglect prevention, developmental interaction with infants or toddlers, family planning assistance, development of problem-solving skills and life skills, educational and work opportunities, and linkage with community services.In addition to home visits, programs can include day care; parent group meetings for support, instruction, or both; advocacy; transportation; and other services.When such services are provided in addition to home visitation, the program is considered multicomponent. The systematic review development team (the team) reviewed studies of home visitation only if they assessed violent outcomes.If violence was not the primary target or outcome of the visitation, the study was included if it met epidemiologic criteria and assessed violent outcomes.The effects of other outcomes were not systematically assessed but are reported insofar as they are addressed in the studies reviewed.The studies reviewed examined any of four violent outcomes: - violence by the visited child, against self or others; - violence against the child (i.e., maltreatment that includes all forms of child abuse and neglect); - violence by the visited parent, other than child maltreatment and intimate partner violence; and - intimate partner violence.The team developed an analytic framework for the early childhood home visitation intervention, indicating possible causal links between home visitation and predefined outcomes of interest.To make recommendations, the Task Force required that studies show decreases in preselected direct or proxy measures for at least one of the four categories of violent behavior described previously.If both direct and proxy measures were available, preference was given to the direct measure. Electronic searches for intervention studies were conducted in MEDLINE, EMBASE, ERIC, National Technical Information Service (NTIS), PsycINFO, Sociological Abstracts, National Criminal Justice Reference Service (NCJRS), and CINAHL. ¶Also reviewed were the references listed in all retrieved articles as well as additional reports as identified by the team, the consultants, and specialists in the field.Journal articles, government reports, books, and book chapters were included in the review. Each study that met the inclusion criteria was evaluated by using a standardized abstraction form (17) for suitability of the study design and threats to validity (14).On the basis of the number of threats to validity, studies were characterized as having good, fair, or limited execution.Results on each outcome of interest were obtained from each study that had good or fair execution.Measures adjusted for the effects of potential confounders were used in preference to crude effect measures.A median was calculated as a summary effect measure for outcomes of interest.For bodies of evidence consisting of seven or more studies, an interquartile range was presented as an index of variability.Unless otherwise noted, the results of each study were represented as a point estimate for the relative change in the violent outcome rate associated with the intervention.Percentage changes were calculated by using the following formulas: - For studies with before-and-after measurements and concurrent comparison groups: Effect size = -1 where Ipost = last reported outcome rate in the intervention group after the intervention; Ipre = reported outcome rate in the intervention group before the intervention; Cpost = last reported outcome rate in the comparison group after the intervention; and Cpre = reported outcome rate in the comparison group before the intervention. -For studies with postmeasurements only and concurrent comparison groups: Effect size = (Ipost -Cpost) / Cpost - For studies with before-and-after measurements but no concurrent comparison: Effect size = (Ipost -Ipre) / Ipre The strength of the body of evidence of effectiveness was characterized as strong, sufficient, or insufficient on the basis of the number of available studies, suitability of study designs for evaluating effectiveness, quality of execution of the studies, consistency of the results, and effect size (14). # Results The systematic review development team identified four studies that evaluated effects of early childhood home visitation on violence by visited children.Because the results of these studies were inconsistent, the Task Force concluded that evidence was insufficient to determine the effectiveness of early childhood home visitation in preventing violence by visited children.Evidence from one study (as assessed by self-reported delinquency, the team's preferred measure) indicated no benefit and was inconsistent with evidence from the same study as assessed by other measures (e.g., arrests and convictions) (18).A second study (19) indicated benefit of home visitation, and the two remaining studies (20,21) suggested no difference.No study evaluated the effects of home visitation on suicide by visited children. The studies also yielded insufficient evidence to determine the effectiveness of early childhood home visitation in preventing violence by visited parents (other than child abuse) or intimate partner violence in visited families.The team identified only one study that evaluated effects of early childhood home visitation on violence by visited parents (other than child abuse) (22).This study indicated a beneficial effect, but one that was statistically significant only among low-income, single mothers.Similarly, only one study evaluated effects of home visitation on intimate partner violence in visited families (23).Evidence from this single study of partner violence indicated no statistically significant effect. The team also identified 22 studies (representing 27 intervention arms) that evaluated effects of early childhood home visitation on child maltreatment.Participation in all programs was voluntary.Outcomes assessed were reported and confirmed abuse and neglect, hospital records of injury or ingestion (which may be associated with abuse or neglect), and out-of-home placement (i.e., removal from the home).One study (representing one intervention arm) was excluded because of limitations in its execution; the remaining 21 studies (with 26 intervention arms) were included in the body of evidence.Additionally, three economic studies were included in the review.Both the costs and benefits of early childhood home visitation were assessed in one study, whereas the other two studies estimated program costs only.A summary of key findings and recommendations is presented (Table ). On the basis of strong evidence of effectiveness, the Task Force recommends early childhood home visitation for prevention of child abuse and neglect in families at risk for maltreatment, including disadvantaged populations and families with low-birthweight infants. Compared with controls, the median effect size of home visitation programs was a reduction of approximately 40% in child abuse or neglect.Benefit was found whether the outcome was directly assessed in terms of reported abuse or neglect or indirectly assessed as reported injury.The only study that assessed the effects of home visitation on out-of-home placement indicated a small nonsignificant increase associated with home visitation (the desired result would be a decrease in out-of-home placement).Effect sizes (and the benefits of home visitation in prevention of child abuse or neglect) may actually be greater than reported here because the presence of the home visitor increases the likelihood that abuse or neglect will be # Key findings Effective in decreasing child maltreatment (by several measures).Median relative percentage point change of -39% (interquartile range: -74%-24%). Programs delivered by professional visitors (nurses, mental health workers) might yield more consistent effects.For paraprofessional visitors, beneficial effects generally found in programs of longer duration (>2 years).

Available studies might underestimate actual effectiveness of programs because home visitors are required by law to report abuse and neglect (thus ascertainment of these outcomes is increased in the intervention group). Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in design and execution of available studies. Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in design and execution of available studies. Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in design and execution of available studies. observed.This likelihood is indicated by the findings from two studies reviewed (24,25) and introduces a bias against the hypothesis that home visitation reduces abuse or neglect (26).Stratified analyses provide information that might be useful in program design.Programs delivered by professional visitors (nurses or mental health workers ) yielded more beneficial effects than did those delivered by paraprofessionals.Programs delivered by nurses demonstrated a median reduction in child abuse of 48.7% (interquartile range: 24.6%-89.0%); programs delivered by mental health workers demonstrated a median reduction in child abuse of 44.5% (interquartile range not calculable).For paraprofessional visitors, effects were mixed: the median reduction in child abuse was 17.7%, but the variability of the findings is reflected in the interquartile range of -41.2%-65.7%.In programs using paraprofessionals, beneficial effects were consistently evident only when programs were carried out for >2 years.No additional benefit of multicomponent home visitation programs over single component programs was apparent.Time of initiation of programs (i.e., pre-or postnatally) did not affect the reduction of subsequent child maltreatment.Evidence from the single study of the effects of home visitation on partner violence (23) indicated that home visitation might not prevent child maltreatment in the presence of ongoing partner violence.The studies on which these conclusions are based are listed (Table ). The only available cost-benefit analysis of a nurse home visitation program to reduce child maltreatment was based on a limited, government perspective (i.e., including only those costs and benefits incurred by the government) (27).In the whole study sample, costs exceeded economic benefits directly attributable to reduced child maltreatment services by $3,000 per family.Including benefits beyond those of the government, such as averted health-care costs, productivity losses, and other costs to the victim, is likely to result in greater net benefits.Program cost estimates -largely dependent upon frequency of home visits and program duration -ranged from $958 to $8,000 per family (in 1997 dollars).In the study subsample of low-income mothers, the analysis showed a net benefit of $350 per family (in 1997 dollars). # Research Needs Most systematic reviews for the Community Guide acknowledge the need for additional research, either to answer questions posed by the review findings or to generate enough information on which to base findings.When the findings indicate that evidence is insufficient to determine effectiveness, as is the case for much of the current review, the need for a research agenda is particularly great.The team has developed such an agenda, and will publish it, along with a full review of the evidence, in a supplement to the American Journal of Preventive Medicine. # Use of the Recommendation in States and Communities Given the substantial burden of child maltreatment in the United States, and the importance of this problem both from public health and societal perspectives, the Task Force saw the need to specifically review the effectiveness of home visitation programs in reducing this and other forms of violence.The finding that these programs are effective in reducing child abuse and neglect should be relevant and useful in various settings. The Task Force recommendation supporting early childhood home visitation interventions for prevention of child abuse and neglect in families at risk of maltreatment can be used to support, expand, and improve existing home visitation programs, and to initiate new ones.In selecting and implementing interventions, communities should carefully assess the need for such programs (e.g., the burden of child maltreatment) and clearly define the target populations.Home visitation programs included in this review were generally directed to those populations and families believed to benefit most from common program components, such as support in parenting and life skills, prenatal care, and case management.Target populations included teenage parents; single mothers; families of low socioeconomic status; families with very low birthweight infants; parents previously investigated for child maltreatment; and parents with alcohol, drug, or mental health problems.The population that might benefit is large.For example, in 1999, approximately 33% of the 4 million births in the United States were to single mothers, 12.2% were to women aged <20 years, and 22% were to mothers with less than a high school education; 43% of births -approximately 1.7 million -were to mothers with at least one of these characteristics (B. Hamilton, National Center for Health Statistics, CDC, personal communication, 2002). Studies included in this review were conducted in a variety of geographic locations in the United States and Canada and in populations with various ethnic and cultural backgrounds.The available evidence on the effectiveness of home visiting programs of sufficient duration indicates benefit for population subgroups in greatest need, provided that appropriate care is taken to tailor programs to local circumstances.Because no study reviewed assessed the effectiveness of home visitation in preventing violence in the general population, the broader applicability of these programs (e.g., to the general population) is uncertain. # MMWR October 3, 2003 Public health professionals and policy makers should carefully consider the attributes and characteristics of the particular program to be chosen for implementation.Given the heterogeneity of home visitation programs in the United States, which differ in focus, curricula, duration, visitor qualifications, and target populations, no single optimal, effective, and costeffective approach could be defined for the multiplicity of possible outcomes, settings, and target populations.However, the robust findings across a spectrum of program characteristics increase confidence that these programs can be effective in a range of circumstances and reduce concern that effectiveness hinges on particular characteristics of one intervention or one context. The Task Force found insufficient evidence to determine the effectiveness of early childhood home visitation in preventing violence by visited children and between adults.This conclusion does not imply that the intervention is ineffective in preventing these outcomes.Rather, the finding reflects a lack of enough high-quality studies with long enough followup periods to make a determination.These areas merit further research. This review considered only studies that evaluated violent outcomes.Home visiting may also affect other outcomes.Other studies have reported many other desirable outcomes of early home visitation (11,28), including health benefits for premature, low birthweight infants and for disabled and chronically ill children as well as long-term benefits, including reductions in need for public support of visited mothers, particularly single mothers of low socioeconomic status.However, all home visiting programs are not equal.Some are narrowly focused, oriented, for example, only toward improving vaccination coverage (29).Others might influence a broader range of outcomes.Program selection and design should consider the range of options relevant to the particular communities.To meet local objectives, recommendations and other evidence provided in the Community Guide should be used in the context of local information -resource availability; administrative structures; and the economic and social environments of communities, neighborhoods, and health-care systems. In conclusion, this review, along with the accompanying recommendation from the Task Force on Community Preventive Services, should prove a useful and powerful tool for public health policy makers, for program planners and implementers, and for researchers.It may help to secure interest, resources, and commitment for implementing these interventions, and will provide direction and scientific questions for additional empirical research in this area, which will further improve the effectiveness and efficiency of these programs. # Additional Information Regarding the Community Guide In addition to the early childhood home visitation intervention reviewed in this report, reviews have been completed for eight firearms laws (30), and for therapeutic foster care to prevent violence.Reviews of several other violence prevention interventions are pending or under way, including those on the treatment of juveniles as adults in the justice system and on school-based social and emotional skill learning programs. Community Guide reviews are prepared and released as each is completed.Findings from systematic reviews on vaccinepreventable diseases, tobacco-use prevention and reduction, motor vehicle occupant injury, physical activity, diabetes, oral health, and the social environment have already been published.A compilation of systematic reviews will be published in book form in 2004.Additional information regarding the Task Force, the Community Guide, and a list of published articles is available on the Internet at guide.org. # First Reports Evaluating the Effectiveness of Strategies for Preventing Violence: Firearms Laws Findings from the Task Force on Community Preventive Services # Summary During 2000-2002, the Task Force on Community Preventive Services (the Task Force), an independent nonfederal task force, conducted a systematic review of scientific evidence regarding the effectiveness of firearms laws in preventing violence, including violent crimes, suicide, and unintentional injury.The following laws were evaluated: bans on specified firearms or ammunition, restrictions on firearm acquisition, waiting periods for firearm acquisition, firearm registration and licensing of firearm owners, "shall issue" concealed weapon carry laws, child access prevention laws, zero tolerance laws for firearms in schools, and combinations of firearms laws.The Task Force found insufficient evidence to determine the effectiveness of any of the firearms laws or combinations of laws reviewed on violent outcomes. (Note that insufficient evidence to determine effectiveness should not be interpreted as evidence of ineffectiveness.)This report briefly describes how the reviews were conducted, summarizes the Task Force findings, and provides information regarding needs for future research. # Background Although firearms-related- injuries in the United States have declined since 1993, they remained the second leading cause of injury mortality in 2000, the most recent year for which complete data are available (1).Of 28,663 firearms-related deaths in 2000 -an average of 79 per day-16,586 (57.9%) were suicides, 10,801 (37.7%) were homicides, 776 (2.7%) were unintentional, and an additional 500 (1.7%) were legal interventions or of undetermined intent.An estimated 24.3% of the 1,430,693 violent crimes (murder, aggravated assault, rape, and robbery) committed in the United States in 1999 were committed with a firearm (2).In the early 1990s, rates of firearms-related homicide, suicide, and unintentional death in the United States exceeded those of 25 other high-income nations (i.e., 1992 gross national product US $8,356 per capita) for which data are available (3).In 1994, the estimated lifetime medical cost of all firearms injuries in the United States was $2.3 # billion (4).October 3, 2003 Approximately 4.5 million new firearms are sold each year in the United States, including 2 million handguns.In addition, estimates of annual secondhand firearms transactions (i.e., sales, trades, or gifts) range from 2 million to 4.5 million (5,6).Further, an estimated 0.5 million firearms are stolen annually (6).Thus, the total number of firearms transactions could be as high as 9.5 million per year. The 1994 National Survey of the Private Ownership of Firearms (NSPOF), conducted by Chilton Research Services for the Police Foundation, under sponsorship of the National Institute of Justice, indicated that American adults owned approximately 192 million working firearms, an average of one per adult (7).The NSPOF also indicated that firearm ownership was unevenly distributed in the population: only 24.6% of U.S. adults owned a firearm (41.8% of men and 9.0% of women).Another survey (2) found that 41% of adult respondents reported having a firearm in their home in 1994, and 35% did so in 1998.A third survey (8) reported that 35% of homes with children aged <18 years had at least one firearm.Rates of firearm ownership in the United States also exceed those of 14 other nations for which data are available, with the exception of Finland (9). Of the estimated 192 million firearms owned in the United States at the time of the 1994 NSPOF survey, 65 million were handguns; 70 million, rifles; 49 million, shotguns; and the remainder were other guns (7).Among handgun owners, 34.0% kept their guns loaded and unlocked.An estimated 10 million handguns, one sixth of the handguns owned, were regularly carried by their owners, approximately half in the own- # Introduction The independent, nonfederal Task Force on Community Preventive Services (the Task Force) is developing the Guide to Community Preventive Services (the Community Guide) with the support of the U.S. Department of Health and Human Services (DHHS) in collaboration with public and private partners.Although CDC provides staff support to the Task Force for development of the Community Guide, the conclusions presented in this report were developed by the Task Force and are not necessarily the conclusions of DHHS or CDC. This report is one in a series of topics included in the Community Guide, a resource that includes multiple systematic reviews, each focusing on a preventive health topic.A short overview of the process used by the Task Force to select and review evidence and summarize its findings is included in this report.A full report on the findings and additional evidence (including discussions of possible additional benefits, potential harms, existing data problems, research gaps, and directions for future research) will be published in the American Journal of Preventive Medicine. # Methods The Community Guide's methods for conducting systematic reviews and linking evidence to recommendations have been described elsewhere (12).In brief, for each Community Guide topic, a multidisciplinary team (the systematic review development team) conducts a review consisting of the following steps: - developing an approach to organizing, grouping, and selecting the interventions to be reviewed; - systematically searching for and retrieving evidence; - assessing the quality of and summarizing the strength of the body of evidence of effectiveness; - assessing cost and cost-effectiveness evidence, identifying applicability and barriers to implementation (if the effectiveness of the intervention has been established); - summarizing information regarding evidence of other effects; and - identifying and summarizing research gaps.Firearms laws were identified as high-priority interventions for violence prevention review in April 1997 by a group of consultants † representing diverse experience.The group generated a comprehensive list of strategies and created a priority list of interventions for review on the basis of 1) the potential to reduce violence in the U.S. population; 2) the potential benefits of expanding use of seemingly effective, but underutilized, interventions and reducing use of seemingly ineffective, but overutilized, interventions; 3) current interest in this intervention among potential audiences; and d) diversity of intervention types. The interventions included in this review address several of the objectives outlined in Healthy People 2010 (13), the disease prevention and health promotion agenda for the United States.Many of the Healthy People 2010 objectives outlined in Chapter 15, "Injury and Violence Prevention," relate to firearms laws and their proposed effects on violence-related outcomes (Box). To be included in the review of effectiveness, studies had to 1) be a primary evaluation of the selected intervention rather than, for example, a guideline or review; 2) provide information on at least one outcome of interest from the list of violent outcomes preselected by the systematic review development team; 3) be conducted in Established Market Economies § ; and 4) compare outcomes in groups of persons exposed to the intervention with outcomes in groups of persons not exposed or less exposed to the intervention (whether the comparison was concurrent between groups or before-and-after within the same group). Electronic searches for any research published before July 2001 were conducted in MEDLINE, EMBASE, ERIC, National Technical Information Service (NTIS), PsychINFO, Sociological Abstracts, National Criminal Justice Reference Service (NCJRS), Public Affairs Information Service (PAIS), Criminal Justice Index, and Gale Group Legal Research Index. ¶The references listed in all retrieved articles were also reviewed, and specialists on the systematic review development team and elsewhere were consulted to identify additional reports.Journal articles, government reports, books, and book chapters were included in this review. Because the purpose of this review was to assess the effectiveness of firearms laws in preventing violence, studies of firearms laws were reviewed only if they assessed at least one violent outcome.The outcome measures evaluated to determine the effect of each intervention were violent crimes (i.e., murder, aggravated assault, robbery, and rape), suicide, and unintentional firearm injury.Aggravated assault was considered a health-related outcome insofar as it is "an unlawful attack by one person upon another for the purpose of inflicting severe or aggravated bodily injury" (2).Similarly, robbery was considered a health-related outcome insofar as it is "the taking or attempting to take § Established Market Economies as defined by the World Bank are Andorra, Australia, Austria, Belgium, Bermuda, Canada, Channel Islands, Denmark, Faeroe Islands, Finland, France, Germany, Gibraltar, Greece, Greenland # MMWR October 3, 2003 At the June 2002 meeting of the Task Force on Community Preventive Services, new terminology was adopted to reflect the findings of the Task Force.Instead of being referred to as "strongly recommended" and "recommended," such interventions are now referred to as "recommended (strong evidence of effectiveness)" and "recommended (sufficient evidence of effectiveness)," respectively.Similarly, the finding previously referred to as "insufficient evidence" is now more fully stated: "insufficient evidence to determine effectiveness."These changes were made to improve the clarity and the intent of the findings. anything of value from the care, custody, or control of a person or persons by force or threat of force or violence or by putting the victim in fear" (2).For each of the firearms laws, the team developed an analytic framework indicating possible causal links between that intervention and one or more of the predefined outcomes of interest. Each study meeting the inclusion criteria was evaluated with a standardized abstraction form (14) and was assessed for suitability of study design and threats to validity (12).On the basis of the number of threats to validity, studies were characterized as having good, fair, or limited execution.

Results for each outcome of interest were obtained from each study that met the minimum quality criteria.Measures that were adjusted for the effects of potential confounders were used in preference to crude effect measures.If two or more studies of a firearms law overlapped in terms of population, time period, and outcomes studied, the systematic review development team chose the study with the fewest execution flaws and the best design to represent effects of the intervention. A median was calculated as a summary effect measure for each outcome of interest.For bodies of evidence consisting of seven or more studies, an interquartile range was calculated as an index of variability.Unless otherwise noted, the results of each study were represented as a point estimate for the relative change in the violent outcome rate associated with the intervention. The body of evidence of effectiveness was characterized as strong, sufficient, or insufficient on the basis of the number of available studies, the suitability of study designs for evaluating effectiveness, the quality of execution of the studies, the consistency of the results, and the median effect size (12). The Community Guide uses systematic reviews to evaluate the evidence of intervention effectiveness, and the Task Force makes recommendations based on the findings of these reviews.The strength of each recommendation is based on the strength of the evidence of effectiveness (i.e., the Task Force can recommend an intervention on the basis of strong evidence of effectiveness or sufficient evidence of effectiveness ).Other types of evidence can also affect a recommendation.For example, evidence that harms from an intervention outweigh improved outcomes might lead to a recommendation against use of the intervention.If interventions are found to be effective, they are evaluated for cost effectiveness by using economic evaluation guidelines developed for the Community Guide (15).Because none of the firearm laws reviewed was found to have sufficient evidence to draw conclusions regarding their effectiveness, no economic reviews were conducted. A finding of insufficient evidence to determine effectiveness should not be interpreted as evidence of ineffectiveness but rather as an indicator that additional research is needed before an intervention can be evaluated for its effectiveness. # Results The systematic review development team identified 51 studies that evaluated the effects of selected firearms laws on violence and met the inclusion criteria for this review.No study was excluded because of limitations in design or execution.Information on violent outcomes was available in 48 studies, and the remaining three studies, which provided information on counts or proportions of regulated firearms used in crime, were used as supplementary evidence.Several studies examined more than one type of firearm law. Several separate studies evaluated effects of the same law in the same populations during overlapping time periods.Such studies were considered nonindependent, and effect estimates from the best study in the group (as determined by the quality of design and execution and the length of the follow-up period) were chosen to represent the effects of the intervention.The total number of studies for each intervention, and the number of studies that actually contributed effect estimates to the body of evidence, are listed (Table ).More extensive evidence tables will be available at when the full evidence review is published. Evidence was insufficient to determine the effectiveness of any of these laws for the following reasons. - Bans on specified firearms or ammunition.Results of studies of firearms and ammunition bans were inconsistent: certain studies indicated decreases in violence associated with bans, and others indicated increases.Several studies found that the number of banned guns retrieved after a crime declined when bans were enacted, but these studies did not assess violent consequences (16,17).Studies of the 1976 Washington, D.C. handgun ban yielded inconsistent results (18)(19)(20).Bans often include "grandfather" provisions, allowing ownership of an item if it is acquired before the ban, complicating an assessment of causality.Finally, evidence indicated that sales of firearms to be banned might increase in the period before implementation of the bans (e.g., the Assault Weapons Ban of 1994) (21). # Intervention description Prohibit acquisition or possession of certain categories of firearms (e.g., machine guns or assault weapons) or ammunition (e.g., large-capacity magazines).Can also include prohibitions on the manufacture of the specified firearms.Often "grandfather" guns acquired before ban. Prohibit purchase of firearms by persons with specified characteristics thought to indicate high risk of illegal or other harmful use.Restriction characteristics include criminal histories (e.g., felony conviction or indictment, domestic violence restraining order, fugitive of justice, conviction on drug charges), personal histories (e.g., adjudicated to be "mentally defective," illegal immigrant, dishonorable military discharge), or other characteristics (e.g., juvenile). Require that the acquisition of a firearm be delayed for a specified period after application for firearm acquisition is filed.Requirement is usually imposed to allow time for a background check on prospective purchaser or to provide "cooling-off" period for persons at risk of committing suicide or an impulsive crime against others. Record of owner of specified firearms must be created and retained. License or other form of authorization or certification is required for purchase or possession of a firearm. Require issuing of concealed weapon carry permit to all applicants not disqualified by specified criteria.Usually implemented in place of "may issue" laws, in which issuing of a concealed weapon carry permit is discretionary (based on criteria such as perceived need or moral character of applicant). Designed to limit child access to, and use of, firearms kept in homes.Require owners to store firearms locked or unloaded and make the firearm owner liable when children use or threaten to use a household firearm to harm themselves or another. Require that participating schools expel for at least 1 year students found carrying a gun in school.Local modifications possible for individual students. Comprehensive firearm laws that include more than one kind of legislation. Cross-national comparisons examining differences in an existing sum of national firearm laws. Use a derived measure of overall restrictiveness of existing firearm laws a basis for comparison. # Key findings Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in execution of available studies.Studies of Washington, D.C. handgun ban produced conflicting results that could not be resolved.Bans may lead to pre-ban increases in sales of firearms to be banned. Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in design and execution of available studies.Record systems for assessing restriction histories of firearms purchase applicants are lacking, especially for restriction histories other than felony. Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in design and execution of available studies.Apparent reduction in rates of firearms suicide among persons aged >55 years, associated with the interim Brady Law, is attributable to waiting period in the interim law. Evidence insufficient because of small numbers of studies and limitations in the design and execution of available studies. Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in design and execution of available studies. Evidence insufficient because of critical flaws in quality of data used in the majority of studies and limitations in execution of available studies. Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in execution of available studies.Inappropriate outcome measures used in studies (e.g., rates of juvenile victimization rather than perpetration of firearm violence by juveniles). Evidence insufficient because of absence of relevant studies; no studies evaluated violent outcomes of zero-tolerance laws.Possible violent and other harmful consequences of expulsion. Evidence insufficient because of small numbers of independent studies, inconsistent evidence of effectiveness, and limitations in study execution. Evidence insufficient because of small numbers of studies, inconsistent evidence of effectiveness, and limitations in the execution of available studies.Difficult to control confounding. Evidence insufficient because of inconsistent evidence of effectiveness and limitations in execution of available studies.As conducted, index studies would not indicate which laws are effective (or ineffective) in which combinations. MMWR October 3, 2003 † † The term "mentally defective" is a determination by a lawful authority that a person, as a result of marked subnormal intelligence or mental illness, is a danger to self or others, or lacks the mental capacity to manage his or her own affairs.The term also includes a court finding of insanity in a criminal case, incompetence to stand trial, or not guilty by reason of lack of mental responsibility.Source: Bureau of Alcohol Tobacco and Firearms.Federal firearms regulations reference guide.Washington, DC: U.S. Department of the Treasury, Bureau of Alcohol, Tobacco and Firearms, 2000, ATF P 5300.4 (01-00).Available at . - Restrictions on firearm acquisition.The federal government and individual states restrict the acquisition and use of firearms by individuals on the basis of their personal history.Reasons for restriction can include prior felony conviction, conviction of misdemeanor intimate partner violence, drug abuse, adjudication as "mentally defective," † † and other characteristics (e.g., specified young age). The Brady Law ( 22) established national restrictions on acquisition of firearms and ammunition from federal firearms licensees.The interim Brady Law (1994-1998) mandated a 5-day waiting period to allow background checks.The permanent Brady Law, enacted in 1998, eliminated the required waiting period.It normally allows 3 days for a background check, after which, if no evidence of a prohibited characteristic is found, the purchase may proceed (23).Certain states have established additional restrictions, and some require background checks of all firearms transactions, not only those conducted by federal firearms licensees. The permanent Brady Law depends on the National Instant Criminal Background Check System (NICS).However, NICS lacks much of the required background information, particularly on certain restriction categories (23).Efforts to improve the availability of background studies examined the effects of registration and licensing on violent outcomes; the findings were inconsistent. - "Shall issue" concealed weapon carry laws.Shall issue concealed weapon carry laws (shall issue laws) require the issuing of a concealed weapon carry permit to all applicants not disqualified by specified criteria.Shall issue laws are usually implemented in place of "may issue" laws, in which the issuing of a concealed weapon carry permit is discretionary (based on criteria such as the perceived need or moral character of the applicant).A third alternative, total prohibition of the carrying of concealed weapons, was in effect in six states in 2001. The substantial number of studies of shall issue laws largely derives from and responds to one landmark study (28).Many of these studies were considered to be nonindependent because they assessed the same intervention in the same population during similar time periods.A review of the data revealed critical problems, including misclassification of laws, unreliable county-level crime data, and failure to use appropriate denominators for the available numerator crime data (29).Methodological problems, such as failure to adjust for autocorrelation in time series data, were also evident.Results across studies were inconsistent or conceptually implausible.Therefore, evidence was insufficient to determine the effect of shall issue laws on violent outcomes. - Child access prevention laws.Child access prevention (CAP) laws are designed to limit children's access to and use of firearms in homes.The laws require firearms owners to store their firearms locked, unloaded, or both, and make the firearm owners liable when children use a household firearm to threaten or harm themselves or others.In three states with CAP laws (Florida, Connecticut, California), this crime is a felony; in several others it is a misdemeanor. Only three studies examined the effects of CAP laws on violent outcomes, and only one outcome, unintentional firearms deaths, was assessed by all three.Of these, two studies assessed the same states over the same time periods and were therefore nonindependent.The most recent study, which included the most recent states to pass CAP laws and had the longest follow-up time, indicated that the apparent reduction in unintentional firearm deaths associated with CAP laws that carry felony sanctions was statistically significant only in Florida and not in California or Connecticut (30).Overall, too few studies of CAP law effects have been done, and the findings of existing studies were inconsistent.In addition, although CAP laws address juveniles as perpetrators of firearms violence, available studies assessed only juvenile victims of firearms violence.information have been supported by the National Criminal History Improvement Program (24).Approximately 689,000 applications to acquire a firearm (2.3% of 30 million applications) were denied under the Brady Law from its first implementation in 1994 through 2000 (25); the majority of denials were based on the applicant's criminal history.However, denial of an application does not always stop applicants from acquiring firearms through other means. Overall, evaluations of the effects of acquisition restrictions on violent outcomes have produced inconsistent findings: some studies indicated decreases in violence associated with restrictions, and others indicated increases.One study indicated a statistically significant reduction in the rate of suicide by firearms among persons aged >55 years; however, the reduction in suicide by all methods was not statistically significant.Furthermore, this benefit appears to have been a consequence of the waiting period imposed by the interim Brady Law (which has since been dropped in the permanent law) rather than of the law's restrictions on the basis of the purchaser's characteristics (26). - Waiting periods for firearm acquisition.Waiting periods for firearm acquisition require a specified delay between application for and acquisition of a firearm.Waiting periods have been established by the federal government and by states to allow time to check the applicant's background or to provide a "cooling-off " period for persons at risk of committing suicide or impulsive acts against others.Studies of the effects of waiting periods on violent outcomes yielded inconsistent results: some indicated a decrease in violent outcome associated with the delay and others indicated an increase.As noted previously, one study of the interim Brady Law indicated a statistically significant reduction in firearms suicide among persons aged >55 years associated with the waiting period requirement of the interim law.Several studies suggested a partial "substitution effect" for suicide (i.e., decreases in firearms suicide are accompanied by smaller increases in suicide by other means) (26). -Firearm registration and licensing of owners.Registration requires that a record of the owner of specified firearms be created and retained (27).At the national level, the Firearm Ownership Protection Act of 1986 specifically precludes the federal government from establishing and maintaining a registry of firearms and their owners. Licensing requires an individual to obtain a license or other form of authorization or certification to purchase or possess a firearm (27) No study reviewed attempted to evaluate the effects of zero tolerance laws on violence in schools, nor did any measure the effect of the Gun-Free Schools Act on carrying of firearms in schools.One cross-sectional study, however, assessed the effectiveness of metal detector programs in reducing the carrying of firearms in schools (33).Although firearms detection is not explicitly required in the Gun-Free Schools Act, the effectiveness of the law may depend on the ability to detect firearms by various means.The study reported that schools with and without metal detectors did not differ in rates of threatening, fights, or carrying of firearms outside of school, but the rate of carrying firearms to, from, or in schools with detection programs was half that of schools without such programs.The effectiveness of zero tolerance laws in preventing violence cannot be assessed because appropriate evidence was not available.A further concern is that "street" expulsion might result in increased violence and other problems among expelled students. - Combinations of firearms laws.Governmental jurisdictions (e.g., states or nations) can be characterized by the degree to which they regulate firearm possession and use.Whether a greater degree of firearms regulation in a jurisdiction results in a reduction of the amount of violence in that jurisdiction still needs to be determined.Three kinds of evidence were reviewed for this study: 1) studies of the effects of comprehensive national laws within nations; 2) international comparisons of comprehensive laws; and 3) studies in which law types within jurisdictions (i.e., regulation of specific, defined aspects of firearm acquisition and use) were categorized and counted, and counts compared with rates of specific forms of violence within the same jurisdictions.The latter type are referred to here as index studies because they developed indices of the degree of regu-lation.In drawing conclusions about law combinations, findings from the three approaches were considered.On the basis of national law assessments (the Gun Control Act of 1968 in the United States and the Criminal Law Amendment Act of 1977 in Canada), international comparisons (between the United States and Canada), and index studies (all conducted within the United States), available evidence was insufficient to determine whether the degree of firearms regulation was associated with decreased (or increased) violence.The findings were inconsistent and most studies were methodologically inadequate to allow conclusions about causal effects.Moreover, as conducted, index studies, even if consistent, would not allow specification of which laws to implement.In summary, the Task Force found insufficient evidence to determine the effectiveness of any of the firearms laws reviewed for preventing violence.References and key findings are listed (Table ). # Research Needs The Task Force's review of firearms laws found insufficient evidence to determine whether the laws reviewed reduce (or increase) specific violent outcomes (Table ).Much existing research suffers from problems with data, analytic methods, or both.Further high-quality research is required to establish the relationship between firearms laws and violent outcomes.Potential areas for further investigation will be discussed in detail in an upcoming article in the American Journal of Preventive Medicine. Several recurring problems were associated with the studies that evaluated the effects of firearms laws on violent outcomes: - The assessment or "measurement" of laws and their provisions has been noted as a problem in certain studies and may occur in others as well.

As with all interventions, assessing the degree of implementation of laws may be important in evaluating their effects; yet this has not been a part of law evaluations.Better information regarding implementation might allow more sophisticated explanation of inconsistent effects. -Several facets of the measurement of violent outcomes have been problematic.Crime data are substantially underreported and, at the county level, may not be sufficiently reliable for research purposes (29).In addition, selected outcome measures are often not directly relevant to the law being assessed (e.g., the evaluation of child access prevention laws by measurement of juvenile victims and the evaluation of shall issue laws by the measurement of crimes occurring in the home ).Another problem is that crime data are often aggregated, so that the circumstances of violent events cannot be determined.Aggregated data hinder the assessment of the ways in which laws might and might not work.Individual record data systems currently being implemented -the National Incident-Based Reporting System of the FBI and the National Violent Death Reporting System of CDC and partners -might resolve some of these difficulties and greatly facilitate the evaluation of firearms laws. -The measurement of potential confounders has been a challenge in evaluating the effects of firearms laws.Potentially important confounders include socioeconomic status and poverty, drug cycles, gang activity, and the intensity of law enforcement.Measuring these phenomena is difficult and requisite data are often not available.In addition, endogeneity (i.e., the presence of common characteristics, such as crime counts, as both dependent and independent variables in equations) has been a problem in firearms law evaluations. -Study designs and analytic techniques used in firearms law evaluations have been problematic.Rates of violence may affect the passage of firearms laws and firearms laws may then affect rates of violence; knowledge of temporal sequence is thus critical in separating cause and effect, and cross-sectional studies are at a disadvantage.Time series analyses of firearms laws and violent outcomes have not consistently adjusted for temporal and spatial autocorrelation, and thus may have exaggerated hypothesized associations.Additionally, firearms studies often fail to note potential biases associated with measurement of outcomes not directly associated with the law in question (e.g., using victims rather than agents of violence in the assessment of CAP laws).In conclusion, the application of imperfect methods to imperfect data has commonly resulted in inconsistent and otherwise insufficient evidence with which to determine the effectiveness of firearms laws in modifying violent outcomes.This is a critical period for focused research on the effectiveness of firearms laws in reducing violence in the United States.International comparisons indicate that the United States is an outlier among developed, industrialized nations in rates of firearms violence (2).Widespread public concern exists about criminal firearms violence, firearms violence among youth, and other forms of firearms violence, and popular support for many firearms laws is evident (34,35).Although the Task Force's systematic review of the existing literature on firearms laws found insufficient evidence to determine the effectiveness of these laws in preventing violence, research should continue on the effectiveness of firearms laws as one approach to the prevention or reduction of firearms violence and firearms injury.Evaluation should include not only the laws reviewed here, but the broad array of other federal, state, and local laws. # Additional Information Regarding the Community Guide In addition to the firearms laws reviewed in this report, reviews for the Community Guide have been completed on the effectiveness of preventing violence through early childhood home visitation (36) and therapeutic foster care (to be published in the near future).Reviews of several other violence prevention interventions are pending or under way, including the effects of school-based, social and emotional skill learning programs, and the treatment of juveniles as adults in the justice system. Community Guide topics are prepared and released as each is completed.The findings from systematic reviews on vaccinepreventable diseases, tobacco use prevention and reduction, motor vehicle occupant injury, physical activity, diabetes, oral health, and the social environment have been published.A compilation of systematic reviews will be published in book form in 2004.Additional information regarding the Task Force, the Community Guide, and a list of published articles is available at .

Individual states have different names for drinking water advisories depending on the situation.Advisories are frequently called "notices," "alerts," and "orders."Advisories can include information about preparing food, beverages, or ice; dishwashing; and hygiene, such as brushing teeth, bathing, and flushing toilets.Public encouraged to take immediate action Severity of situation (lesser) (greater)Address potential call center issues in advisory protocols.Considerations include: - Are there enough phone lines# Drinking Water Advisory Communication Toolbox Table 1: # List of Figures Our goal is to provide a protocol and practical toolbox for communicating with stakeholders and the public about water advisories that is based upon research and identified practices.The project focuses on water systems and addresses the range of situations that generate drinking water advisories.This project was a collaborative effort among the U.S. Centers for Disease Control and Prevention (CDC), the U.S. Environmental Protection Agency (EPA), the American Water Works Association (AWWA), the Association of State and Territorial Health Officials (ASTHO), the Association of State Drinking Water Administrators (ASDWA), and the National Environmental Health Association (NEHA). A technical workgroup of public health and drinking water agencies and drinking water system experts advised and guided the project.The project also engaged a broad cross-section of relevant stakeholders and technical experts including local government officials and emergency response and hazard communication experts.This toolbox was reviewed by EPA and state primacy agencies.Every effort was made to ensure that the toolbox complies with the Public Notification Rule when necessary. More than 500 documents, protocols, regulations, and other resources related to the issuing of drinking water advisories were compiled.Nearly 100 interviews were conducted with water systems, primacy agencies, and local public health departments in the United States and Canada.These findings revealed: - Advice to the public varies widely from state to state and community to community. - Advisories are a common occurrence in some states and a rare event in others. - Major events or disasters were the primary reasons for collaboration between drinking water systems and health departments. - Terminology for advisories is inconsistent. - Templates and advisory content are difficult to change or adapt to specific audiences or needs. - The EPA Public Notification Handbook is the primary information source for drinking water advisories. - Agency responsibilities for communicating with institutions, such as hospitals, schools, and restaurants, are highly variable. - Good relationships between water systems and local public health departments are often dependent on established relationships between individuals. - Local health departments may lack the resources or expertise to address drinking water issues. - Local health departments are willing to be consulted by water systems when requested. # About the Drinking Water Advisory Communication Toolbox # Introduction - Overview - Why Are Drinking Water Advisories Issued? - Small Water Systems The Drinking Water Advisory Communication Toolbox provides information on how to plan for, develop, implement, and evaluate drinking water advisories.The approach presented recognizes the differences in scope, scale, and severity of situations that trigger advisories-a main break, a hurricane, a drop in pressure, or intentional contamination.These differences affect the types of tools, planning, and communication used by drinking water systems. This toolbox includes instructions on how to prepare before an event, what to do during an event, templates and tools to use, and recommendations for follow-up actions and assessments after an event. The purpose of the toolbox is to enable water systems to communicate effectively with partners and the public in order to protect public health. Figure 1 shows the process for preparing for, issuing, and following up after a drinking water advisory.Each toolbox section includes a checklist of steps.Not every step applies in all circumstances.Each section has a set of tools that applies to its content.The tools can be adapted by water systems to fit their needs. # Overview Before an Event # Interagency Communication - Communication Planning # Testing During an Event # Icon Key # Tools and Templates # Resources This toolbox complements the EPA's Revised Public Notification Handbook. Water systems and state or local agencies issue drinking water advisories when they believe water quality is or may be compromised.Advisories tell individuals, schools, hospitals, businesses, and others about the situation and how to take immediate action. Drinking water advisories: - Provide information-An advisory may be issued when consumers need to receive important information but do not need to take any action.For example, a water system may issue an advisory to inform households about seasonal changes in water taste. - Encourage preparedness-Advisories may help customers prepare for planned disruption in service or anticipated water quality threats.Advisories may affect a small area, such as during distribution system construction or repair.Advisories also can urge customers to prepare for a large area event, such as an approaching hurricane.This type of advisory alerts people to watch or listen for more information. - Recommend action-Advisories may tell customers to take specific actions, such as to boil water or use bottled water.These advisories may be issued as a precaution or in response to a waterborne disease outbreak. - Meet public notification requirements-Advisories are required by the Safe Drinking Water Act (SDWA) when specific circumstances exist.The SDWA requires communication with customers when the water system does not comply with a regulation. # Precautionary and Mandatory Advisories State and federal regulations specify when drinking water advisories are required.In other instances, water systems or the local public health department may issue precautionary advisories at their discretion. - Precautionary advisories are issued as a protective measure. - Mandatory advisories are issued as required by state and federal law to protect public health. # Main Types of Advisories - Informational-Communicate planned or anticipated changes in water quality and provide advice on appropriate action. - Boil Water-Tells customers to boil water before use.Most common type of advisory.They may be precautionary if there is a potential threat to the drinking water supply, or they may be mandatory as required by state and federal regulations.Boil water advisories typically are issued because of concern about microbial contamination. - Do Not Drink-Tells customers to use an alternative source of water.Do Not Drink advisories are typically issued for chemical contamination. - Do Not Use-Warns customers not to use tap water for any purpose, including flushing toilets and bathing.Do Not Use advisories are typically used only in cases of known microbial, chemical, or radiological contamination when any contact, even with the skin, lungs, or eyes, can be dangerous.Such advisories are rare because of the risks associated with the lack of water for sanitation and fire protection. Figure 2 shows the range of situations that might trigger a drinking water advisory and the type of advisory that would be issued in each situation. Consult with state primacy agency when developing drinking water advisory protocols. # Informational Boil Water Do Not Drink Do Not Use Occasional Used for a range of purposes: - Failure to meet drinking water standards with non-acute endpoints or administrative requirements - Efforts to build rapport with customers - Customer education to increase preparedness for emergencies # Water conservation messaging # Frequent Used for potential or demonstrated microbial contamination: - Low/loss of pressure - Tier 1 microbial violation (e.g., high turbidity, positive E. coli) - Natural disasters (e.g., flooding, hurricanes) - Vandalism # Infrequent Used for potential or demonstrated contamination that could cause acute health effects: - Nitrite/nitrate MCL violation* - Chemical overfeed into the water supply # Rare Used with caution due to risk associated with lack of sanitation and fire protection: - Microbial, chemical, or radiological contamination in which any contact is hazardous to public health - Error in treatment leading to water with a high or low pH that could lead to chemical burns Note: These are examples of potential reasons to issue an advisory; this is not intended to be a comprehensive list.Consult your primacy agency for more information. # Figure 2: Range of Situations for Drinking Water Advisories Because small water systems often have less capacity to implement advisory protocols than larger systems, this toolbox also was designed and tested with small water systems in mind. Implementing the actions described in this toolbox generally should not require outside support from consultants or others.However, building an effective network by collaborating with other public sector partners and community organizations will help small systems succeed in their efforts. # Suggestions for Small Systems - Identify and prioritize specific tools or sections from this toolbox to use. - Incorporate water advisory protocol planning into regular activities, such as sanitary surveys and updating emergency response plans (ERPs). - Build water advisory protocols into regular communication, such as customer updates. - Partner with local public health authorities and neighboring water systems # Small Water Systems # Section 1: Before an Event-Preparing for an Advisory To issue a drinking water advisory, a water system must act quickly and in close coordination within its organization and among its partner agencies.Preparation is essential.Most of the work can be done in advance of a planned or unplanned event. Pre-event planning allows a water system to design advisories and issue them through a predetermined process.Advance preparation speeds delivery of accurate and useful information to affected customers.This information can be reused for future events. # Overview Icon Key # Organizing for Drinking Water Advisories Conduct an assessment of assets and resources needed to issue a drinking water advisory. Review state regulations and guidance for public notification and the EPA Revised Public Notification Handbook. Consult your organization's strategic communication plan. Plan for media activities. Integrate communications as part of your emergency response standard operating procedures (SOPs). # Collaborating with Partners Identify partners and critical and wholesale customers. Record and regularly update contact information. Develop a communication network of public agencies and private entities for collaboration during an advisory. Meet and discuss protocols and resources for drinking water advisories with agency partners and community organizations. Plan and conduct regular communication among partner agencies and private organizations. # Notes # Developing a Message Collaborate with your communication network to develop messages for various advisories and specific audiences. Translate and format messages for special populations (e.g., non-English speakers, visually impaired). # Conducting Exercises Refer to the National Incident Management System (NIMS) and the Homeland Security Exercise and Evaluation Program (HSEEP). Plan exercises. Conduct exercises. Debrief after exercises and incorporate appropriate changes in protocols. # Conduct an Assessment Understanding your system's operations, vulnerabilities, stakeholders, partners, and audiences is an important first step in your planning efforts.Begin by evaluating the following: - Existing relationships among partners, including public health, public safety, schools, businesses, and local government. See Table 1 for examples. - Internal and external audiences and stakeholders. - Information needs of different audiences. - Existing communication plans and resources (e.g., bill inserts, Consumer Confidence Reports, media contacts). - Skills, technologies, staff, time, and money available to support an exchange of information with target audiences and agencies.See Table 1 for examples. - Resources for public outreach, such as Reverse 911 or e-mail alerts. - Existing requirements set by state or local agencies or by the water system's governing body. - Threats and infrastructure vulnerabilities. - Emergency response plans (ERPs). # Gap Analysis Once you've conducted the assessment, it is important to identify the gaps and additional resources needed to meet responsibilities for issuing drinking water advisories. # Organizing for Drinking Water Advisories # Considerations When planning for a drinking water advisory, consider: - A range of event scenarios - Normal and challenging operating conditions - Time of day, day of the week, and season of the year # Review Regulations and Guidance # Primacy Agency Each state that has primacy has specific regulations for public notification and information sharing.Local public health and water systems personnel need information for a 24/7 point of contact at the primacy agency. # Federal Guidance There is federal guidance for developing public notices under the Safe Drinking Water Act (SDWA).Resources are also available from the Environmental Protection Agency (EPA): - PNiWriter-A web-based tool for preparing public notices. - Revised Public Notification Handbook-EPA guidance explaining regulatory requirements. # Know Your Primacy Agency # Consult Strategic Communication Plan A strategic communication plan is the foundation for decision-making and resource allocation, both ongoing and in times of crisis. A strategic communication plan helps a water system prepare to issue a drinking water advisory by identifying ahead of time: - Audiences and stakeholders. - Critical issues for the water system (e.g., risk, safety, quality, infrastructure). - Points of integration for operations and communication SOPs. - Communication objectives (e.g., information, preparedness). - Strategies to accomplish objectives. - Actions required to carry out the strategies. See Information for Communication Planning for more information. # Effective Risk Communication Drinking water advisories are a form of risk communication. The protocols for issuing an advisory must effectively describe: - When to distribute an advisory (and when not to). - What information to provide. - Who is(are) the specific audience(s) for that event (including susceptible populations). - How to recognize and communicate the conclusion of the event. - Where to distribute messages. - What actions must be taken. - Why these actions must be taken. - For more information on effective risk communication, see Appendix B: Online Resources, Risk Communication. # Where to Find Help If your water system does not have a strategic communication plan, see Appendix B: Online Resources, Risk Communication for more information that may be helpful in developing one. # Plan for Media Activities Successful advisories rely on multiple types of communication.Door hangers, websites, automated messages, and other methods of communication must be combined for an effective drinking water advisory.The media is a primary channel for public notification and is critical to issuing an advisory. Planning for media activities can improve implementation of the advisory.Scope, scale, and severity determine the level of media involvement-the larger the event, the larger the media effort.Factors to consider include the following: - Timing: Consider the operations of your local media.Many media outlets are not able to respond on weekends or after hours.Contact local media outlets to understand their staffing, hours, or other limitations.Plan appropriately for media outlets and communication channels.For example, if an advisory is issued during business hours or commuting times, radio reaches homes, offices, and cars. - Audiences: If an advisory covers a wide area, use a media release to multiple outlets.Smaller areas may call for use of specific media channels as well as other methods of communication.Audiences with special needs, such as a large population of people who speak little or no English, are part of the decisions about media, including ethnic media.See the Communicating with Susceptible Populations Worksheet and Appendix B: Online Resources, Risk Communication. - Channels: Identify the media outlets that cover specific areas of the water system service area and the region.In rural areas, television news may come out of a large urban area far away.Partners and their communication networks will have additional information about communication channels.Identify criteria on which to prioritize media outlets based on the scope, scale, and severity of the situation.For example, if an advisory is issued during working hours, radio, e-mails, and news websites may be the most immediate and viable outlets to use to distribute the message to the working public. # Media Messages: Use the Message Mapping Template and Sample Message Map or the Single Overriding Communication Objectives (SOCO) Worksheet to prepare press releases and statement templates specific to the water system and different scenarios.These materials can be generalized # Tip Ask media outlets about their timing.How long will it take them to post and announce information on websites and announce on television?Also ask how they would use maps and graphics to show the advisory area. # Small System Note If a press list or wire service is not available, work with partners and local government to set up access for communicating advisories to the media and put into electronic or paper formats.Insert the prepared materials into emergency response plans (ERPs) and protocols. - Approval: Note the procedures on how media materials will be reviewed and who will approve them.Work with partners in the communication network and understand their approval process. - Other Information: Include external sources of additional information in media materials.Contact names and numbers for primacy agencies and local public health departments are good sources for reporters.Links to primacy agencies and health departments can be added to media websites to help answer customer questions.Work with partners to identify additional information sources.See Appendix B: Online Resources, Risk Communication. # Designate and Train Spokespersons The spokesperson's role is to communicate directly with media through briefings and interviews and to interact with the public.Designate a primary and backup spokesperson during planning activities.The spokesperson may be the water system's Public Information Officer (PIO), a manager assigned to communication, or someone within the communication network, such as a local public health department representative.The spokesperson is someone in authority who is honest, credible, competent, accessible, and sensitive to public concerns.Use the Spokesperson Assessment Tool. The spokesperson must be ready to interpret scientific and technical information into clear language and must understand the water system's operations.Professional training in media management, effective listening, and handling sensitive situations is helpful in preparing a spokesperson to be ready to meet the media and the public at any time. # Integrate Communication into Emergency Response and SOPs SOPs must be clear and allow users to take actions based on the information they will have at the time.SOPs should establish clear chains of command and communication so that authorized personnel can make situation-specific decisions.SOPs may include the following: - Purpose: Objective of the SOP (e.g., delineation of authority, roles, and procedures). - Scope: People involved, and the authority and responsibilities they have. -

Communication Structure: Organizational chart that demonstrates levels of command and communication linkages. # Notes - Protocols: Procedures for action within the SOP's purpose. - Training: Requirement(s) and schedule. - Exercising: Procedures and schedule. - Oversight/Update: Person(s) responsible for assuring compliance with and maintenance of SOP. # Customer Call Center Call centers and customer service (CS) staff are on the front lines during an advisory.Call centers must have the resources to respond to customers above and beyond normal operations and hours.Information provided through the call center must be accurate, timely, and consistent. The actions described below apply to local government call lines such as 411, community lines such as 211, or other agencies that may respond to an advisory. - Briefings: Meet with call center and CS staff before issuing the advisory and provide essential information on the scope, scale, and severity of the advisory. - Scripts: Provide scripts to call center and CS staff developed with essential information and frequently asked questions (FAQs). - Updates: Meet with call center and CS staff to check for adequate staffing and customer concerns.Add and revise information in scripts as needed. - Resources: Ensure enough phone lines and staff for the scope and scale of the advisory.Staff will need current information and referral contacts. - Debriefing: Include call center and CS staff in the advisory debriefing to identify communication activities and resources. - Are other phone lines available if they are needed? - Are off-site phone lines or call centers available? - Is there a backup plan if phone lines are not available or power is out during an emergency response? - Are there enough people to staff the call center 24/7, if needed? # Identify Partners Partners are simply any organization or agency that can help you plan, develop, and distribute messages.Having a network of agencies and organizations can help advisories to be more effective and timely. To identify partners, start with public agencies, especially those focused on local public health.Agencies and organizations to consider include the following: - Drinking water primacy agency. - Local and state public health departments. - Consecutive, wholesale, and neighboring water systems. - Critical and priority customers, including hospitals and businesses. - Emergency management, public works, public safety, social services, and other government agencies. - Community organizations. See the Critical Customer Checklist for more information. Table 1 provides examples of target audiences and partner organizations and agencies. # Collaborating with Partners # Key Questions for Collaboration with Partners - Who needs to know? - Who is responsible for coordinating communication? - Who makes decisions related to advisories? - Who needs specific types of information, including technical information? - What are the procedures to inform public officials? - What are partners' capacities for outreach? # Public Health: A Key Partner Developing a working relationship with local and state public health authorities can help water systems identify community organizations, develop specific messages and materials, and work through issues like translation.Working with the public health officer can put the risk of illness into perspective for public outreach. Public health departments at the local, regional, and/or state levels work with susceptible populations and critical customers such as: - Hospitals and medical facilities. - Health care providers (HCPs), physicians, pharmacists, home health nurses. - People who are elderly, low income, and homebound. - Schools and childcare providers. - Pregnant women and parents of young children. - Food establishments. Include public health departments in planning and discussions about advisories.Since in many cases they license these establishments, they can help with notifying these groups and developing specific messages.This allows water systems to focus on their core responsibilities.Local public health can assist with outreach through contact lists, websites, and newsletters. See Communicating with Susceptible Populations Worksheet. Planning before an advisory is crucial to understanding the capacity of local public health departments to participate in a communication network.Formalized agreements, such as a memorandum of understanding (MOU), will clearly define capacity and responsibilities for both the health department and the water system. Public health codes may have different requirements for the various types of establishments that prepare or process food, such as restaurants, community kitchens, grocery stores, and cafeterias.Knowing these codes for each locality will help water systems work with critical customers. For more information about public health and outreach, refer to the guidance for the Lead and Copper Rule (LCR).See Appendix B: Online Resources, Safe Drinking Water Act. # Public Health Capacity Capacity is the ability to respond to a situation with resources such as staff, materials, and expertise.Local, regional, and state public health departments vary greatly in their ability to support activities around drinking water advisories. # Public Health and Critical Customers Local public health departments often license food establishments and childcare facilities.They are good resources for contact information. # Record Contact Information Collect and record the contact information of each partner in a list or database.Include name, phone numbers, postal and e-mail addresses, after-hours contact information, and social media information. (The Information for Communication Planning and Point of Contact Template will help with this activity.)Be sure to verify and update all contact information on a regularly scheduled basis. # Develop a Communication Network Water systems generally are responsible for issuing advisories.However, timely, effective, and extensive outreach simply cannot be done by one entity.Water systems must work collaboratively with public health and other partners to get the job done effectively.Some communities have an established communication network, usually coordinated around emergency management.If there is a communication network in your community, learn how to become a part of it.If there is no such network, develop one. # Collaborations for Reaching Susceptible Populations A key element of effective communication planning is to consider populations that can be defined as a group with common characteristics that make them a susceptible population.For a drinking water advisory, water systems and public health agencies need to communicate with three specific susceptible populations: 1.Persons with communication needs, including low literacy levels, limited English proficiency, cognitive disabilities, and hearing or vision impairments. 2.Persons with medical needs that make them sensitive to water quality issues, such as babies, young children, pregnant women, and people who are immunocompromised, elderly, or on dialysis. 3.Persons with low income or who may lack the resources to act on information in a drinking water advisory or the awareness of a possible threat to their health and their family's well-being. For more information, see the Communicating with Susceptible Populations Worksheet. # Did you know? # Communication Network Advance collaboration, communication, and cooperation with other public agencies and private organizations before an actual event provides the opportunity to: - Determine existing resources. - Distribute advisories quickly and effectively. - Develop protocols to assure coordinated, consistent messaging during an advisory. - Share the communication tasks amongst partners. Figure 3 shows how creating a local network can extend an agency's outreach capacity. # Meet and Discuss Protocols and Resources Schedule a meeting with partners to discuss how collaboration can improve drinking water advisory communication.Determine where and when you will meet and for how long.Set a brief agenda that includes communication protocols within the network and resources (translation services, other contact information, websites) that are available for message distribution. # Plan and Conduct Regular Communication Keep partners engaged through regular communication within the network.Send copies of meeting notes.At least four times a year, send e-mails or make phone calls to ask partners about: - Additional information they may want to know; - Their suggestions for activities, such as participating in an exercise; and - Other organizations that can be invited into the network. Plan meetings to address other issues that network members may have in common. # Collaborate with Your Communication Network Drinking water advisories are issued in response to a specific event or situation.Communication materials can be prepared in advance by collaborating with your partners.The Essential Information list outlines the questions and information that a drinking water advisory must address. # Message Development Tools and templates that can help guide pre-event message development include: - Worksheets: # Developing a Message # What's a Message? Information a specific audience MOST needs or wants to know. # Essential Information # Health Literacy Health literacy is the ability to receive, understand, and act on basic health information needed to make good decisions.Nine out of 10 people in the United States have limited health literacy-regardless of their education levels.Since advisories require customers to understand a message and take action, health literacy is an important factor for messages and materials. A first step to ensuring that your advisory can be easily understood by most audiences is to check the readability and grade level of the advisory content.For a general audience, the grade level should be between 5th and 8th grades.Word-processing programs can provide information about a document's readability.If you are not sure how to check for readability, go to the "Help" section on your word-processing program and search for the term "readability. " For more information on health literacy guidelines, see Appendix B: Online Resources, Health Literacy. # Translate and Format Messages Advisories need to be translated to reach many customers.Consult with local government to identify the main languages in the service area.Public health departments are a very good resource.Many states and local governments have programs and resources specifically for translation, including sign language and Braille. # Writing Messages Provide the public with a clear concise advisory by: - Limiting messages # Plan Exercises Preparation for a drinking water advisory entails the consideration of a range of situations relevant to the water system and its community so that: - Pertinent information is compiled and evaluated to support sound decisions. - Credibility with customers is maintained through coordination with state and local agencies. - Public outreach is effective. # Conduct Exercises A communication network for issuing drinking water advisories must be tested in advance to determine if it works and where gaps in outreach remain.Testing the network can prevent illness and even save lives during a real drinking water advisory event.Exercises are one way to test the network. - Seminars, workshops, tabletop exercises, games, drills, functional exercises, and full-scale exercises are terms for various types of practice sessions based on a scenario.A scenario could include developing messages and testing the dissemination of an advisory. - Larger events can include other agencies and can evaluate collaboration. - Exercises can be scaled to the size of an advisory and to community needs. # Exercise Plan Numerous resources and opportunities exist for exercises.While most of these resources are associated with preparedness and security, they can be used for the full range of advisories.All-hazards planning can incorporate advisory scenarios.After action reports, comments, and observations are used to revise communication and operations protocols. # Exercise Basics Exercises come in many sizes and creating them can seem complex.Water systems have multiple opportunities for exercises.Both small exercises limited to the water system or water sector and larger drills and exercises at the community and state level are important in community planning.These exercises help water systems connect with public health, emergency management, and other sectors to build relationships and networks in preparation for advisories. Exercise resources in this Toolbox give some basic tools for water systems to create and conduct their own drinking water advisory exercises.These exercises can be scaled for water system staff and other partners, such as public health.See Appendix B: Online Resources, Exercise Planning and Preparedness. - Design a scenario: Scenarios can be based on an actual advisory or can test a new protocol.The scenario should unfold in stages; participants act on one decision point or action before moving to the next. # Did You Know? Exercises can be for one water system or multiple systems and partners. # Communicating with Susceptible Populations Worksheet # PURPOSE Advisories and risk communication plans must consider the needs of specific populations who may be sensitive to water quality issues or who have communication barriers, such as limited English proficiency or limited vision. The advisory network is critical for reaching these populations.Regulations and public expectations for outreach require collaboration with public health departments, other local agencies, including schools, and community organizations. # DIRECTIONS Use the contact list or database to identify, list, and note contacts for public health, local government agencies, and community organizations to help with outreach to susceptible populations. - Complete this form with public health, local agencies, and community partners. - Include responsibilities and a time frame for developing materials and taking actions.Review the Lead and Copper Rule (LCR) Guidance (see Appendix B: Online Resources, Susceptible Populations ). - Include completed contact lists in emergency response plans (ERPs) and standard operating procedures (SOPs). - Adapt them to reflect specific needs in a community.Some strategies may work for several populations.Include a schedule for updates.Add identified facilities to the water system's critical customer list. # Low Literacy Encourage television news stations to announce advisory and contact phone numbers in addition to posting them on screen.Follow up with press releases. Use radio to distribute information.Radio is a key accessible source of information. Identify and coordinate with local organizations that serve low literacy populations and can help disseminate drinking water advisories in appropriate formats. # Limited English Proficiency Identify languages widely spoken in the area.See www.mla.org/map or www.census.gov. Determine local government and agency translation services and providers. Consider contracting for professional translation services. Work with public health, local government, and schools to identify, coordinate, and contract with skilled translators in the community. Use ethnic media outlets. List resources, specific messages, and materials needed to communicate with this population group. # Blind or Visually Impaired Work with social services and local government to identify organizations and communication options that serve people who are blind or visually impaired.Consider how a boil water advisory could be tailored for this audience. Use radio to distribute information.Radio is a key accessible source of information. Encourage television stations to announce advisories and contact numbers. Identify formats and tools to make written materials and web pages accessible for this audience. List resources, specific messages, and materials needed to communicate with this population group. # Communicating with Susceptible Populations Worksheet, continued # Deaf or Hard of Hearing Coordinate with local government, schools, and other agencies on policies for interpretation and resources. Encourage television news stations to broadcast all drinking water advisory information in open caption format and in their on-screen scrolls. Identify, coordinate, and contract with a sign language interpreter for news conferences in public forums and other events. Use automated messages in text and e-mail formats.They are a good method of distribution for this audience. Check with water system and local government on capacity to handle calls through Video Relay Service. List resources, specific messages, and materials needed to communicate with this population group. # Older Adults and Frail Elderly Work with public health, local government agencies, and community organizations to identify nursing homes, agencies, and organizations that assist older adults to help disseminate drinking water advisory information. Design messages with a clear alternative to boiling water.Boiling water may not be an option for this population. Identify resources, such as home health care, to help older adults and the elderly with support services during an emergency. Add meal delivery services, such as Meals on Wheels, to critical customer lists. List resources, specific messages, and materials needed to communicate with this population group. # Communicating with Susceptible Populations Worksheet, continued Children Identify and coordinate with local health departments, school districts, pediatrician offices and clinics, and other agencies to disseminate drinking water advisory information. Target materials and messages to parents and teachers.Visual cues, such as posters or covering water fountains, will assist this group. List resources, specific messages, and materials needed to communicate with this population group. # Pregnant Women Identify and coordinate with local health departments, health clinics, hospitals, other health care facilities, obstetrician offices, and schools to disseminate drinking water advisory information relevant to pregnant women. List resources, specific messages, and materials needed to communicate with this population group. # Physically and Mentally Impaired Work with public health and local government agencies to identify community organizations, such as independent living facilities and home health care, that assist people with physical and mental impairments to help disseminate drinking water advisories. Consider targeting messages both to care providers and to individuals. List resources, specific messages, and materials needed to communicate with this population group. # Communicating with Susceptible Populations Worksheet, continued Homeless Identify locations where drinking water advisories can be posted (e.g., libraries, shelters, soup kitchens). Add homeless shelters and meal centers/food banks to critical customer lists. Design messages with a clear alternative to boiling water.Boiling water may not be an option for this population. List resources, specific messages, and materials needed to communicate with this population group. # People with Compromised Immune Systems Work with the local public health department to identify and coordinate with medical facilities, health care providers and organizations that serve people with compromised immune systems to disseminate drinking water advisories. Design messages with a clear alternative to boiling water.Boiling water may not be an option for this population.This information is for Tier 1 Public Notices.For a waterborne disease outbreak, consult with local and state public health authorities to adapt the information. # DIRECTIONS - Brackets indicate places to insert specific information, such as the water system name, health department information, or the contaminant. - Limit fact sheets for customers to one page front and back. - Spanish versions are available for selected Q&As on pages 61-63 and 70-71. - Refer to the fact sheets on pages 51-76 for additional topics.

Uses include: - Briefing materials for public health departments and other partners # Quick Reference Facts # PURPOSE: This is an easy-to-use, quick reference tool for customers. # DIRECTIONS: Use this information in fact sheets and on websites; adapt as necessary to suit the type of advisory (e.g., Boil Water, Do Not Drink, Do Not Use) and primacy agency guidance.Be sure to provide links to additional information or guidance.This information is for Tier 1 Public Notices.For a waterborne disease outbreak, consult with local and state public health authorities to adapt the information. # DIRECTIONS - Brackets indicate places to insert specific information, such as the water system name, health department information, or the contaminant. - Limit fact sheets for customers to one page front and back. - Refer to the fact sheets from the "Tools and Templates" in Section 1 and Section 2 of this toolbox for additional topics. Use the Q&As to develop scripts or fact sheets for water system staff, especially customer service and field crews.Uses include - Briefing materials for public health departments and other partners. - Media kits and updates. - Customer fact sheets. - Websites and widgets. # Boiling Water How do I boil my water during an advisory? - Fill a pot with water. - Heat the water until bubbles come from the bottom of the pot to the top. - Once the water reaches a rolling boil, let it boil for 1 minute. - Turn off the heat source and let the water cool. - Pour water into a clean container with a cover for storage # Why do I have to boil my water? Your water contaminated by .Contamination due to .The Boil Water Advisory gives you information so you can take action to protect your health. # I cannot boil my water.How do I disinfect my water to make it safe to drink? (Caution: Water contaminated with fuel or a toxic chemical will not be made safe by boiling or disinfection.Use another source of water if you know or suspect that water might be contaminated with fuel or a toxic chemical.) If tap water is clear: - Use unscented bleach (bleach that does not have an added scent). - Add 1/8 teaspoon (8 drops or about 0.75 milliliters) of unscented household liquid bleach to 1 gallon (16 cups) of water. - Mix well and wait 30 minutes or more before drinking. - Store disinfected water in a clean contain with a cover. If tap water is cloudy: - Filter through a clean cloth - Use unscented bleach (bleach that does not have an added scent). - Add 1/4 teaspoon (16 drops or 1.5 milliliters) of unscented household liquid bleach to 1 gallon (16 cups) of water. - Mix well and wait 30 minutes or more before drinking. - Store disinfected water in a clean container with a cover. Remember that containers may need to be sanitized before using them to store safe water: To sanitize containers: - Use unscented bleach (bleach that does not have an added scent). - Make a sanitizing solution by mixing 1 teaspoon (5 milliliters) of unscented household liquid bleach in 1 quart (32 ounces, 4 cups, or about 1 liter) of water. - Pour this sanitizing solution into a clean storage container and shake well, making sure that the solution coats the entire inside of the container. # Comprehensive List of Q&As for Boil Water Advisories, continued - Let the clean storage container sit at least 30 seconds, and then pour the solution out of the container. - Let the empty container air dry OR rinse it with clean water that has already been made safe, if available. Never mix bleach with ammonia or other cleaners.Open windows and doors to get fresh air when you use bleach. # Should I use bottled water? You may choose to use bottled water if it is available. # I don't like the taste of boiled water.What can I do? To improve the taste of boiled water you can: - Pour cooled boiled water back and forth from one clean glass or container into another to add air to the water, or - Let the water stand for a few hours, or - Add a pinch of salt to each quart of boiled water. # Food and Beverages Can I use my coffee maker, ice machine, or water or soda dispenser? Do not use water from any appliance connected to your water lines.This includes the water and ice dispensers in your refrigerator/freezer.Most kitchen and other household water filters typically do not remove or kill all bacteria or viruses. - Use boiled or bottled water to make coffee and ice. - Most kitchen and other household water filters typically do not remove or kill all bacteria or viruses. - When the boil water advisory is lifted, consult the owner's manual to find out how to sanitize appliances. # Can I use ice from my refrigerator/freezer ? - Do not use ice from ice trays, ice dispensers, or ice makers. - Throw out all ice made with tap water. - Make new ice with boiled or bottled water. # Comprehensive List of Q&As for Boil Water Advisories, continued What should I do about preparing food and beverages?How should I wash fruit, vegetables, and food preparation surfaces? - Wash fruits and vegetables with boiled water that has cooled or bottled water. - Bring water to a rolling boil for 1 minute before adding food to cook. - Use boiled water when preparing drinks, such as coffee, tea, and lemonade. - Wash food preparation surfaces with boiled water. # What should I do about feeding my baby? Breastfeeding is best.Continue to breastfeed.If breastfeeding is not an option: - Use ready-to-use baby formula, if possible. - Prepare powdered or concentrated baby formula with bottled water.Use boiled water if you do not have bottled water.Disinfect water for baby formula if you cannot boil your water (see above for directions on how to use bleach to disinfect water). - Wash and sterilize bottles and nipples before use. - If you cannot sterilize bottles, try to use single-serve, ready-to-feed bottles. # How do I wash dishes during a Boil Water Advisory? Household dishwashers generally are safe to use if the water reaches a final rinse temperature of at least 150°F or if the dishwasher has a sanitizing cycle. To wash dishes by hand: - Wash and rinse the dishes as you normally would using hot water. - In a separate basin, add 1 teaspoon of unscented household liquid bleach for each gallon of warm water. - Soak the rinsed dishes in the water for at least 1 minute. - Let the dishes air dry completely. # Health I already drank the water.Will I get sick? Most people who happen to drink this water will not get sick.If you do get sick, the symptoms are similar to food poisoning: nausea, diarrhea, cramps, and possibly a mild fever. # Comprehensive List of Q&As for Boil Water Advisories, continued What should I do if I have symptoms? The most important thing to do is avoid dehydration.Drink plenty of fluids and avoid drinks with caffeine, such as soda, coffee, and tea.If you are concerned about your health or the health of a family member, contact your health care provider or . # Household Information Should I give my pets boiled water? Pets can get some of the same diseases as people.It is a good idea to give them boiled water that has been cooled. Do I need to worry about my fish or aquatic pets (e.g., reptiles, frogs)? Most germs that infect people do not infect reptiles or fish.If your water system is using more chlorine or changing disinfection, be cautious about changing the water in your fish tank or aquarium.Contact your local pet store or veterinarian for more advice. # Is it safe to water my garden and house plants? You can use tap water for household plants and gardens. # What might be in the water? Many types of microbes could be in the water.Water systems are concerned about bacteria such as E. coli, viruses such as norovirus, and parasites such as (Cryptosporidium). Human illness from these microbes is usually caused by eating raw or undercooked food, ingesting contaminated recreational or other untreated water, or poor hand-washing.Diarrheal illness from these microbes is not usually life threatening, except in the elderly, the very young, or those with weak immune systems.If you are concerned, consult your health care provider or contact . # Hygiene Can I use tap water to brush my teeth? No.Do not use untreated tap water to brush your teeth.Use boiled or bottled water. # Is it safe to take a shower or bath? Yes, it is safe to take a bath or shower, but be careful not to swallow any water.Use caution when bathing babies and young children.Consider giving them a sponge bath to reduce the chance of them swallowing water. # Comprehensive List of Q&As for Boil Water Advisories, continued What about shaving? Yes, you can shave as usual. # What about doing laundry? Yes, it is safe to do laundry as usual. Where can I get more information? - Personal Preparation and Storage of Safe Water: CDC provides guidance on the amount of water needed for good health, as well as how to prepare and store safe water before and during an emergency. - Hygiene and Handwashing: CDC provides guidance on alternative hygienic practices when water is not available or is contaminated. - A Guide to Water Filters: CDC maintains a guide for filters that remove Cryptosporidium or Giardia. - EPA Safe Drinking Water Hotline: 1-800-426-4791 - Consumer Information: EPA provides information and guidance about drinking water quality, emergencies, contaminants, public health issues, and treatment and storage. -Fill a pot with water. - Heat the water until bubbles come from the bottom of the pot to the top. - Once the water reaches a rolling boil, let it boil for 1 minute. - Turn off the heat source and let the water cool. - Pour the water into a clean container with a cover for storage. # Disinfecting water If you are unable to boil your water, disinfect it instead. # If tap water is clear: - Use unscented bleach (bleach that does not have an added scent). - Add 1/8 teaspoon (8 drops or about 0.75 milliliters) of unscented household liquid bleach to 1 gallon (16 cups) of water. - Mix well and wait 30 minutes or more before drinking. - Store disinfected water in clean container with a cover. # If tap water is cloudy: - Filter water using clean cloth. - Use unscented bleach (bleach that does not have an added scent). - Add 1/4 teaspoon (16 drops or 1.5 milliliters) of unscented household liquid bleach to 1 gallon (16 cups) of water. - Mix well and wait 30 minutes or more before drinking. - Store disinfected water in clean container with a cover. Remember that containers may need to be sanitized before using them to store safe water. To sanitize containers: - Use unscented bleach (bleach that does not have an added scent). - Make a sanitizing solution by mixing 1 teaspoon (5 milliliters) of unscented household liquid bleach in 1 quart (32 ounces, 4 cups, or about 1 liter) of water. - Pour this sanitizing solution into a clean storage container and shake well, making sure that the solution coats the entire inside of the container. - Let the clean storage container sit at least 30 seconds, and then pour the solution out of the container. - Let empty container air dry OR rinse it with clean water that has already been made safe, if available. Never mix bleach with ammonia or other cleaners.Open windows and doors to get fresh air when you use bleach. # Water filters Boil tap water even if it is filtered.Most kitchen and other household water filters typically do not remove bacteria or viruses. # Preparing and cooking food - Wash all fruits and vegetables with boiled water that has cooled or bottled water. - Bring water to a rolling boil for 1 minute before adding food to cook. - Use boiled water when preparing drinks, such as coffee, tea, and lemonade - Wash food preparation surfaces with boiled water. # Feeding babies and using formula Breastfeeding is best.Continue to breastfeed.If breastfeeding is not an option: - Use ready-to-use baby formula, if possible. - Prepare powdered or concentrated baby formula with bottled water.Use boiled water if you do not have bottled water.Disinfect water for baby formula if you cannot boil your water (see above for directions on how to use bleach to disinfect water). - Wash and sterilize bottles and nipples before use. - If you cannot sterilize bottles, try to use single-serve, ready-to-feed bottles. # Ice - Do not use ice from ice trays, ice dispensers, or ice makers. - Throw out all ice made with tap water. - Make new ice with boiled or bottled water. # Bathing and showering Be careful not to swallow any water when bathing or showering. Use caution when bathing babies and young children.Consider giving them a sponge bath to reduce the chance of them swallowing water. # Fact Sheet About What to Do During a Boil Water Advisory, continued # Brushing teeth Brush teeth with boiled or bottled water.Do not use untreated tap water. # Washing dishes Household dishwashers generally are safe to use if the water reaches a final rinse temperature of at least 150 degrees or if the dishwasher has a sanitizing cycle. To wash dishes by hand: - Wash and rinse the dishes as you normally would using hot water. - In a separate basin, add 1 teaspoon of unscented household liquid bleach for each gallon of warm water. - Soak the rinsed dishes in the water for at least one minute. - Let the dishes air dry completely. # Laundry It is safe to do laundry as usual. # Pets Pets can get some of the same diseases as people.It is a good idea to give them boiled water that has been cooled. For more information, see or contact: - Personal Preparation and Storage of Safe Water: CDC provides guidance on the amount of water needed for good health, as well how to prepare and store safe water before and during an emergency. - Hygiene and Handwashing: CDC provides guidance on alternative hygienic practices when water is not available or is contaminated. - A Guide to Water Filters: CDC maintains a guide for filters that remove Cryptosporidium or Giardia. - EPA Safe Drinking Water Hotline: 1-800-426-4791 - Consumer Information: EPA provides information and guidance about drinking water quality, emergencies, contaminants, public health issues, and treatment and storage. -Llene una olla con agua fría. - Caliente el agua hasta que se formen burbujas desde el fondo de la olla. - Una vez que el agua llegue a hervir con fuerza, deje que hierva así durante un minuto. - Apague la fuente de calor y deje que el agua se enfríe. - Para guardar el agua, vacíela en un recipiente limpio que tenga tapa. # Para desinfectar el agua Si no hay forma de hervir el agua, desinféctela en vez de hervirla. Si el agua de la llave está transparente: - Use blanqueador de cloro al que no se le haya añadido aromatizante (como olor a limón). - Agregue 1/8 de cucharadita (8 gotas o aproximadamente 0.75 mililitros) de blanqueador de cloro para uso doméstico a 1 galón (16 tazas) de agua. - Mezcle bien y espere 30 minutos o más antes de beber el agua. - Guarde el agua desinfectada en un recipiente limpio que tenga tapa. Si el agua de la llave está turbia: - Filtre el agua con un trapo limpio. - Use blanqueador de cloro al que no se le haya añadido aromatizante (como olor a limón). - Agregue 1/4 de cucharadita (16 gotas o aproximadamente 1.5 mililitros) de blanqueador de cloro para uso doméstico a 1 galón (16 tazas) de agua. - Mezcle bien y espere 30 minutos o más antes de beber el agua. - Guarde el agua desinfectada en un recipiente limpio que tenga tapa. Recuerde que es posible que deba desinfectar los envases antes de usarlos para almacenar agua adecuada para beber. # Para desinfectar los envases: - Use blanqueador de cloro al que no se le haya añadido aromatizante (como olor a limón). - Agregue 1 cucharadita (64 gotas o 5 mililitros) de blanqueador de cloro para uso doméstico a 1 cuarto de galón (32 oz, 4 tazas, o aproximadamente 1 litro) de agua. - Ponga esta solución en un envase limpio y agite bien, asegurándose de que la solución haga contacto con todo el interior del envase. - Deje esta solución en el envase por lo menos durante 30 segundos, y luego vacíe el envase. - Deje que el envase se seque al aire o enjuáguelo con agua que ya haya desinfectado, si es que la tiene. Nunca mezcle blanqueador de cloro con amoniaco o con algún otro tipo de producto de limpieza.Abra las ventanas y las puertas cuando use blanqueador de cloro para que entre el aire fresco. # Filtros para el agua Hierva el agua de la llave, incluso si está filtrada.Los filtros de agua no eliminan las bacterias ni los virus. # Preparación de alimentos - Lave todas las frutas y las verduras con agua hervida. - Deje hervir bien el agua durante un minuto antes de agregarle los alimentos. - Prepare bebidas como café, té o limonada con agua hervida. # Alimentación de bebés y uso de leche preparada para lactantes Lo mejor es amamantar.

Continúe amamantando al bebé.Si amamantar no es posible: - De ser posible use leche preparada para lactantes ya lista para usarse. - Use agua embotellada para preparar leche para lactantes en polvo o concentrada.Si no tiene agua embotellada, use agua hervida.Si no puede hervir el agua, desinfecte el agua que usará para la leche preparada para lactantes siguiendo las instrucciones mencionadas anteriormente sobre la forma de usar blanqueador). - Recuerde que debe esterilizar las botellas y los chupones antes de usarlos. - Si no puede esterilizar las botellas, trate de usar botellas listas para usar y no reciclables (que se puedan usar solo una vez). # Hielo - No use hielo del fabricador de cubitos de hielo ni del recipiente de hielo del congelador. - Deseche todo el hielo que haya hecho con agua de la llave. - Haga hielo nuevo con agua hervida o embotellada. Hoja informativa sobre qué hacer durante una advertencia para hervir el agua, continuación # Limpieza del cuerpo Debe tener cuidado de no tragar agua al bañarse en la tina o la regadera. Tenga cuidado al bañar a bebés y a niños pequeños.Considere darles baños de esponja para evitar que traguen agua. # Lavado de dientes Para lavarse los dientes use agua hervida o embotellada. # Para lavar los trastes Se puede usar el lavador de platos sin problemas si el agua llega a una temperatura de por lo menos 160 grados, o si el lavador de platos tiene un ciclo de sanitación. Para lavar los trastes a mano: - Lave y enjuague los trastes como lo hace normalmente, pero con agua caliente. - En otra pileta, agregue 1 cucharadita de cloro para uso doméstico, sin aromatizante, por cada galón de agua tibia. - Remoje los trastes ya enjuagados en el agua con cloro por lo menos durante un minuto. - Deje que los trastes se sequen por completo al aire. # Lavandería Puede lavar la ropa sin problemas de la forma en que acostumbra a hacerlo. # Mascotas caseras Las mascotas caseras sufren de las mismas enfermedades que los humanos.Es una buena idea darles agua hervida para tomar. # Para obtener más información, comuníquese con: - Preparación personal y almacenamiento de agua segura: Los CDC ofrecen una guía acerca de la cantidad de agua necesaria para la buena salud, así como la forma de preparar y almacenar el agua segura antes y durante una emergencia. - Higiene y lavado de manos: Los CDC ofrecen una guía acerca métodos de higiene alternativos cuando no hay agua disponible o está contaminada. Hoja informativa sobre qué hacer durante una advertencia para hervir el agua, continuación - Una guía sobre los filtros de agua: Los CDC tienen una guía de los filtros que eliminan el criptosporidio o la giardia. - Línea gratuita sobre agua potable segura de la EPA: 1-800-426-4791 - Información para el consumidor: La Agencia de Protección Ambiental de los Estados Unidos (EPA, por sus siglas en inglés) ofrece información sobre la calidad del agua potable, emergencias, contaminantes, problemas de salud pública, y tratamiento y almacenamiento.Coliforms are a group of bacteria found in plant material, water, and soil.Coliforms are also present in the digestive tracts and feces of humans and animals.Most of the time, these bacteria are not harmful. # Why does a water system test for coliforms? Water systems test for indicators such as total coliforms, fecal coliforms, or E. coli to monitor water quality.If the water system has a positive test for one of these indicators, it can mean recent contamination with soil or human feces. # What does a positive coliform test result mean? A positive coliform test means possible contamination and a risk of waterborne disease.A positive test for total coliforms always requires more tests for fecal coliforms or E. coli.A confirmed positive test for fecal coliforms or E. coli means you need to take action as advised by your water system. # Will coliform bacteria make me sick? Most coliform bacteria are a normal part of the environment.They do not cause disease but do indicate the water might be contaminated by soil or feces.Some rare types of coliforms, such as E. coli O157:H7, can cause serious illness.Although most E. coli O157:H7 outbreaks are from eating raw or undercooked food, cases from contaminated drinking water can occur, but are rare. # Why test for indicator organisms? A biological pathogen is any organism, such as a bacteria, virus, protozoa, or parasite, that causes a disease.Biological pathogens are commonly called "germs. "There are many different possible pathogens.It is not possible to test for every type of pathogen in every water sample, so water systems use indicators instead. Water systems test for indicator organisms, like coliforms, to check for possible contamination by biological pathogens.Most coliforms are not harmful, but they come from the same sources as other bacteria and organisms that could make you sick. What are "indicator" organisms? - Indicator organisms come from the same sources as organisms that make you sick.Indicator organisms are easier to identify, are present in larger numbers, and respond to water treatment the same way as harmful bacteria and many other biological pathogens.A biological pathogen is any organism, such as a bacteria, virus, protozoa, or parasite, that causes a disease.Biological pathogens are commonly called "germs". - Total coliforms is another term for the full group of coliforms.They are indicators of possible water contamination. - Fecal coliforms are one type of coliform bacteria that is found found mainly in animal digestive tracts and feces.Fecal coliforms are a more specific indicator of fecal contamination of water. - E. coli (Escherichia coli) is a species of fecal coliform bacteria.E. coli almost always comes from animal feces.E. coli is considered the best indicator of fecal water contamination. If E. coli is present, harmful bacteria or other pathogens may also be present. For more information see or contact: - Personal Preparation and Storage of Safe Water: CDC provides guidance on the amount of water needed for good health, as well as how to prepare and store safe water before and during an emergency. - Hygiene and Handwashing: CDC provides guidance on alternative hygienic practices when water is not available or is contaminated. - A Guide to Water Filters: CDC maintains a guide for filters that remove Cryptosporidium or Giardia. - EPA Safe Drinking Water Hotline: 1-800-426-4791 - Consumer Information: EPA provides information and guidance about drinking water quality, emergencies, contaminants, public health issues, and treatment and storage. # What's different about the Groundwater Rule? We used to think that groundwater was protected from fecal contamination.New information shows that groundwater can have fecal contamination and people could get sick.This is why EPA developed the Groundwater Rule. # What indicator organisms does a groundwater system test for? Groundwater systems test for one of three indicator organisms-E. coli, enterococci, or coliphages-to monitor water quality.If the water system has a positive test for any one of these three organisms, it can mean recent contamination with human feces. Water systems test for indicator organisms to check for possible contamination.There are many different possible pathogens.It is not possible to test for every pathogen in every water sample, so they test for indicators instead. # What are "indicator" organisms? Indicator organisms come from the same sources as organisms that might make you sick.Indicator organisms are easier to identify, are present in larger numbers, and respond to water treatment in the same way as harmful bacteria and many other biological pathogens.A biological pathogen is any organism, such as a bacteria, virus, protozoa, or parasite that causes disease.Biological pathogens are commonly called "germs. " # What does a positive test result for an indicator organism mean? A positive test for an indicator means possible water contamination and a risk of waterborne disease.A positive test in groundwater for E. coli, enterococci, or coliphages means you and your water system need to take action. # Will indicator organisms make me sick? Coliphages do not infect humans or cause illness.Some enterococci can cause disease in humans.Most coliform bacteria are a normal part of the environment and do not cause disease.However, some rare types of E. coli, such as O157:H7, can cause serious illness.Although most E. coli O157:H7 outbreaks are from eating raw or undercooked food, cases from contaminated drinking water can occur, but are rare. # What are coliphages? A virus that infects bacteria is called a phage.Phages infect specific species of bacteria.Coliphages infect coliform bacteria.Coliphages do not infect humans or cause illness.A positive test for coliphages indicates the water may be contaminated with feces or E. coli. # Frequently Asked Questions About Groundwater Rule Advisories What are coliforms? Coliforms are a group of bacteria found in plant material, water, and soil.Coliforms are also present in the digestive tracts and feces of humans and animals.Most of the time, these bacteria are not harmful. Total coliforms is another term for the full group of coliforms.They are indicators of possible water contamination.Fecal coliforms is one type of coliform bacteria found mainly in animal digestive tracts and feces.Fecal coliform tests are a more specific indicator of water contamination.E. coli is a species of fecal coliform bacteria.E. coli almost always comes from animal feces and is considered the best indicator of fecal water contamination.If E. coli is present, harmful bacteria or other pathogens may also be present # What is E. coli? E. coli (Escherichia coli) is a species of fecal coliform bacteria.E. coli almost always comes from animal feces.E. coli is considered the best indicator of fecal water contamination.If E. coli is present, harmful bacteria or other pathogens may also be present.Not all E. coli make people sick.Some rare types of E. coli, such as O157:H7, can cause serious illness. # What are Enterococci? Enterococci are a type of bacteria mainly found in the gut and feces of animals.They are used as an indicator organism for groundwater because they closely link water quality with contamination by human feces.Some enterococci can cause disease in humans.Enterococci are not coliform bacteria. For more information see or contact: - Personal Preparation and Storage of Safe Water: CDC provides guidance on the amount of water needed for good health, as well as how to prepare and store safe water before and during an emergency. - Hygiene and Handwashing: CDC provides guidance on alternative hygienic practices when water is not available or is contaminated. - A Guide to Water Filters: CDC maintains a guide for filters that remove Cryptosporidium or Giardia. - EPA Safe Drinking Water Hotline: 1-800-426-4791 - Consumer Information: EPA provides information and guidance about drinking water quality, emergencies, contaminants, public health issues, and treatment and storage.Frequently Asked Questions About Groundwater Rule Advisories, cont'd When I turn on the faucet, the water sputters.Why? You have air in your lines.Turn on your tap slowly and run the water until the sputtering stops. # The water is discolored.What should I do? Flush water pipes by running the water until it is clear. Do not wash clothes if the water is discolored.Wait until the water runs clear at the tap.Wash a load of dark clothes first. # Why does my water have a strong smell? The smell is probably chlorine.Often, water systems will increase chlorine levels to disinfect the pipes. # What should I do if my water pressure is low? Check the faucet screens for trapped particles.Remove the screens and clean out any particles.Put the screens back on the faucet. # Do I need to clean out my faucets? Yes.You should flush your faucets after the drinking water advisory. - Turn on the main water valve. - Turn on the cold water tap at all faucets and run the water until you feel a change in temperature (i.e. the water gets noticeably colder).This may take several minutes.Begin with the faucet that is highest up in your home or building and then open the other faucets one at a time moving from the highest floor to the lowest. # Do I need to clean appliances? Yes.Read the owner's manual for directions to clean appliances such as water softeners and filter units. # Frequently Asked Questions About What to Do After a Drinking Water Advisory My refrigerator has a water dispenser/ice maker.Do I need to clean them? Yes.Water dispensers and ice makers are connected to your water line.You need to flush and clean them. Follow the directions in the owner's manual or: - Change the filter cartridges. - Throw out ice. - Flush the water dispenser for 3 to 5 minutes. - Run the ice maker for 1 hour. - Throw out all the ice. - Wash and sanitize bin areas. # Do I need to do something for the water softener? Yes.You may need to run through a regeneration cycle.Follow the directions in the owner's manual. # I have a water treatment unit for the house.Does it need special care? Yes.Change the filter cartridges.Some units need disinfecting.Follow the directions in the unit's owner's manual. # Frequently Asked Questions About What to Do After a Drinking Water Advisory, continued Cuando abro una llave de agua, ésta salpica, ¿por qué? Hay aire en las tuberías de agua.Abra la llave de agua lentamente y deje correr el agua hasta que deje de salpicar. # El agua está turbia, ¿qué debo hacer? Deje abiertas las llaves de agua hasta que el agua salga transparente. No lave ropa si el agua está turbia.Espere a que salga el agua transparente del grifo de agua.Primero lave una carga de ropa obscura. ¿Por qué huele muy fuerte el agua que sale del grifo? El olor es probablemente cloro.Con frecuencia los sistemas de agua aumentan los niveles de cloro para desinfectar las tuberías. # ¿Qué debo hacer si la presión de agua es baja? Revise si hay desperdicios atrapados en las mallas que están en la salida de las llaves de agua.Saque estas mallas y límpielas bien.Vuelva a colocar las mallas en las llaves de agua. # ¿Debo limpiar mis llaves de agua? Sí; abra las llaves de agua que no haya usado durante la advertencia para hervir el agua potable. - Abra la toma de agua principal. - Abra la llave de agua fría en todos los grifos usados para obtener agua de beber en el hogar y deje correr el agua hasta que cambie de temperatura (por ejemplo que se sienta más fría).Esto puede tardar varios minutos.Empiece con el grifo más elevado de su casa o edificio y luego abra los otros grifos uno por uno en orden del piso más alto al piso más bajo. # Preguntas frecuentes acerca de qué hacer después de una advertencia para hervir el agua Mi refrigerador tiene surtidor de agua fría y fabricador automático de cubitos de hielo, ¿debo limpiarlos? Sí; los surtidores de agua fría y los fabricadores de cubitos de hielo están conectados a su tubería de agua.Debe desinfectarlos.Siga las instrucciones del manual del usuario o: - Cambie los cartuchos de filtro. - Tire el hielo. - Deje correr el agua en el surtidor, de tres a cinco minutos. - Deje funcionar el fabricador automático de cubitos de hielo por una hora. - Deseche los cubitos de hielo. - Lave y desinfecte los recipientes de agua y hielo. ¿Debo hacer algo con el suavizador de agua? Sí; es posible que deba hacerlo funcionar durante todo un ciclo de regeneración.Siga las instrucciones del manual del usuario. Tengo un sistema de tratamiento de agua para el hogar. ¿Necesito hacer algo en especial? Sí.Cambie los cartuchos de filtro.Algunas unidades deben ser desinfectadas.Siga las instrucciones del manual del usuario. # Preguntas frecuentes acerca de qué hacer después de una advertencia para hervir el agua # Point of Contact for Coordination During an Advisory # PURPOSE This form is designed to facilitate planning for exercises.The first section will help state objectives and desired outcomes from the planning session.The second section identifies participants and helps prepare them for discussion.The more preparation, the better the end product. # DIRECTIONS - Identify exercise leads and type of exercise (seminar, workshop, tabletop, game, drill, functional, full scale). - Complete the purpose, scope, goal, and objectives.Invite staff and other organizations as appropriate. - Include name and contact information for each participant. - Identify and assign specific materials for participants to develop or provide. # Section 2: During an Event-Issuing an Advisory A drinking water advisory can occur at any time.Water systems must act quickly when an event is suspected or identified.The first action must be to assess the situation and follow standard operating procedures (SOPs) for issuing a drinking water advisory. # Overview Icon Key # Initiating an Advisory Identify the situation and collect facts. Notify your drinking water primacy agency. Decide to issue an advisory. Identify the geographic boundaries. Notify your internal staff and external partners. # Preparing an Advisory Develop, format, and translate the message. Approve the advisory. Identify the spokespersons. Assign communication responsibilities. # Distributing an Advisory Brief elected and public officials. Implement your communication platforms. Use your communication network to expand distribution of the advisory. Work with the media. # Ending an Advisory Issue End of Advisory notice. # Checklist: During an Event # Identify the Situation and Collect Facts Drinking water advisories are issued for reasons identified in federal or state regulations or by decisions made by the water system.

The situation and characteristics of the contaminant(s) of concern determine what type of advisory to distribute: - Informational - Boil Water - Do Not Drink - Do Not Use Use the Essential Information list to collect data and develop communication materials. # Notify Your Drinking Water Primacy Agency Each state that has primacy specifies particular mechanisms for state notification.Be familiar with your water system's protocols for notifying your primacy agency.See Appendix B: Online Resources, Primacy Agency. # Decide to Issue an Advisory Work with senior management and follow your communication SOP in making the decision to issue an advisory.Use your best professional judgment. # Initiating an Advisory # Essential Information # Identify the Geographic Boundaries Boundaries A key component of a drinking water advisory is to communicate clearly the area affected.Many customers do not know which water system provides their service and broadcast media usually reach a large audience beyond the affected area. Clearly describe the boundaries of the affected area using street names, place names, and well known reference points. # Maps Maps help illustrate the affected area.Water systems can generate maps using internal or online mapping tools (e.g., geographic information system ).These maps can be posted on agency websites, or distributed electronically or as printed material.Update the map as the situation changes. # Maps Help Define The Area Affected When possible, use maps and brief descriptions of the boundaries of the area affected.Maintain and update maps of the water service area.Maps can be sent out as printed or electronic versions.Make sure the maps - Are presented at a legible scale with legible fonts. - Are uncluttered. - Reflect commonplace names and reference points. - Have crisp lines. - Are easy to read. # Descriptions Clearly communicating the boundaries of affected areas also requires careful consideration of verbal descriptions so that spokespersons, radio, and other media can briefly but accurately depict the service area affected. # Notify Your Internal Staff and External Partners Activate your internal communication SOP.Use information collected to brief staff.Depending on the situation, also brief your partners: - Wholesale, consecutive, and neighboring water systems. - Public health department. - Critical customers (see Critical Customer Checklist to assist in identifying at-risk populations served by a water system). - Public officials. - Emergency management. - Community organizations. - Businesses, childcare facilities, correctional facilities, food service, health care providers and facilities, and schools. Provide Call Center Data Checklist to call center or customer service staff and partners.Unless a state requires specific templates, revise the order and content of these templates based on the local circumstances.Remember to include the 10 required elements from the Public Notification Rule. # Notes Understand the translation needs of your community.Use community partners or professional translation services to translate the message.Avoid using online dictionaries or other computer software. Community partners are responsible for producing the message in formats that people they serve can read and understand, such as Braille, large font, or text messages. # Required Elements of a Public Notice All public notices must include a clear and readily understandable explanation of each violation containing the following 10 elements from EPA's Public Notification Rule (PNR) Quick Reference Guide. # Description of the violation or situation, including contaminant(s) of concern and the contaminant level(s).2.When the violation or situation occurred.3.Any potential adverse health effects from drinking the water and standard language regarding the violation or situation.4.Population at risk, including subpopulations that may be particularly vulnerable if exposed to the contaminant in their drinking water.5.Whether alternate water supplies should be used.6.Actions consumers should take, including when they should seek medical help, if known.7.What the water system is doing to correct the violation or situation.8.When the water system expects to return to compliance or resolve the situation.9.Name, business address, and phone number of the water system owner, operator, or designee who can provide additional information concerning the notice.10.A statement encouraging the notice recipients to share the notice with other persons, where applicable. # Preparing an Advisory # Abbreviated Messages Some channels of communication only allow for brief messages because of time or space constraints.Brief messages are appropriate for: - On-screen scroll (local televised news, cable television, public service television channels, Emergency Broadcast System announcements). - Text message systems (SMS). - Social media (Facebook, Twitter). - Reverse 911 phone message systems. - Highway variable message signs and portable message boards. See the Automated Messages tool. # Abbreviated Message Template-Boil Water Advisory The is asking customers to boil tap water or use bottled water.For more information, go to -r call . # Message Development The information on which to base the advisory can be captured in the Information for Communication Planning tool.The Required Elements of a Public Notice (see page 86) outlines the questions and information the drinking water advisory must address in its materials.Key Questions for the Public Information Officer may help in preparation for working with the media. # Approve the Advisory Once the message has been developed and produced in appropriate formats, follow your communication SOP to have management approve the advisory. # Identify the Spokespersons The person to serve as a spokesperson during a drinking water advisory can come from water system management or from an outside partner agency, such as a public health department.The spokesperson should be someone in authority who is honest, credible, competent, accessible, and sensitive to public concerns. # Tip Abbreviated messages should include: - Basic message of action to take - Location - Contact information - Where to get more information Follow the communication protocols discussed in Section 1 and use essential information to prepare spokespersons for interacting with the public and media.See Basic Elements of a Spokesperson Statement. If there is not a designated spokesperson, assess staff options and identify an individual to fill this role.See Spokesperson Assessment Tool. # Assign Communication Responsibilities Exchanging information and developing materials, such as news releases, among partners and water systems must be a coordinated effort.Liaisons should be designated staff who are the communication link for issuing an advisory and also for updating and lifting the advisory.Each organization or water system involved in an advisory should identify a liaison.Work with your partners to assign specific communication roles and responsibilities.Develop a list that identifies who (which partner) will be contacting whom (a specific audience) and when that contact will occur. # Tip When possible, the spokesperson should not be someone who is directly involved in operations. # Brief Elected and Public Officials Brief the appropriate public officials on the essential information before you notify the media.Media often will contact public officials rather than a water system for information and comments. # Implement Your Communication Platforms Determining the most appropriate strategies and tools for a particular situation is a reflection of the severity of the public health concern and the ability to define clearly the affected area.Effective communication will require distribution through multiple methods: - News media outlets(are a primary means of distributing the advisory) - Automated message systems (helps reach specific service areas quickly).See Automated Messages for more information. - Door-to-door contact or door hangers (often used for small areas) - Hand-delivered fliers # Websites - Social media (e.g., Facebook, Twitter) # Distributing an Advisory # Automated Messages Broadcast notification systems use a variety of commercially available systems that include: - Prerecorded or synthesized voices for brief messages, - Text (SMS) for messages to cell phones, and - E-mail for detailed messages to large groups. For more information, see Automated Messages. # Use Your Communication Network to Expand Distribution of the Advisory As noted in the Collaborating with Partners (see pages 23-28) portion of Section 1: Before an Event, network partners can assist with translating, formatting, and distributing messages to specific audiences. - Coordinate with local public health departments to help alert hospitals, health care providers, childcare providers, and food service and preparation facilities (See Appendix B: Online Resources, Additional Water and Health Resources and Appendix B: Online Resources, Disinfecting Water - Coordinate with school districts and private schools, including colleges and universities. - Use your communication network to reach diverse populations that may be outside mass media communication channels. # Communication Network # Work with the Media The Public Notification Rule requires wide distribution and encourages the use of mass media.General circulation newspapers, radio, television, websites, and ethnic media are good channels for issuing advisories.After issuing a press release, call media outlets to verify they received the release.Ask for the duty editor or news director.Take time to explain the importance of this information to the public.This is especially important for lifting an advisory. Monitoring the media, customer calls, and the status of the advisory will guide decisions about the need for media activities.Press conferences, additional calls to reporters, or expanding media work to partners are necessary in large-scale advisories. # Media log Use a log to track media contacts and reports.Logging media contacts gives a structure for follow up with updates or end-of-advisory notices.If the advisory includes multiple agencies or water systems, each organization should keep a log. # Tip To meet the intent of the Public Notification Rule , health effects and other details must be included in the press release. # Include phone numbers and websites in the full advisory.See Required Elements of a Public Notice # Did You Know? Ethnic media reach 25 percent of the U.S. adult population.These adults are far more responsive to messages delivered by media from a similar culture or ethnic group.Forty-five percent of all African-American, American Indian, Hispanic, Asian-American, and Arab-American adults prefer ethnic television, radio, or newspapers to mainstream media channels.See Appendix B: Online Resources, Susceptible Populations. # Media Evaluation Look at media coverage during and after an advisory: - Does media coverage reflect the scope and scale of the event? - What is the tone of the coverage? - What are the reactions in the community? - Were updates covered by the media? - How do the timing and placement of media stories link with the volume of customer service calls? (Look for the media's effect on customer questions.) # Digital Media Blogs and comments on websites DO NOT represent general public opinion.They DO give an idea of reactions and concerns. # Working with the Media - Get the facts straight.Who?What?When?Where?Why?How? - Write the message to fit the circumstances. - Keep all messages consistent. - Edit, review, and get clearance for all media releases. - Use standard press release format. - Link to other information from relevant entities. - Use e-mail, fax, and other methods to deliver the press release. - Make follow-up calls to the media. - Track contact with the media. - Post the release and the advisory on the water system's website. - Be honest with the media.If you do not know the answer to a question, say so, then offer to find the information. - Discuss use of maps and visual aids with media outlets. - Consider issuing a joint press release with the state and/or local health department. - Send a release announcing the end of the advisory to media outlets and partners and post the announcement on your website. - Make follow-up contact with media to encourage publicizing the end of the advisory. - If the advisory is large or long-term, consider scheduling regular press conferences to keep the media up to date.These should be at a time that allows the media to meet press deadlines. # Tier 1 PNR Compliant Press Releases News editors will edit and reformat releases to fit their style and available space.Some of the required elements or language may be omitted.It is the water system's responsibility to post the official advisory in public places, apartments, schools, businesses, on websites, and other places as required by your state. See the following tools and templates for guidance: - How to Use Press Release Templates # Press Conferences and Briefings News conferences or briefings become necessary during some advisories.Press conferences and briefings create additional work and demand extra resources, but they can eliminate the need to answer large numbers of media inquiries individually.Preparation helps ensure a successful press event. # Planning a Press Conference The first step is to refer to the messages and essential information developed for the advisory.These messages and information are the basis for media kits, advisories, and statements.Messages should be consistent in all communication. Media kits are simply a collection of information to provide to the media.Media kits should have: - A copy of the official advisory distributed to customers When planning a press conference, coordination with partners is absolutely required. - Work with partners to plan the press conference, develop materials for media kits, and ensure appropriate clearance is obtained from each agency. - Designate one person or group to organize the press conference and one person to act as the emcee.Emcee responsibilities include introducing speakers, managing the question and answer period, and closing the press conference. - Identify a spokesperson for each organization participating in the press conference See Spokesperson Assessment Tool. - Use the essential information and messages to develop statements for each speaker.Brief the spokespersons prior to the event and review messages and materials.Speakers need to know the order of their appearance and roles.See Basic Elements of a Spokesperson Statement and Spokesperson Assessment Tool. - Rehearse before the session and practice statements and possible questions and answers.It is important to prepare for difficult questions.Plan a strategy in case the situation becomes contentious.Include all spokespersons if other agencies are involved.Phone calls can work if spokespersons cannot meet inperson ahead of time. - Plan logistics.This is central to a successful press conference.Study the location.The space should be accessible and have enough room, no echo, a central focus point, and a designated sign-in area.Media kits should be provided at the sign-in area.If possible, set aside a separate space for one-on-one interviews.On-site press conferences are more of a challenge.Use tape or cones to designate a specific safe area.Limit work noise and activity, if possible.Make it clear how long the press conference will last. - Announce the press conference through media contacts.Develop a media alert and distribute it by e-mail, fax, or other methods.Follow up with calls to the media to make sure the right persons received the advisory.Select a time that will allow sound and video crews to set up equipment and all media to meet press deadlines.Use the Media Alert Template. # Conducting a Press Conference With the right planning in place, the press conference should go more smoothly.Make sure each media outlet signs in and has a media kit.Press conferences have a standard format: - Entrance: Spokespeople enter the room or area in the order they are speaking. - Introductions: The emcee gives a short summary of the reason for the press conference and introduces each spokesperson.One spokesperson may play this role if necessary. - Statement: Spokespeople stand up, give their names and titles, and proceed with their statements. - Questions: It is standard practice to have a question and answer session.The person doing the introductions should handle media questions and refer them to the best spokesperson for the topic. - Close: Stick to the time allotted.The emcee thanks the media for their interest, states that the session is closed, and announces where to get more information and/or the time of the next update.Spokespersons leave the room. # After the Press Conference If appropriate, the media can conduct one-on-one interviews directly after the press conference.Make sure to get back to any member of the media that asked for more information. A debriefing, either in person or by phone, will identify concerns that are not addressed, determine changes needed in messages, and prepare participants for the next update.Information from a press debriefing should be incorporated into the advisory protocol during the evaluation process. # Notes # Issue End of Advisory Notice Federal regulations do not specify when to end an advisory.Water systems and drinking water primacy agencies consult with one another on the specific events around the advisory and use water quality criteria and protocols to make the decision to end or lift an advisory.State primacy agency criteria are typically based on laboratory testing (sampling) results. When the water system and primacy agency end the advisory, communication moves to lifting the advisory.Develop and coordinate the end of the advisory messages with partners.The same communication methods, media partners, and outlets used to distribute the advisory should also be used to lift the advisory. Be clear about the information used to end the advisory and the timing.Specifically, include the information on which you are basing your decision to end the advisory (e.g., the lab tested the water and it was negative for indicators). Be sure to send the end of advisory notice to all partners in the communication network and the media.Post this information on websites clearly showing date and time.See the Ending an Advisory Press Release Template as an example. # Ending an Advisory Steps to Issue an End to the Advisory - Update the media and partners. - Update notifications in the affected area, including websites. - Update affected customers electronically; for example, by automated messages or e-mail. - Follow up earlier press releases with an end of advisory press release and phone calls.Calls abandoned (caller hung up without listening to recorded information). Caller demographics (city, ZIP, county). Caller contact information (phone number or e-mail) if needed to provide follow-up information.

Call topic (drinking water advisory, outage, discoloration, taste, illness). Call reason (information request, report case, provide information). # Key Questions for the Public Information Officer # PURPOSE This list provides a quick review of important points to consider for public communication during an advisory. # DIRECTIONS Compare available public communication materials available to this list.Provide this list to other water systems or organizations responding to an advisory.Use this list when working with the media.As a public information officer, consider the following before releasing information to the media: 1.Ability-Do you have the appropriate information on the subject? 2.Competency-Are you qualified to discuss the topic with the news media?If you are not the expert, find out who the expert is and arrange to have him or her brief the media. 3.Authority-Do you have jurisdiction over the issue?It's always advisable to stay in close contact with upper management to coordinate your response. 4.Security-Is the information classified?The security limitation is extremely important because of the need to safeguard classified and operationally sensitive information. 5.Accuracy-Is the information accurate?Public information officers have an obligation to provide accurate, factual information and to avoid speculation. 6.Propriety-Is the information appropriate to the situation?Ensure that information released displays sensitivity and dignity.For example, do not release photographs that could distress individuals or their family members. 7.Policy-Do the policies of your organization permit release of this information? # Automated Messages # PURPOSE Automated messages take many forms.Developing the content for advisories requires careful planning.This information addresses automated messages specifically for drinking water advisories. # DIRECTIONS Review the information about automated messages.Be sure your communication plan addresses automated messages specific to the water system and community capabilities and tools.Automated broadcast notification is used to send messages quickly to large numbers of people.Broadcast notification systems, use a wide variety of commercially available systems that include the following: - Voice: Delivering messages by prerecorded or synthesized voice is suited for brief messages.Automated systems like Reverse 911 can be programmed to leave messages on answering machines if there is no answer. - Text (SMS): Short Messaging Service (SMS) delivers messages of up to 160 characters to cell phones. - E-mail: E-mail is suitable for more detailed messages and can be sent to large groups relatively quickly.E-mail is delivered over the Internet, which is typically a reliable network unless there is a power outage. # Note: SMS and e-mail systems cannot guarantee delivery to a contact. Effective broadcast systems require: - Accurate contact information. - Delivery to a relevant contact point (e.g., reaching a cell phone versus a home landline). - Simple, concise language. - Coordination with other communication tools to provide access to more detailed information (e.g., website, customer call center). # Coordinate with other tools Automated messages are useful tools in combination with press releases, door hangers, call center information, website information, and other outreach tools.These brief messages are useful in building awareness but are inadequate to provide all the information customers need to receive. # Accurate Contact Information A notification system is only as good as the contact data.Uploading contact data is not ideal; data can be inaccurate (entry errors), false (purposefully wrong data), or invalid (phone number has changed or been disconnected).This is more likely when data are uploaded from customer records or purchased phone lists, or gathered from available databases.Even converting data from enhanced 911 systems to Reverse 911 programs will not assure accurate contact information.Automatically entering contact data into a system also has problems.Notification system vendors are wary of violating anti-spam laws and blacklisting. Opt-in data collection can provide and validate content for notification.Individuals can be invited to join a list on a website, or indicate their interest when opening an account.This option can make it easier for subscribers to update their own contact information.This improves the results and reach of a broadcast.Opt-in processes for collecting data help protect the provider from unlawful use, because each recipient is giving the notification provider permission for future contact. # Timing Automated notification systems are quick, but not instantaneous.Time is required: - To prepare the message - To direct the message to appropriate audiences (e.g., customers in specific subsections of the distribution system) - To distribute the advisory » Voice systems may only make 1,000 calls per hour » E-mail or text message distribution to similar numbers occurs in minutes, and - For the recipient to listen to or read the message and take action. # Automated Messages, continued Content The purpose of an automated broadcast notification is to prompt people to seek information and take appropriate action.Messages for automated notification systems must be simple and concise.It is not practical to use language from standard public notification templates.Because these messages must be short, they cannot convey the detail required in EPA's Public Notification Rule. - Key elements of abbreviated messages related to water quality concerns are: # Working with the Media Template # PURPOSE These are sample statements to use if members of the media call before a press release is issued.Getting the facts correct is a priority.Do not give information to the media before confirming facts with field staff, the emergency operations center, and management.Changing information after it is released can lead to media confusion and loss of focus on the key messages. # DIRECTIONS Review these statements and adapt them with specific information about the water system.Incorporate the template into your standard operating procedures (SOPs) and emergency response plans (ERPs).Add specific information during an advisory.Rehearse the responses prior to speaking with media. # Pre-scripted Immediate Responses to Media Inquiries Use this template if the media is "at your door" and you need time to assemble the facts for the initial press release statement. Getting the facts is a priority.It is important that your organization not give in to pressure to confirm or release information before you have confirmation (e.g., from your scientists and emergency operations center). # Media Alert Template # PURPOSE Water systems can invite the media to attend press conferences and briefings or to tour facilities related to advisories.This type of activity provides the media with a better understanding of drinking water infrastructure and why advisories occur. # DIRECTIONS Use this template for media releases about press conferences, briefings, and facility tours.Replace information in brackets with specific water system and advisory information.Adapt the information as needed. # Tier I Public Notification Rule Compliant Press Release Template # PURPOSE Use when a corresponding Tier 1 Public Notice boil water advisory is required and issued. # DIRECTIONS: Replace information in brackets with specific water system and advisory information.Adapt it as needed. issues a boil water advisory for all customers in advises all customers to boil their drinking water.The boil water advisory is in effect until further notice. # Denotes required element of a public notice per EPA's Public Notification # Customers should: - Bring water to a rolling boil for 1 minute. - Allow the water to cool before using. - Store the cooled water in a clean container with a cover. .Customers should use boiled water that has cooled or bottled water for: These symptoms are caused by many illnesses other than drinking water. Please share this information with all the other people who drink this water, especially those who may not have received this notice directly (for example, people in apartments, nursing homes, schools, and businesses). For more information, go to Customers should use boiled water that has cooled or bottled water for: - Bring water to a rolling boil for 1 minute. - Allow the water to cool before using. - Store the cooled water in a clean container with a cover. Customers should use boiled water that has cooled or bottled water for: - Drinking. - Brushing teeth. -Washing fruits and vegetables - Preparing food and baby formula. - Making ice. - Giving to pets.Post-event activities are essential to improve, learn, and prepare for future events.They should reflect the scope and scale of the event. The key is to understand what worked and what did not work during a drinking water advisory in order to improve the process in the future. # Overview Icon Key # Tools and Templates # Resources # Assessing Expectations Each advisory incident is an opportunity to compare planning to performance, and expectations to outcomes. # Modifying Standard Operating Procedures (SOPs) Incorporate changes into SOPs. # Updating Public Outreach Identify additional communication steps. Follow up with the public. # Notes # Debrief and Conduct an After Action Review with Staff and Partners Debriefing after an advisory helps organizations and communities understand what happened and why it happened during a drinking water advisory.A debriefing offers an opportunity to voice concerns and offer potential improvements.It often is informal and may be led by a neutral facilitator. The format and size of the debriefing is based on the scope and scale of the drinking water advisory.In general, each division or organization that participated should be involved.Debriefings may benefit from having the perspective of an organization that was not involved but was affected by the drinking water advisory. An After Action Review (AAR) is a structured form of debriefing that can compare planning with real activity.AARs can provide a clear understanding of what contributed to success and how to replicate it in the future.They also can provide a common understanding of where improvements canbe made and who will be responsible for following through on agreed action steps.AARs describe outcomes and planned actions. The debriefing and AAR process and tools can be adapted for individual exercises and debriefings.See the Exercise Planning Template. See the Debriefing Discussion Guide as an example. The following are steps for conducting a debriefing. 1.Prepare: The Advisory Feedback Form can be used to plan a debriefing. Conduct: Ground rules should be established.Consider using an outside neutral facilitator. 3.Report: Results of a debriefing can be incorporated into future planning efforts. # Debriefing an Event # Debriefing Ground Rules To facilitate a debriefing: - Respect colleagues.Refrain from personal remarks or assigning blame. - Be honest and willing to share your knowledge and experience. - Keep discussions about individual performance within the group. - Read through the background information and consider the discussion questions. - Accept the drinking water advisory as it happened. - Avoid getting bogged down in small details. - Think about the big picture. - Provide paths forward and solutions where possible. - Observe the time limits allotted for the debriefing. # Perform an Evaluation Evaluation is an ongoing assessment of a drinking water advisory protocol.It is the comparison of SOP criteria to performance.The collection and analysis of subjective experiences along with the analysis of objective forms of data or information provide the foundation for evaluation.Even the most basic evaluation provides insight and can improve future advisories and overall communication. The scope of an advisory and a water system's resources and capacities guide the evaluation process.The time, resources, and expertise needed for an evaluation vary with the scope.Evaluations can be conducted over time and in different stages.Evaluations draw on many sources of information, including, operational reports, debriefings, surveys, and public comment.See the Debriefing Evaluation Form. # Collect Data and Information Related to the Advisory Different types of data are described below: - Quantitative data, such as water quality data, Web analytics, and epidemiology statistics. - Qualitative data, such as customer comments, media reports, staff memos, etc.See Appendix B: Online Resources, Data Management for links to information on qualitative data collection. # See the Advisory Feedback Form and Call Center Data Collection Framework for collecting information from partners. # Conducting an Evaluation # Evaluation Tips - Make a list of evaluation questions. - Identify the data sources. - Link the sources. - Proceed with the evaluation. Participants of the advisory and debriefing need to know the results of the evaluation process.Reports should reflect the size and scope of the drinking water advisory and can range from a simple memo to a fullscale report.A report should summarize essential information for other post-event steps.See the Follow-Up Memo. Routine updating of contact lists is an essential task.Use the debriefing process as an opportunity to improve this resource.Ensure routine updating by including it in regular protocols.Build reminders, such as online calendar prompts, into plans to update contact lists. # Modifying Standard Operating Procedures (SOPs) # Tip Use the same approach for modifying SOPs after an exercise or an advisory. (See page 34). # Call Center Data Collection Framework # PURPOSE This data framework provides an example of how to apply call center or customer service (CS) data to an evaluation. The framework provides a more complete data set and includes measurements and goals.The framework approach can be used to evaluate other data from an advisory.This framework example uses specific goals and measurements for evaluation. # DIRECTIONS Adapt the framework to reflect water system data.The survey below will take about minutes to complete.All information collected is confidential.We cannot identify who does or does not participate, or link answers to any one person. We will use the results of this survey to . For more information or if you have questions, please contact: Post-Advisory Community Survey 1.Which type of water do you prefer to drink?Please rank your preferences using a scale of 1-4, with 1 as the most preferred type and 4 as the least preferred. # Debriefing Evaluation Form # PURPOSE This evaluation form can provide data to help evaluate an exercise, advisory, and debriefing.The information can be used to improve advisories, as well as to develop and evaluate future protocols and exercises. # DIRECTIONS Copy this form and give to the debriefing or exercise participants after the session.Ask them to complete the form before they leave.Collate the results and use them to evaluate the debriefing, advisory, or exercise.The form can also be used as an informal discussion guide for debriefings and exercises.Coliphage: A virus that infects bacteria is called a phage.Phages infect specific species of bacteria.Coliphages infect coliform bacteria.Coliphages do not infect humans or cause illness.A positive test for coliphages indicates the water may be contaminated with feces or E. coli. Consecutive system: A water system that purchases its water supply from another water system. Contaminant: An unwanted and/or undesirable chemical or microbe found in drinking water. Corrective Action: The activities taken by a water system to fix an identified deficiency. # Crisis communication: A communication approach that relays the risks and benefits of different actions to agencies, consumers, and other stakeholders during an emergency or disaster. Critical customer: Customers that receive priority notification during a drinking water advisory. CS: Customer service. # D Drinking Water Advisory: Water systems and state or local agencies issue drinking water advisories when they believe water quality is or may be compromised.Advisories tell individuals, schools, hospitals, businesses, and others about the situation and how to take immediate action. Debriefing: An informal, semi-structured discussion with stakeholders, partners, and other participants, after an advisory, exercise, or event, used to obtain useful information and improve or enhance operations. Do Not Drink advisory: Communication to customers of a water system to avoid tap water and to use other sources of water for human consumption.A Do Not Drink advisory is used if boiling the water will not kill, inactivate, or remove the contaminant of concern, or if boiling would concentrate or release it into the air.Do Not Use advisory: Communication to customers of a water system not to use tap water for any purpose, including sanitation and fire protection. # E Escherichia coli (E. coli): A species of fecal coliform bacteria.E. coli almost always comes from animal feces.E. coli is considered the best indicator of fecal water contamination.If E. coli is present, harmful bacteria or other pathogens may also be present in the water.Some rare types of E. coli, such as O157:H7, can cause serious illness. EPA: U.S. Environmental Protection Agency.

This report is a revision o f the General Recomm endations on Im m unization a?id updates the 2 0 0 6 statement by the Advisory Committee on Im m unization Practices (ACIP) (CDC.General recommendations on im m unization: recommendations o f the Advisory Committee on Im m unization Practices , M M W R 2006;55, M M W R 1991;40); the assessment a n d feedback strategy to increase vaccination rates (CDC.Recommendations o f the Advisory Committee on Im m unization Practices: programmatic strategies to increase vaccination rates-assessment a nd feedback o f provider-based vaccination coverage information.# C D C , our planners, and our content experts wish to disclose that they have no financial interests or other relationships w ith the manufacturers o f commercial products, sup pliers o f commercial services, or commercial supporters.This report w ill not include any discussion o f the unlabeled use o f a product or a product under investigational use w ith the exception o f the follow ing situations: 1.The nonsimultaneous administration o f yellow fever (YF) vaccine and inactivated vaccines.A tla n ta , G A 3 0 3 3 3 .Telephone: 4 0 4 -6 3 9 -1 9 5 8 ; Fax: 4 0 4 -6 3 9 -8 8 2 8 ; E -m a il: aok2@ cdc.gov. T h e guidance in this report will help vaccination provid ers to assess vaccine benefits and risks, use reco m m ended ad m inistratio n and storage practices, u n d erstan d the m ost effective strategies for ensuring that vaccination coverage in the p o pulatio n rem ains high, and com m unicate the im portance o f vaccination to reduce the effects o f vaccine-preventable disease.T hese recom m endations are in ten d ed for use in the U nited States; vaccine availability, use, and epidem iologic cir cum stances m ight differ in o th er countries and m ight w arrant different recom m endations. # M ethods T h e Advisory C om m ittee on Im m unization Practices (ACIP) General Recom mendations W ork G roup (GRW G) revises the General Recommendations on Im m unization every 3 to 5 years.Relevant topics are those identified by A C IP as topics that relate to all vaccines, including tim ing and spacing o f doses, vaccine administration, and vaccine storage and handling.N ew topics often are added w hen A C IP decides that previous A C IP state ments on general issues such as com bination vaccines, adolescent vaccination, or adult vaccination should be revised and combined with the General Recommendations on Immunization. T h e recom m endations in this rep o rt are based n o t only on available scientific evidence b u t also o n expertise th a t comes directly from a diverse group o f health-care providers and public h ealth officials.G R W G includes professionals from academ ic m ed icin e (pediatrics, fam ily practice, and pharm acy); international (C anada), federal, and state public health professionals; and a m em ber from the nongovernm ental Im m unization A ction C oalition.G R W G , w hich m et m onthly beginning June 2007, form ed subgroups o n the basis o f in ter est in topics such tim in g and spacing, vaccine adm inistration, and storage and handling.T hese subgroups also m et m onthly, conducted literature reviews, and co n trib u ted expert opinion on the need for revisions to specific language.In O ctober 2008, G R W G consulted A C IP to determ ine the best m echanism for approving the resulting docum ent.A C IP concluded that the docum ent could be approved and finalized increm entally w ith a final vote on the entire docum ent. Revisions to the following sections were approved through con sensus vote in O ctober 2008 (i.e., were approved as a part o f the entire docum ent and not through separate votes on each section): l)T im in g and Spacing oflm munobiologics; 2) Contraindications and Precautions; 3) Preventing and M anaging Adverse Reactions; 4) Reporting Vaccine Adverse Events; 5) the N ational Vaccine Injury Com pensation Program; and 6) Vaccine Administration.In February 2009, revisions were made to Storage and H andling o f Immunobiologies, and A C IP approved the section.In June 2009, A CIP voted to incorporate the contents of a 1999 ACIP statem ent on com bination vaccines.T he statem ent was revised by G RW G and the A C IP C om bination Vaccines W ork Group.A C IP also approved m inor changes to the section on Special Situations and the section on Vaccination Records.In O ctober 2009, ACIP voted to revise the entire General Recommendations on Immunization, which incorporated ACIP recommendations on adolescent vaccination (1996) and adult vaccination (1991) into the section on Vaccination Programs.Three votes were taken to approve various sections o f the docum ent, and one vote was taken to approve the entire docum ent.At this final meeting, ACIP also discussed concerns about the lack o f evidence that supports use o f antipyretics before or at the time o f vaccination for the prevention o f fever. # Tim ing and Spacing of Im m unobiologies # General Principles for Vaccine Scheduling O ptim al response to a vaccine depends on m ultiple factors, including the type o f vaccine, age o f the recipient, and im m une status o f the recipient.R ecom m endations for the age at w hich vaccines are adm inistered are influenced by age-specific risks for disease, age-specific risks for com plications, age-specific responses to vaccination, and potential interference w ith the im m une response by passively transferred m aternal antibodies.Vaccines are recom m ended for m em bers o f the youngest age group at risk for experiencing the disease for w hich efficacy and safety have been dem onstrated. C ertain products, including inactivated vaccines, toxoids, recombinant subunit vaccines, polysaccharide conjugate vaccines, and live vaccines, require >2 doses to elicit an adequate antibody response.Tetanus and diphtheria toxoids require booster doses to m aintain protective antibody concentrations.Unconjugated polysaccharide vaccines do not induce T-cell memory, and addi tional doses (although they elicit the same or a lower antibody concentration) might increase the level o f protection.Conjugation w ith a protein carrier improves the effectiveness o f polysaccharide vaccines by inducing T-lymphocyte-dependent im m unologic function.M any vaccines th at stim ulate b o th cell-m ediated im m unity and neutralizing antibodies (e.g., live, attenuated virus vaccines) usually can induce prolonged immunity, even if antibody titers decline over time (7).Subsequent exposure to such viruses usually results in a rapid anamnestic antibody response w ithout viremia. A pproxim ately 9 0 % -95% o f recipients o f a single dose o f certain live vaccines adm inistered by injection at the recom m ended age (i.e., measles, rubella, and yellow fever vaccines) develop protective antibodies, generally w ith in 14 days o f the dose.For varicella and m um ps vaccines, 8 0% -85% o f vaccinees are protected after a single dose.However, because a lim ited p roportion (5% -15% ) o f measles, m um ps, and rubella (M M R ) or varicella vaccinees fail to respond to 1 dose, a sec ond dose is recom m ended to provide another o p p o rtu n ity to develop im m u n ity (2).O f those w ho do n o t respond to the first dose o f M M R or varicella vaccine, 9 7 % -99% respond to a second dose (3,4). T h e Recommended Im m unization Schedules fo r Persons Aged 0 Through 18 Years and the Recommended A d u lt Im m unization Schedule are revised annually.Physicians and oth er health-care providers should ensure th at they are following the m ost upto-date schedules, w hich are available from C D C at h ttp :// www.cdc.gov/vaccines. # Spacing of Multiple Doses of the Same Antigen V accination providers should adhere as closely as possible to recom m ended vaccination schedules (Table 1).A dm inistration at recom m ended ages and in accordance w ith recom m ended intervals betw een doses o f m ultidose antigens provide optim al protection. A dm inistration o f doses o f a m ultidose vaccine using inter vals th at are shorter th an recom m ended m ight be necessary in certain circum stances, such as im pending international travel or w hen a person is behind schedule on vaccinations but needs rapid protection.In these situations, an accelerated schedule can be im plem ented using intervals betw een doses that are shorter than intervals recom m ended for rou tin e vaccination. T h e accelerated or m in im u m intervals and ages for schedul ing catch-up vaccinations are available at w w .cdc.gov/ vaccines.Vaccine doses should not be adm inistered at intervals less than these m in im u m intervals or at an age th at is younger th an the m in im u m age.- - D u rin g measles outbreaks, i f cases are occurring among infants aged 5 days earlier than the m inim um interval or age should n o t be counted as valid doses and should be repeated as age appropriate.T h e repeat dose should be spaced after the invalid dose by the recom m ended m inim um interval (Table 1).For example, if the first and second doses o f Haemophilus influenzae type b (H ib) were adm inistered only 14 days apart, the second dose w ould be invalid and need to be repeated because the m in im u m interval from dose 1 to dose 2 is 4 weeks.T h e repeat dose should be adm inistered >4 weeks after the invalid dose (in this case, the second).T h e repeat dose is counted as the valid second dose. If the first dose in a series is given >5 days before the recom m ended m in im u m age, the dose should be repeated on or after the date w hen the child reaches at least the m in im u m age.If the vaccine is a live vaccine, ensuring that a m in im u m interval o f 28 days has elapsed from the invalid dose is recom m ended.For example, if the first dose o f varicella vaccine were inadver tently adm inistered at age 10 m onths, the repeat dose w ould be adm inistered no earlier than the child's first birthday (the m in im u m age for the first dose).I f the first dose o f varicella vaccine were adm inistered at age 11 m onths and 2 weeks, the repeat dose should be adm inistered no earlier than 4 weeks thereafter, w hich w ould occur after the first birthday. C ertain vaccines (e.g., adult tetanus and d iphtheria toxoids , pediatric diphtheria and tetanus toxoids ; and teta nus toxoid) produce increased rates o f local or systemic reac tions in certain recipients w hen adm inistered m ore frequently than recom m ended (6,/) .Careful record keeping, m aintenance In certain situations, local o r state requirem ents m ig h t m andate th a t doses o f selected vaccines be adm inistered o n o r after specific ages.F or example, a school e n try re quirem ent m ig h t n o t accept a dose o f M M R o r varicella vaccine ad m inistered before the c h ild 's firs t birthday.A C IP recommends th a t physicians and other health-care providers co m p ly w ith local o r state vaccination require m ents w hen scheduling and a d m inistering vaccines. -f patient histories, use o f im m u n izatio n inform ation systems (IISs), and adherence to recom m ended schedules can decrease the incidence o f such reactions w ith o u t adversely affecting im m u n ity # Sim ultaneous Administration S im u lta n e o u s a d m in is tra tio n o f vaccines is d efin ed as adm inistering m ore th an one vaccine on the same clinic day, at different anatom ic sites, and n o t com bined in the same syringe.Experim ental evidence and extensive clinical experi ence provide the scientific basis for adm inistering vaccines sim ultaneously Sim ultaneously adm inistering all vaccines for w hich a person is eligible at the tim e o f a visit increases the probability th a t a child, adolescent, or adult will be vaccinated fully by the appropriate age (8).A stu d y conducted during a measles outbreak dem onstrated th at approxim ately one third o f measles cases am o n g unvaccinated b u t vaccine-eligible preschool children m ight have been prevented if M M R had been adm inistered at the same visit w hen another vaccine was adm inistered (9).Sim ultaneous adm inistration also is criti cal w hen preparing for foreign travel and w hen a health-care provider is u ncertain th at a p atien t will retu rn for additional doses o f vaccine.W ith som e exceptions, sim ultaneously adm inistering the m ost w idely used live and inactivated vaccines has produced seroconversion rates and rates for adverse reactions sim ilar to those observed w hen the vaccines are adm inistered separately {10-13).R outine adm in istratio n o f all age-appropriate doses o f vaccines sim ultaneously is recom m ended for children for w hom no specific contraindications exist at the tim e o f the visit.M M R and varicella vaccine can be adm inistered sim ul taneously.Live, atten u ated influenza vaccine (LAIV) does n o t interfere w ith the im m u n e response to M M R or varicella vaccines adm inistered at the sam e visit.N o data exist about the im m u n o g e n ic ity o f oral T y21a ty p h o id vaccine w hen ad m inistered concurrently or w ith in 30 days o f live virus vac cines.In the absence o f such data, if typhoid vaccination is w arranted, adm inistration should n o t be delayed because o f recent adm inistration o f live, attenuated virus vaccines (14).Sim ultaneous ad m inistration of pneum ococcal polysaccharide vaccine (PPSV) and inactivated influenza vaccine elicits a satis factory antib o d y response w ith o u t increasing the incidence or severity o f adverse reactions (75).Sim ultaneous adm inistration o f PPSV and inactivated influenza vaccine is recom m ended for all persons for w h o m b o th vaccines are indicated.Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) and trivalent inactivated influenza vaccine (TIV) can be adm in istered sim ultaneously (76).H epatitis B vaccine adm inistered w ith yellow fever vaccine is as safe and im m unogenic as w hen these vaccines are adm inistered separately (77).Measles and yellow fever vaccines have been adm inistered safely at the same visit and w ith o u t reduction o f im m unogenicity o f either o f the com ponents (18,19). D epending on w hich vaccines are adm inistered during the first year o f life, a child m ight receive up to nine injections at the 12-through 1 5 -m o n th visit (M M R , varicella, H ib, pneum ococcal conjugate vaccine , pediatric diphtheria and tetanus toxoids and acellular pertussis , inacti vated poliovirus , hepatitis A, hepatitis B, and influenza vaccines).A lthough there is no exact lim it on the n u m b er o f injections, w ith a little flexibility, a provider can ensure that the prim ary series doses are given w ith o u t adm inistering too m any injections at each visit.To reduce the n um ber o f injec tions at the 12-through 15-m onth visit, the hepatitis B series and 3 doses o f IP V (20) can be adm inistered before the child's first birthday. T h ere are m any o ther examples o f ways the vaccination schedule provides flexibility.T h e m ajority o f children aged 1 year w'ho have received 2 H ib vaccine doses (polyribosylribitol phosphate-m eningococcal o u te r m em brane p ro te in ) or 3 H ib vaccine doses (PR P-tetanus ' P R P -T ) and 3 previous doses o f D TaP and P C V have protection against H ib, diphtheria, pertussis, tetanus, and pneum ococcus, w hich lasts th ro u g h o u t infancy (21,22).T h e third (P R P -O M P ) or fourth (PR P-T ) dose o f the H ib series and the fo u rth doses o f D TaP and P C V are critical in boosting antibody titer and ensuring continued protection (22-25).

T he fourth dose o f D TaP is rec om m ended at age 15-18 m onths b u t m ay be adm inistered as early as age 12 m onths if 6 m onths have elapsed since the third dose and if there is concern that the child m ight n o t return by age 18 m onths (23).For infants at low risk for infection w ith hepatitis B virus (i.e., m other tested negative for hepatitis B surface antigen at the tim e o f delivery and is not in a high risk group), the hepatitis B series can be com pleted at any tim e for children aged 6-18 m onths (26).T h e m inim um age for adm inistration o f com bination vaccines is the oldest m inim um age for any o f the individual com ponents; the m ini m um interval betw een doses is equal to the greatest m inim um interval o f any o f the individual com ponents.W ith use o f the com bination H ib-hepatitis B vaccine, the m in im u m age o f adm inistration o f the final dose is 12 m onths because o f the m inim um age requirem ent for the last dose o f the H ib series (26).R ecom m ended spacing o f doses should be m aintained (Table 1). # Com bination Vaccines # Licensed Com bination Vaccines In this report, a com b in atio n vaccine is defined as a p ro d uct containing com ponents that can be divided equally into indepen d en tly available routine vaccines.A dash ( -) between vaccine products indicates th at products are supplied in their final form by the m anufacturer and do n o t require mixing or reconstitution by the user.A slash ( / ) indicates th at the products m ust be mixed or reconstituted by the user.Seven com bination vaccines for w hich separate antigens or antigen com binations exist have been licensed by F D A since 1996 in the U nited States (Table 2) (39-45).In the future, com bina tion vaccines m ight include increasing num bers o f com ponents in different arrays to protect against these and other diseases.Situations m ight arise in w hich one com p o n en t o f a com bination vaccine is specifically preferred to another com po nen t in that same vaccine.Future research considerations for new ly licensed com bination vaccines should focus on safety o f doses th a t are n o t needed because a p atient is already vac cinated against the agents, w hether the com bination vaccine w ill im prove the tim eliness o f v accination, and p o ten tial reduced costs from disease prevention resulting from timely vaccination. # C om bination Vaccines and FDA Licensure O n ly com bination vaccines licensed by FD A should be used.V accination providers should not com bine separate vaccines into the same syringe to adm inister together unless m ixing is indicated for the p a tie n t's age and is explicitly specified on the FD A -approved p ro duct label inserts.O n ly two com bination vaccines (D T aP -IP V /H ib vaccine, m arketed as Pentacel, and D T aP /H ib , m arketed as T riH ibit) contain separate antigen com ponents for w hich FD A approves m ixing by the user.T h e safety, im m unogenicity, and effectiveness of unlicensed com binations are unknow n. # Interchangeability o f Form ulations F D A generally licenses a co m b in atio n vaccine based on studies dem onstrating th at the p ro d u ct's im m unogenicity (or efficacy) and safety are com parable or equivalent to m onova lent or com bination products licensed previously (46).FD A licensure also generally indicates that a com bination vaccine m ay be used interchangeably w ith m onovalent form ulations and o th e r co m b in atio n p ro d u cts w ith sim ilar c o m p o n en t antigens produced by the same m anufacturer to continue the vaccination series.For example, DTaP, D T aP /H ib , and future D T aP vaccines th at contain sim ilar acellular pertussis antigens from the same m anufacturer m ay be used interchangeably if licensed and indicated for the p atien t's age (45). # In terch an geability o f Com bination Vaccines from D ifferen t M anufacturers Licensure o f a vaccine by F D A does n o t necessarily indicate th at the vaccine is interchangeable w ith products from other m anufacturers.Such data are ascertained and interpreted more readily for diseases w ith know n correlates o f protective im m u nity (e.g., specific serologic m arkers).For diseases w ith o u t such surrogate laboratory m arkers, prelicensure field vaccine efficacy (phase III) trials or postlicensure surveillance generally are required to determ ine pro tectio n (47).A C IP prefers that doses o f vaccine in a series com e from the sam e m anufacturer; however, if this is n o t possible or if the m anufacturer of doses given previously is u n k now n, provid ers should adm inister the vaccine th at they have available. # Vaccine Supply A lth o u g h v accin atio n providers should stock sufficient quantities o f com bination and m onovalent vaccines needed to vaccinate children, adolescents, and adults against all diseases for w hich vaccines are recom m ended (20,28), all available types o r b rand-nam e products need n o t be stocked.Potential advantages o f stocking a lim ited n u m b er o f vaccines include 1) reducing confusion and p otential errors w hen staff m em bers m ust handle re d u n d a n t products and form ulations, 2) m inim izing waste w hen less com m only used products expire, 3) decreasing cold storage capacity requirem ents, and 4) m ini m izing adm inistrative costs related to accounting, purchasing, and handling. # Extra Doses o f Vaccine Antigens A dm inistering extra antigens contained in a com bination vaccine should be avoided in m ost situations.Using com bina tion vaccines containing certain antigens n o t indicated at the tim e o f adm in istratio n to a patient m ight be justified w hen 1) the extra antigen is n o t contraindicated, 2) products th at contain only the needed antigens are n o t readily available, and 3) potential benefits to the patient outw eigh the potential risk for adverse events associated w ith the extra antigens.An extra dose o f m any live-virus vaccines and H ib or hepatitis B vaccine has n o t been found to be harm ful (48).However, the risk for an adverse event m ight increase w hen extra doses are adm inistered at an earlier tim e than the recom m ended interval for certain vaccines (e.g., tetanus toxoid vaccines and PPSV) (16,24,49). A vaccination provider m ight n o t have vaccines available th at contain only the antigens needed as indicated by a child's vaccination history.Alternatively, although the indicated vac cines m ight be available, the provider m ight prefer to use a com bination vaccine to red uce the required n u m b er o f injec tions.In such cases, the benefits and risks o f adm inistering the com bination vaccine w ith an unneeded antigen should be care fully considered and discussed w ith the patient or parent.W h e n inactivated (i.e., killed), or particularly su b u n it vac cines (which are often adsorbed to alum inum -salt adjuvants), are adm inistered, the reactogenicity o f the vaccine m ust be considered in balancing the benefits and risks o f extra doses.Because clinical experience suggests low reactogenicity, an extra dose o f H ib or hepatitis B vaccine m ay be adm inistered as part o f a com bination vaccine to com plete a vaccination series for another com ponent o f the com bination.A dm inistration o f extra doses o f tetanus toxoid vaccines earlier than the recom m ended intervals can increase the risk for hypersensitivity reactions (16,24,50).Examples o f such vaccines include DTaP, D T aP /H ib, D T (for ch ild ren ),T d (for adolescents and adults), and T dap.Extra doses o f tetanus-toxoid-containing vaccines m ight be appropriate for certain patients, including for children w ho previously received D T o r T d vaccine and need protec tio n from pertussis (in D TaP or T dap) or for im m igrants w ith u ncertain vaccination histories. # C onjugate Vaccine Carrier Proteins C ertain carrier proteins in existing conjugated H ib vaccines also are used as com ponents o f other vaccines (e.g., p n eu m o coccal and m eningococcal vaccines) (51).Protein conjugates used in H ib conjugate vaccines produced in the U nited States include an outer m em brane protein com plex from Neisseria m eningitidis (in P R P -O M P ), and tetanus toxoid (in PR P-T ).Sim ultaneous adm inistration o f quadrivalent m eningococcal conjugate vaccine (M C V 4), PCV, and T d ap , all o f w hich con tain diphtheria toxoid, is n o t associated w ith reduced im m u nogenicity or an increase in local adverse events (24,51). # Nonsim ultaneous Administration T here is no evidence th at inactivated vaccines interfere w'ith the im m une response to o th er inactivated vaccines or to live vaccines.A ny inactivated vaccine can be adm inistered either sim ultaneously or at any tim e before or after a different inac tivated vaccine or live vaccine (Table 3). Lim ited data are available regarding interference between live vaccines used in the U nited States.T h e im m une response to one live-virus vaccine m ight be im paired if adm inistered w ithin 28 days (i.e., 4 weeks) o f another live-virus vaccine (52,53).In a study conducted in two U.S. health m aintenance organiza tions, the risk for varicella vaccine failure (i.e., varicella d isease in a vaccinated person) am ong persons wrho received varicella vaccine w ith in 28 days o f M M R vaccination was threefold higher than am ong persons w ho received varicella vaccine >28 days after M M R vaccination (54).A no th er stu d y determ ined th at the response to yellow fever vaccine is n o t affected by m onovalent measles vaccine adm inistered 1-27 days earlier (18).T h e effect ofn o n sim u ltan eo u s adm inistration o f rubella, m um ps, varicella, and yellow fever vaccines is unknow n. To m inim ize the potential risk for interference, injectable or nasally adm inistered live vaccines not adm inistered on the same day should be adm inistered >4 weeks apart (Table 3).If injectable or nasally adm inistered live vaccines are separated by 4 weeks after the last invalid dose.O ral vaccines (Ty21a typhoid vaccine and rotavirus) can be adm inistered sim ultaneously or at any interval before or after other live vaccines (injectable or intranasal) if indicated. # Spacing of Vaccines and Antibody-Containing Products # Live Vaccines Ty21a typhoid, yellow fever, LAIV, zoster, and rotavirus vaccines m ay be adm inistered at any tim e before, concurrent w ith, o r after adm inistration o f any im m u n e globulin, hyper im m un e globulin, or intravenous im m une globulin (IGIV ) (55).Blood (e.g., w hole blood, packed red blood cells, and plasma) and oth er an tibody-containing blood products (e.g., im m un e globulin, h y p erim m u n e globulin, and IG IV ) can in hibit the im m u n e response to measles and rubella vaccines for >3 m onths.T h e effect o f blood and im m u n e globulin preparations on the response to m um ps and varicella vaccines is unknow n; however, commercial im m une globulin preparations contain antibodies to these viruses.Blood prod ucts available in the U nited States are unlikely to contain a substantial am ount of antib o d y to yellow fever vaccine virus.T h e length o f tim e th at interference w ith injectable live-virus vaccine (other th an yellow' fever) can persist after the antibody-containing product is a function of the am o u n t o f antigen-specific antib ody con tained in the p ro d u ct (56-58).T herefore, after an antibodycontaining prod u ct is received, live vaccines (other th an yellow fever, o ralT y 2 1 a typhoid, LAIV, zoster, and rotavirus) should be delayed u n til the passive antib o d y has degraded (Table 4).I f a dose o f injectable live-virus vaccine (other than yellow fever and zoster) is adm inistered after an an tibody-containing p roduct b u t at an interval shorter than recom m ended in this report, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine.T h e repeat dose o r serologic testing should be perform ed after the interval indicated for the an tibody-containing p roduct (Table 5). A lthough passively acquired antibodies can interfere w ith the response to rubella vaccine, the low dose o f anti-R ho(D ) globulin adm inistered to p o stp artu m w om en has n o t been dem onstrated to reduce the response to the RA 27/3 strain rubella vaccine (59).Because o f the im portance o f rubella and varicella im m u n ity am ong w om en o f child-bearing age (4,60), the postpartum vaccination o f w om en w ithout evidence o f im m u n ity to rubella or varicella w ith M M R , varicella, or M M R V vaccines should n o t be delayed because o f receipt o f anti-R ho(D ) globulin or any other blood p ro d u ct during the last trim ester o f pregnancy or at delivery.T hese w om en should be vaccinated im m ediately after giving b irth and, if possible, tested >3 m onths later to ensure im m u n ity to rubella and, if appropriate, to measles (2). Interference m ight occur if adm inistration o f an antibodycontaining p ro d u ct becomes necessary after adm inistration o f M M R or varicella vaccines.Usually, vaccine virus replication and stim ulation o f im m u n ity occurs 1-2 weeks after vaccina tion.If the interval between adm inistration o f any o f these vac cines and subsequent adm inistration o f an antibody-containing product is <14 days, vaccination should be repeated after the recom m ended interval (Tables 4 and 5) unless serologic testing indicates a protective antibody response. A hum anized m ouse m onoclonal antibody p ro d u ct (palivizum ab) is available as prophylaxis for serious lower respiratory tract disease from respiratory syncytial virus am ong infants and young children.T his p ro d u ct contains only antibody to respi ratory syncytial virus and does n o t interfere w ith the im m une response to licensed live or inactivated vaccines. # Inactivated Vaccines A ntibody-containing products interact less w ith inactivated vaccines, toxoids, recom binant su bunit, and polysaccharide vaccines th an w ith live vaccines (61).Therefore, adm inistering inactivated vaccines and toxoids either sim ultaneously w ith or at any interval before or after receipt o f an antibody-containing p ro d u c t should n o t substantially im pair developm ent o f a protective antibody response (Table 4).T h e vaccine or toxoid and antibody preparation should be adm inistered at different sites using the standard recom m ended dose.Increasing the vaccine dose volum e or num ber o f vaccinations is n o t indicated or recom m ended. # Interchangeability of Single-Com ponent Vaccines from Different M anufacturers C ertain vaccines th at provide p ro tectio n from the same diseases are available from different m anufacturers, and these vaccines usually are n o t identical in antigen co n ten t or in am o u n t or m ethod o f form ulation.M anufacturers use differ ent production processes, and their products m ight contain different co ncentrations o f antigen per dose or a different stabilizer or preservative. Available data indicate th at infants w ho receive sequential doses o f different H ib conjugate, hepatitis B, and hepatitis A vaccines produce a satisfactory antib o d y response after a com plete prim ary series (62-65)-All brands o f H ib conju gate, hepatitis B ,î hepatitis A, rotavirus, and quadrivalent m eningococcal conjugate vaccines are interchangeable w ithin their respective series.

I f different brands o f a particular vaccine require a different nu m b er o f doses for series com pletion (e.g., H ib and rotavirus vaccines) and a provider mixes brands, the higher n u m b er o f doses is recom m ended for series com pletion (e.g., 3 doses o f either rotavirus or H ib vaccines). Lim ited data are available about the safety, im m unogenicity, and efficacy of using acellular pertussis (e.g., DTaP) vaccines from different m anufacturers for successive doses o f the per tussis series.D ata from one study indicate th at for the first 3 doses of the D TaP series, 1 -2 doses ofT ripedia (Sanofi Pasteur) followed by Infanrix (GlaxoSmithKline) for the rem aining dose (or doses) is com parable to 3 doses o fT rip ed ia w ith regard to im m unogenicity, as m easured by antibodies to diphtheria, tetanus, and pertussis toxoids, and filam entous hem agglutinin (66).However, in the absence o f a clear serologic correlate o f protectio n for pertussis, the relevance o f these im m unogenic ity data for protectio n against pertussis is unknow n. W h e n feasible, the same bran d o f D TaP vaccine should be used for all doses of the vaccination series.I f vaccination providers do n o t know or have available the type o f D TaP vaccine previ ously adm inistered to a child, any D TaP vaccine m ay be used to continue or com plete the series.For a child w ho needs 2 doses o f influenza vaccine (T IV or LAIV), it is preferable to use the sam e type o f vaccine for both doses.However, if the child is eligible for either T IV or LAIV, and the type o f vaccine used for the first dose is n o t available, either vaccine can be used for the second dose.For vaccines in general, vaccination should n o t be deferred because the brand used for previous doses is n o t available or is u n k n o w n (23,67). # Lapsed Vaccination Schedule V accination providers should adm inister vaccines as close to the recom m ended intervals as possible.However, intervals betw een doses th at are longer than recom m ended typically do n o t reduce final antibody concentrations, although protection m ight n o t be attained until the recom m ended num ber o f doses has been adm inistered.W ith exception o f oral typhoid vaccine, an in terru p tio n in the vaccination schedule does n o t require restarting the entire series o f a vaccine or toxoid or addition o f extra doses. # Unknown or Uncertain Vaccination Status V accination providers frequently encounter persons w ho do n o t have adequate d o cum entation o f vaccinations.W ith the exception o f influenza vaccine and PPSV, providers should only accept w ritten, dated records as evidence o f vaccination; self-reported doses o f influenza vaccine and PPSV are accept able (49,68).A lthough vaccinations should n o t be postponed if records cannot be found, an attem pt to locate missing records should be m ade by contacting previous health-care providers, reviewing state or local IISs, and searching for a personally held record.If records cannot be located w ithin a reasonable tim e, these persons should be considered susceptible and started on the age-appropriate vaccination sched ule.Serologic testing for im m u n ity is an alternative to vaccination for certain antigens (e.g., measles, rubella, hepatitis A, and tetanus).However, com m ercial serologic testing m ight n o t always be sufficiently sensitive o r standardized for detectio n o f vaccine-induced im m unity (with the exception o f hepatitis B vaccination at 1-2 m onths after the final dose), and research laboratory testing m ight not be readily available. # Contraindications and Precautions C ontraindications and precautions to vaccination are con ditions under w hich vaccines should n o t or likely should not be adm inistered.Because the m ajority o f contraindications and precautions are tem porary, vaccinations often can be adm inistered later if one or m ore exist.A con traindication is a condition in a recipient th at increases the risk for a serious adverse reaction.A vaccine should n o t be adm inistered w hen a c o n tra in d ica tio n is present; for exam ple, M M R vaccine should n o t be adm inistered to severely im m unocom prom ised persons.In contrast, certain conditions are com m only misperceived as contraindications (i.e., are n o t valid reasons to defer vaccination). N ational standards for pediatric vaccination practices have been established and include descriptions o f valid contraindica tions and precautions to vaccination.Persons w ho adm inister vaccines sh o u ld screen p atien ts for c o n train d icatio n s and p recautions to the vaccine before each dose o f vaccine is adm inistered (Table 6).Screening is facilitated by consistent use o f screening questionnaires, w hich are available from certain sta te v a c c in a tio n p ro g ram s a n d o th e r so u rces (e.g., th e Im m unization Action Coalition, w w .im m unize.org). T h e only co n train d icatio n applicable to all vaccines is a history o f a severe allergic reaction (i.e., anaphylaxis) after a previous dose o f vaccine or to a vaccine co m p o n en t (unless the recipient has been desensitized; see Special Situations section).In addition, severely im m uno co m p ro m ised persons generally should n o t receive live vaccines.C hild ren w ho experienced encephalopathy w ith in 7 days after adm inistration o f a pre vious dose o f d ip h th eria and tetanus toxoids and whole-cell pertussis vaccine (D T P ), DTaP, or T d ap n o t attributable to another identifiable cause should n o t receive additional doses of a vaccine th a t contains pertussis.Because of the theoreti cal risk to the fetus, w om en know n to be p regnant generally should n o t receive live, attenuated virus vaccines (see Special Situations section). A precaution is a condition in a recipient that m ight increase the risk for a serious adverse reaction or that m ight com prom ise the ability o f the vaccine to produce im m u n ity (e.g., adm in istering measles vaccine to a person w ith passive im m u n ity to measles from a blood transfusion or adm inistering influenza vaccine to som eone w ith a history o f G uillain-Barre syndrom e w ithin 6 weeks o f a previous influenza vaccination).A person m ight experience a m ore severe reaction to the vaccine than w ould have otherw ise been expected; however, the risk for this happening is less than the risk expected w ith a contraindication.In general, vaccinations should be deferred w hen a precaution is present.However, a vaccination m ight be indicated in the presence o f a p recaution if the benefit o f pro tectio n from the vaccine outweighs the risk for an adverse reaction.For example a dose o f D T aP should be considered for a person in a com m u n ity w ith a pertussis outbreak even if th at person previously developed G uillain-B arre syndrom e after a dose. T h e presence o f a m oderate or severe acute illness w ith or w ith o u t a fever is a precaution to adm inistration of all vaccines (Table 6).A personal or family history o f seizures is a precaution for M M R V vaccination.A recent study found an increased risk for febrile seizures in children w ho receive M M R V com pared w ith M M R and varicella vaccine (35). Clinicians or other health-care providers m ight misperceive certain conditions or circumstances as valid contraindications or precautions to vaccination when they actually do not preclude vaccination (Table 7).These m isperceptions result in missed opportunities to administer recom m ended vaccines (69).Among the m ost com m on conditions mistakenly considered to be con traindications are diarrhea, m inor upper respiratory tract illnesses (including otitis media) w ith or w ithout fever, mild to moderate local reactions to a previous dose o f vaccine, current antimicrobial therapy, and being in the convalescent phase o f an acute illness.Routine physical exam inations and procedures (e.g., measur ing tem peratures) are n o t prerequisites for vaccinating persons w ho appear to be healthy.T h e provider should ask the parent or guardian if the child is ill.I f the child has a m oderate or severe illness, the vaccination should be postponed. # Preventing and M anaging Adverse R eactions # Benefit and Risk Com munication Parents, guardians, legal representatives, and adolescent and adult patients should be inform ed about the benefits of and risks from vaccines in language th at is culturally sensitive and at an appropriate educational level.O p p o rtu n ity for questions should be provided before each vaccination.D iscussion o f the benefits o f and risks from vaccination is sound medical practice and is required by law. T h e N atio n al C h ild h o o d Vaccine In ju ry A ct o f 1 9 8 6 : : requires th at vaccine inform ation m aterials be developed for each vaccine covered by the act.T hese m aterials, know n as vaccine inform ation statem ents (VI Ss), m ust be provided by all public and private vaccination providers each tim e a vaccine is adm inistered.Copies ofV ISs are available from state health authorities responsible for vaccination and from C D C (h ttp :// www.cdc.gov/vaccines).Translations o fV IS s into languages o th er th an English are available from certain state vaccination programs and from the Im m unization A ction C oalition website ( w w .im m unize.org).T h e act does n o t require th at a signature be obtained; however, d o cu m en tatio n o f consent m ight be recom m ended or required by certain state or local h ealth authorities or school authorities.C ertain parents or patients question the need for or safety o f vaccinations and w ant to discuss the risks from and benefits o f certain vaccines.Some refuse certain vaccines or reject all vaccinations for personal or religious reasons.H aving a basic understanding of how patients and parents o f patients view vac cine risk and developing effective approaches to address vaccine safety concerns are im perative for vaccination providers. Each person understands and reacts to vaccine inform ation on the basis o f different factors, including previous experience, education, personal values, m eth o d o f data presentation, per ceptions o f the risk for disease and perceived ability to control these risks, and risk preference.Increasingly, decisions about vaccination are based o n inaccurate inform ation about risk provided by the m edia and certain websites.W ebsites and other sources o f vaccine info rm atio n m ight be inaccurate or incom plete.H ealth-care providers can be a pivotal source o f science-based credible inform ation by discussing w ith parents and patients the risks from and benefits o f vaccines, w hich helps patients m ake inform ed decisions.W h e n a parent or p atien t initiates a discussion about a per ceived vaccine adverse reaction, the health-care provider should discuss the specific concerns and provide factual inform ation, using appropriate language.Effective, em pathetic vaccine risk com m u n icatio n is essential in responding to m isinform ation and concerns, w'ith health-care providers recognizing that risk assessment and decision-making can be difficult and confusing.C ertain vaccines m ight be acceptable to a parent who is resistant to other vaccines.This partial acceptance can be used to facilitate additional communication.T heir concerns can be addressed using the VIS and offering other resource materials (e.g., vaccination inform ation from C D C : ). T h e A m erican A cadem y o f Pediatrics (AAP) does n o t rec om m en d th at providers exclude from their practice patients whose parents or guardians question or refuse vaccination.A lim ited nu m b er o f providers m ight exclude patients on this basis; however, an effective public health strategy is to identify com m on ground and discuss measures that need to be followed if the decision is to defer vaccination.H ealth-care providers should reinforce key p o in ts ab o u t each vaccine, including safety, and emphasize risks for disease am ong unvaccinated children.Parents should be advised o f state laws regarding entry to schools or child-care facilities, w hich m ight require th at unvaccinated children be excluded from the facility d u r ing outbreaks.T hese discussions should be docum ented in the patient's medical record, including the refusal to receive certain vaccines (i.e., inform ed refusal). # Preventing Adverse Reactions Vaccines are intended to produce active im m u n ity to spe cific antigens.A n adverse reaction is an undesirable side effect th at occurs after a vaccination.Vaccine adverse reactions are classified as 1) local, 2) system ic, or 3) allergic (additional inform ation available at w w .fda.gov).Local reactions (e.g., redness) are usually the least severe and m ost frequent.Systemic reactions (e.g., fever) occur less frequently th an local reactions, and severe allergic reactions (e.g., anaphylaxis) are the least frequent reactions.Severe adverse reactions are rare. Syncope (vasovagal or vasodepressor reaction) can occur after vaccination and is m ost com m on am ong adolescents and young adults.In 2005, the Vaccine Adverse Event R eporting System (VAERS) began detecting a trend o f increasing syncope reports th at coincided w ith the licensure o f three vaccines for adolescents: h u m an papillom avirus (H PV ), M C V 4, and T dap (77).O f particular concern am ong adolescents has been the risk for serious secondary injuries, including skull fracture and cerebral hem orrhage.O f 463 VAERS reports o f syncope during January 1, 2005, to July 31, 2007, a total o f 41 listed syncope w ith secondary injury w ith inform ation on the tim ing after vaccination, and the m ajority o f these syncope reports (76% ) occurred am ong adolescents.A m ong all age groups, 80% o f reported syncope episodes occur w ithin 15 m inutes o f vaccine ad m in istratio n (additional in fo rm atio n available at h ttp :// w w w .cdc.gov/vaccinesafety/concern/syncope.htm ).Providers should take appropriate measures to prevent injuries if a patient becom es weak or dizzy or loses consciousness.Adolescents and adults should be seated or lying dow n during vaccination.Vaccine providers, particularly w hen vaccinating adolescents, should consider observing patients (with patients seated or lying down) for 15 m inutes after vaccination to decrease the risk for injury should they faint (77).I f syncope develops, patients should be observed until the sym ptom s resolve. # Managing Acute Vaccine Reactions A lthough anaphylactic reactions are rare after vaccination, their im m ediate onset and life-threatening nature require that all personnel and facilities providing vaccinations have proce dures in place for anaphylaxis m anagem ent.All vaccination providers should be fam iliar w ith the office em ergency plan and be currently certified in cardiopulm onary resuscitation.Epinephrine and equipm ent for m aintaining an airway should be available for im m ediate use. A naphylaxis usually begins w ith in m in u te s o f vaccine adm inistration (78-80).Rapid recognition and initiation o f treatm ent are required to prevent possible progression to car diovascular collapse.If flushing, facial edema, urticaria, itching, swelling o f the m o u th or throat, w heezing, dyspnea, or other signs or sym ptom s o f anaphylaxis occur, the patient should be placed in a recum bent position w ith the legs elevated if possible (81,82).A d m inistration o f epinephrine is the m anagem ent o f choice.A dditional drugs also m ight be indicated (Table 8) (83).M aintenance o f the airway and oxygen adm inistration m ight be necessary.A fter the p atien t is stabilized, arrangem ents should be m ade for im m ediate transfer to an em ergency facility for additional evaluation and treatm ent. # Reporting Adverse Events After Vaccination M o d ern vaccines are safe and effective; however, adverse events have been reported after adm inistration o f all vaccines (84).M ore com plete inform ation about adverse reactions to a specific vaccine is available in the package insert for each vac cine and from C D C at w w .cdc.gov/vaccines/vac-gen/ side-effects.htm .An adverse event is an untow ard event that occurs after a vaccination th at m ight be caused by the vaccine p roduct or vaccination process.

These events range from com m on, m inor, local reactions to rare, severe, allergic reactions (e.g., anaphylaxis).Establishing evidence for cause and effect on the basis o f case reports and case series alone is usually n o t possible because health problem s that have a tem poral associa tion w ith vaccination do n o t necessarily indicate causality. M an y adverse events require m ore detailed epidem iologic studies to com pare th e incidence o f the event am ong vaccinees to the in cidence am o n g u n v accinated persons.R ep o rtin g adverse events, including serious events, to VAERS is a key m echanism for identifying p o tential vaccine safety concerns.Potential causal associations betw een reported adverse events after vaccination can be assessed th ro u g h epidem iologic or clinical studies. T h e N a tio n a l C h ild h o o d V accin e In ju ry A ct requires health-care providers and vaccine m anufacturers to report to VAERS specific adverse events th at occur after vaccination.T h e reporting requirem ents are different for m anufacturers and health-care providers.M anufacturers are required to report all adverse events th at occur after vaccination to VAERS, whereas health-care providers are required to report events th at appear in the reportable events table on the VAERS website at http:/./ vaers.hhs.gov/reportable.htm . In add itio n to the m andated reporting o f events listed on the reportable events table, health-care providers should report to VAERS all events listed in p ro d u ct inserts as contraindica tions, as well as all clinically significant adverse events, even if they are u ncertain th at the adverse event is related causally to vaccination.Persons other than health-care providers also can report adverse events to VAERS. # National Vaccine Injury Com pensation Program T h e N a tio n a l V accine In ju ry C o m p e n sa tio n P rogram , established by the N ational C hild h o o d Vaccine In ju ry A ct o f 1986, is a no-fault system in w hich persons th o u g h t to have experienced an injury or to have died as a result o f adm inistra tion o f a covered vaccine can seek com pensation.T h e program became operational on O ctober 1, 1988, and is intended as an alternative to civil litigation un d er the traditional to rt system in th at negligence need n o t be proven.C laim s arising from covered vaccines m ust first be adjudicated through the program before civil litigation can be pursued. T h e program relies on the Vaccine In ju ry Table, w hich lists the vaccines covered by the program and the injuries (including death), disabilities, illnesses, and conditions for w hich com pensation m ight be awarded.T he table defines the tim e during w hich the first sym ptom or substantial aggravation o f an injury m ust appear after vaccination to be eligible.Successful claim ants receive a legal presum ption o f causation if a condition listed in the table is proven, thus avoiding the need to prove actual causation in an individual case.C laim ants also can prevail for conditions n o t listed in the reportable events table if they prove causation for covered vaccines.A dditional inform ation is avail able from the H ealth Resources and Services A dm inistration (H RSA ) (h ttp w w .h rsa. # V accine Administration # Infection Control and Sterile Technique # General Precautions # Needles and Syringes Needles and syringes used for vaccine injections m ust be sterile and disposable.A separate needle and syringe should be used for each injection.C hanging needles betw een draw ing vaccine from a vial and injecting it into a recipient is not necessary unless the needle has been dam aged or contam i nated.D ifferent vaccines should never be mixed in the same syringe unless specifically licensed for such use, and no attem pt should be m ade to transfer betw een syringes.Single-dose vials and m anufacturer-filled syringes are designed for single-dose adm inistration and should be discarded if vaccine has been w ithdraw n or reconstituted and subsequently n o t used w ithin the tim e fram e specified by the m anufacturer.T h is typically is no longer th an th e sam e clinic day (typically recom m ended as a m axim um for inactivated vaccines). Som etim es providers prefill syringes themselves.A C IP dis courages the routine practice o f prefilling syringes because o f the potential for adm inistration errors and vaccine wastage.Because the m ajority o f vaccines have a similar appearance after being draw n into a syringe, prefilling m ight result in adm inis tration errors.In certain circum stances in w hich a single vac cine type is being used (e.g., in p reparation for a co m m u n ity influenza vaccination cam paign), filling a small n u m b er o f syringes m ay be considered.Vaccine doses should n o t be drawn into a syringe u n til im m ediately before adm inistration.W h e n syringes are filled, the type o f vaccine, lot num ber, and date o f filling m ust be labeled on each syringe, and the doses should be adm inistered as soon as possible after filling.U nused syringes filled by the end user (i.e., n o t filled by the m anufacturer) should be discarded at the end o f the vaccination session.In ad ditio n to adm inistration errors, prefilling o f syringes is a concern because F D A does n o t license adm inistration syringes for vaccine storage.U nused syringes th at are prefilled by the m anufacturer and activated (i.e., syringe cap removed or needle attached) should be discarded at the end o f the clinic day.T h e act directed O S H A to strengthen its existing bloodborne pathogen standards.T h e revised standards becam e effective in 2001 (86).These federal regulations require th at safetyengineered injection devices (e.g., needle-shielding syringes or needle-free injectors) be used for injectable vaccination in all clinical settings.T h e regulations also require m aintenance o f records docum enting injuries caused by needles and other m edical sharp objects and th at nonm anagerial employees be involved in the evaluation and selection o f safety-engineered devices before they are procured. Safety-engineered needles and syringes or needle-free injec tion devices are preferred and should be encouraged to reduce risk for injury.To prevent inadvertent needle-stick injury or reuse, safety m echanism s should be deployed after use and needles and syringes sh o u ld be discarded im m ed iately in labeled, p u n c tu re -p ro o f containers located in the same room w'here the vaccine is adm inistered.Used needles should never be recapped . N eedle-shielding or needle-free devices th at m ight satisfy the occupational safety regulations for adm inistering injectable vaccines are available in the U nited States (87-89).A dditional inform ation about im plem entation and enforcem ent of these regulations is available from O S H A ( w w .osha.gov). # Route of Administration # Oral Route Rotavirus and oral typhoid vaccines are the only vaccines adm inistered orally in the U nited States.O ral typhoid capsules should be adm inistered as directed by the m anufacturer.T h e capsules should n o t be opened or mixed w ith any other sub stance.Rotavirus vaccines are licensed for infants.T here are two brands o f rotavirus vaccine, and they have different types o f applicators.Providers should consult the package insert for details.A dose of rotavirus vaccine need n o t be repeated if the vaccine is spit up or vom ited.T h e infant should receive the rem aining recom m ended doses o f rotavirus vaccine following the routine schedule. # Intranasal Route LAIV is licensed for healthy nonpregnant persons aged 2-A9 years and is the only vaccine administered by the intranasal route.T he adm inistration device is a nasal sprayer w ith a dose-divider clip that allows introduction o f one 0.1 -m L spray into each naris.T he tip should be inserted slightly into the naris before adm in istration.Even if the person coughs or sneezes immediately after adm inistration or the dose is expelled any other way, the vaccine dose need not be repeated .Introduction o f low levels o f vaccine viruses into the environm ent likely is unavoidable w hen adminis tering LAIV; however, no instances have been reported o f illness or attenuated vaccine virus infections am ong inadvertently exposed health-care providers or im m unocom prom ised patients.T h e risk for acquiring vaccine viruses from the environm ent is unknow n but is likely low; in addition, vaccine viruses are cold-adapted and attenuated and unlikely to cause sym ptom atic influenza.Severely immunosuppressed persons should not administer LAIV However, other persons at higher risk for influenza complications can adm inister LAIV.These include persons w ith underlying medical conditions placing them at higher risk or w ho are likely to be at risk, including pregnant w om en, persons w ith asthma, and persons aged >50 years (68). # Injectable Route W ith the exception o f bacille C alm ette-G uérin (BCG ) vac cine and sm allpox vaccine, injectable vaccines are adm inistered by the intram uscular or subcutaneous route.T h e m ethod o f adm inistratio n o f injectable vaccines is determ ined, in part, by the presence o f adjuvants in som e vaccines.A n adjuvant is a vaccine co m p o n en t d istinct from the antigen th at enhances the im m u n e response to th e antigen.Inactivated vaccines c o n tain in g an ad ju v an t sh o u ld be injected in to a m uscle because adm inistration subcutaneously or intraderm ally can cause local irritation, induration, skin discoloration, inflam m a tion, and granulom a form ation.Routes o f adm inistration are recom m ended by the m anufacturer for each im m unobiologic (Table 9).D eviation from the recom m ended route o f adm in istration m ight reduce vaccine efficacy (90, 91) or increase the risk for local adverse reactions (92)(93)(94). # Intramuscular Injections # N ee d le Length Injectable im m unobiologies should be adm inistered where local, neural, vascular, or tissue injury is unlikely.Use o f longer needles has been associated w ith less redness or swelling than occurs w ith shorter needles because o f injection into deeper muscle mass (92).A ppropriate needle length depends on age and body mass.Injection technique is the m ost im p o rtan t param eter to ensure efficient intram uscular vaccine delivery. F or all in tra m u sc u la r in jectio n s, th e need le sh o u ld be long enough to reach the m uscle mass and prevent vaccine from seeping into subcutaneous tissue, b u t not so long as to involve underlying nerves, blood vessels, or bone (91,(95)(96)(97).Vaccinators should be fam iliar w ith the anatom y o f the area into w hich they are injecting vaccine.Intram uscular injections are adm inistered at a 90-degree angle to the skin, prefer ably into the anterolateral aspect o f the thigh or the deltoid muscle o f the upper arm , depending on the age o f the patient (Table 10). A decision on needle size and site o f injection m ust be m ade for each person on the basis o f the size o f the muscle, the thickness o f adipose tissue at the injection site, the volum e o f the m aterial to be adm inistered, injection technique, and the depth below the muscle surface into w hich the m aterial is to be injected (Figure 1).A spiration before injection o f vaccines or toxoids (i.e., pulling back on the syringe plunger after needle insertion b u t before injection) is n o t necessary because no large blood vessels are present at the recom m ended injection sites, and a process th at includes aspiration m ight be m ore painful for infants (98). # In fan ts (Aged < 1 2 M on th s) For the m ajority o f infants, the anterolateral aspect o f the thigh is the recom m ended site for injection because it provides a large m uscle mass (Figure 2).In certain circum stances (e.g., physical obstruction to other sites and no reasonable indication to defer doses), the gluteal muscle can be used.I f the gluteal muscle m ust be used, care should be taken to define the ana tom ic la n d m a r k s .I n je c tio n technique is the m ost im portant param eter to ensure efficient intram uscular vaccine delivery.I f the subcutaneous and m uscle tissue are bunched to m inim ize the chance o f striking bone (95), a 1-inch needle is required to ensure intram uscular adm inistration in infants aged >1 m onth.For the m ajority o f infants, a 1-inch, 22-to 25-gauge needle is sufficient to penetrate the thigh muscle.For neonates (first 28 days o f life) and preterm infants, a % -inch needle usually is adequate if the skin is stretched flat between the th u m b and forefinger and the needle is inserted at a 90-degree angle to the skin (97). # Toddlers (Aged 12 M o n th s -2 Years) For toddlers, the anterolateral thigh muscle is preferred, and if used, the needle should be at least 1 inch long.T h e deltoid muscle can be used if the muscle mass is adequate.A % -inch needle is adequate only for the deltoid m uscle and only if the skin is stretched flat betw een th u m b and forefinger and the needle is inserted at a 90-degree angle to the skin. # C hildren (Aged 3 -1 8 Years) T h e deltoid m uscle is preferred for children aged 3-18 years (Figure 3); the needle size for deltoid site injections can range from 22 to 25 gauge and from Vs to 1 inch on the basis o f tech nique.Knowledge o f body mass can be useful for estim ating the appropriate needle length (99)', however, neither a physical exam ination n o r m easurem ent o f body mass is necessary to adm inister vaccines.M ost children in this age range require a %-or 1-inch needle (or interm ediate size, if available). # A dults (Aged > 1 9 Years) For adults, the deltoid muscle is recom m ended for routine intram uscular vaccinations.T h e anterolateral thig h also can be used.For m en and w om en w ho weigh 200 lbs (>90 kg) or m en w ho w eigh >260 lbs (> 1 18 kg), a 1 Vi-inch needle is recom m ended (Table 10) (96). # Subcutaneous Injections Subcutaneous injections are adm inistered at a 45-degree angle, usually into the thigh for infants aged 12 m onths.Subcutaneous injections m ay be adm inistered into the upperouter triceps area o f an infant if necessary.A % -inch, 23-to 25-gauge needle should be inserted into the subcutaneous tissue (Figures 4 and 5). # Multiple Injections I f m ultiple vaccines are adm inistered at a single visit, adm in ister each preparation at a different anatom ic site.For infants and younger children, if m ore th an tw o vaccines are injected in a single lim b, the thigh is the preferred site because o f the greater muscle mass; the injections should be sufficiently sepa rated (i.e., >1 inch if possible) so th at any local reactions can be differentiated (92,100) # Jet Injections Jet injectors are needle-free devices th at pressurize liquid m edication, forcing it th ro u g h a nozzle orifice into a narrow' stream capable o f penetrating skin to deliver a drug or vac cine into intraderm al, subcutaneous, or intram uscular tissues (101,102).Jet injectors prevent needle-stick injuries to health care providers (86) and can overcome im proper, unsterile reuse and other drawbacks o f needles and syringes in developing countries (87, .Im m u n e responses generated by jet injectors against b o th attenuated and inactivated viral and bacterial antigens are usually equivalent to, and occasionally greater than, im m une responses induced by needle injection.However, local reactions or injuries are som etim es m ore fre quent on delivery o f vaccine by jet injectors com pared w'ith needle injection, depending on the inherent irritability o f the vaccine and operator technique (102).Jet injectors that use the same nozzle for consecutive injections w ithout intervening sterilization were used in mass vaccination cam paigns from the 1950s through the 1990s (102); however, these were found to be unsafe because o f the possibility o f bloodborne pathogen transm ission (105-108) and should n o t be used.

A new gen eration o f jet injectors w ith disposable cartridges and syringes has been developed since the 1990s.W ith a new, sterile dose cham ber and nozzle for each p atien t and correct use, these devices do n o t have the same safety concerns as m ultiple-use nozzle jet injectors.Several o f the new er devices have been approved by FD A for sale in the U nited States (102). # M ethods for Alleviating Discomfort and Pain Associated with Vaccination C o m fort measures, such as distraction (e.g., playing m usic or p re ten d in g to blow away the pain), ingestion o f sweet liquids, breastfeeding, cooling of the injection site, and topi cal analgesia, can help infants or children cope w ith the dis com fort associated w ith vaccination (109,110).P retreatm ent (30-60 m inutes before injection) w ith a 5% topical lidocaineprilocaine em ulsion m ight decrease the pain o f vaccination by causing superficial anesthesia (111,112) # Nonstandard Vaccination Practices Recommendations for route, site, and dosage o f immunobiolog ies are derived from data from clinical trials, practical experience, norm al periodicity o f health-care visits, and theoretical consider ations.A CIP discourages variations from the recommend ed route, site, volume, or num ber o f doses o f any vaccine. Variation from the recom m ended route and site can result in inadequate protection.In adults (but not in infants) (117), the im m unogenicity o f hepatitis B is substantially lower w hen the gluteal rather than the deltoid site is used for adm inistration (90).Hepatitis B administered intraderm ally might result in a lower seroconversion rate and final titer o f hepatitis B surface antibody than w hen administered by the deltoid intramuscular route (118,119).Hepatitis B administered by any route other than intramuscular, or in adults at any site other than the deltoid or anterolateral thigh, should not be counted as valid and should be repeated.Similarly, doses o f rabies vaccine administered in the gluteal site should not be counted as valid doses and should be repeated (120).M C V 4 should be administered intram uscu larly; however, revaccination is not necessary if a vaccine dose is administered subcutaneously (121).Inactivated influenza vaccine is im m unogenic w hen administered in a lower than standard dose by the intraderm al route to healthy adult volunteers (122).However, the im m unogenicity for persons aged >60 years is inadequate, and varying the recom m ended route and dose is not recomm ended. Live, attenuated injectable vaccines (e.g., M M R , varicella, and yellow fever) and certain inactivated vaccines (e.g., meningococ cal polysaccharide) are recom m ended by the manufacturers to be adm inistered by subcutaneous injection.PPSV and IPV are recom m ended by the m anufacturer to be administered by the subcutaneous or intram uscular route.Response to vaccines rec om m ended by the subcutaneous route are unlikely to be affected if the vaccines are administered by the intram uscular rather than subcutaneous route.Repeating doses o f vaccine administered by the intram uscular route w hen recom m ended to be by the subcutaneous route is not necessary. Adm inistering volumes smaller than recom m ended (e.g., inap propriately divided doses) m ight result in inadequate protection.Using reduced doses administered at m ultiple vaccination visits that equal a full dose or using smaller divided doses is not recom mended.Any vaccination using less than the standard dose should not be counted, and the person should be revaccinated according to age unless serologic testing indicates that an adequate response has developed.If less than a full recommended dose o f a parenteral vaccine is administered because o f syringe or needle leakage, the dose should be repeated.Using larger than recommended dosages can be hazardous because o f excessive local or systemic concentra tions of antigens or other vaccine constituents. # Storage and Handling of Im m unobiologies # Storage Temperature Vaccines licensed for refrigerator storage should be stored at 35°F-46°F (2°C-8°C).L iquid vaccines containing an alum i num adjuvant perm anently lose potency w hen exposed to freez ing tem peratures.Live, attenuated virus vaccines th at should be frozen lose potency w'hen exposed to higher tem peratures because the viruses degrade m ore quickly at storage tem pera tures th at are w arm er than recom m ended (Table 11). # Storage Units Refrigerators and freezers used for vaccine storage m ust m aintain the required tem perature range year-round, be large enough to hold the year's largest inventory, and be dedicated to storage o f vaccines.Vaccine storage units m ust be carefully selected, used properly, and consistently m onitored to ensure that recom m ended tem peratures are m aintained.Refrigerators w ithout freezers and stand-alone freezers (either m anual defrost or autom atic defrost) are usually the m ost effective at m aintain ing the precise tem peratures required for vaccine storage.Such single-purpose units sold for hom e use are less expensive alter natives to medical specialty equipm ent (123) and are preferable to com bination units.A com bination refrigerator-freezer unit sold for hom e use m ight be adequate for storing lim ited qu an tities o f vaccines if the refrigerator and freezer com partm ents have separate external doors.Before using the refrigerator for vaccine storage, the tem perature should be allowed to stabilize and then be m easured in various locations w ithin the refrigera tor co m p artm en t to d o cum ent th at a consistent tem perature can be m aintained w ithin the co m p artm en t (Table 11) (124).N ew units m ight need >2 days o f operation to establish a stable operating tem perature; vaccine should n o t be stored in the unit until the u n it m aintains an appropriate and stable storage tem perature.Refrigerator tem peratures are m ost reflective o f the actual co m p artm en t tem perature after the door has rem ained closed and u n d istu rb ed for several hours (e.g., overnight).T h e refrigerator tem perature should be set at the m idpoint o f the recom m ended range (i.e., 40°F ) (125,126).A storage u n it should be sufficiently sized so that vaccines can be placed away from the walls in the p art o f the u n it best able to m aintain the constant, required tem perature.C o m bination units, w ith separate com partm ents o f sm aller size, can only be used to store lim ited quantities o f vaccines.Frequent opening and closing o f doors can cause fluctuations in com partm ent tem perature; food, beverages, and clinical specimens should n o t be stored in vaccine storage units.I f it becomes necessary to store clinical specim ens in the same u n it as vaccines, the clinical specim ens should be o n a shelf below the vaccine to prevent co n tam in atio n should the specim en leak. # Temperature Monitoring Tem perature m onitoring is a critical com ponent o f tem pera ture m anagem ent.All office and clinical staff m em bers should be aware o f vaccine vulnerabilities and storage requirem ents.Assigning one person in the office the prim ary responsibility for m aintaining and reviewing tem perature logs (Figure 6) gener ally is m ost effective, w ith a second person assigned as backup.Tem peratures for b o th the refrigerator and freezer should be docum ented twice a day and recorded.T h e backup person should review the log at least once each week.Tem perature logs should be m aintained for 3 years unless state or local authorities require a longer tim e. A n autom ated m onitoring system th at alerts staff w hen a tem perature deviation occurs is optim al.However, even if an autom ated m o n ito ring system is used, tem peratures still should be m anually checked and recorded twice each day. T o f the m anufacturing process, this recom m endation refers to a second calibration process that occurs after m anufacturing b u t before m arketing and is docum ented w ith a certificate that comes w ith the product.Some products (e.g., continuous chart recorder therm om eters) usually include a m anufacturerdefined schedule for additional recalibration.For m any types o f therm om eters, replacem ent m ight be less expensive than recalibration.T herm om eters that require batteries need to have the batteries changed; review the d o cum entation th at comes w ith the p ro duct for guidance. # Response to Out-of-Range Temperature Reading A n o u t-o f-ra n g e te m p e ra tu re re a d in g sh o u ld p ro m p t im m ediate action.A plan should be d eveloped ahead o f tim e to address various types o f emergencies th at m ight require removal o f vaccine from the original storage unit.Transfer o f vaccines to a predesignated alternative em ergency storage site m ight be necessary if a tem perature problem cannot be resolved im m ediately (e.g., plugging in an unplugged unit or closing a door th a t has been left open).Vaccine should be m arked "do n o t use" and moved to the alternate site after verifying that the alternate u n it is at the proper tem perature.After the vac cine has been moved, determ ine w hether the vaccine is still useable by contacting the state or local health d epartm ent or m anufacturer.D am age to the im m unogenicity o f a vaccine exposed to tem peratures outside o f the recom m ended range m ight n o t be apparent visually.As a general rule, vaccines that have been stored at inappropriate tem peratures should not be adm inistered.I f such vaccines already have been adm inis tered, guidance is available from the state health departm ent or C D C .Vaccine exposed to inappropriate tem peratures that is inadvertently adm inistered should generally be repeated.Clinicians should consult w ith state or local health depart m ents in these situations. # Expiration Dates and Windows All vaccines have an expiration date determ in ed by the m anufacturer th at m ust be observed.Providers should record the vaccine expiration dates and lot num bers on a stock or inventory record for each vaccine vial w hen a sh ip m en t is received.W h e n vaccines are rem oved from storage, clinicians and other health-care providers should note w hether an expira tion w indow exists for vaccine stored at room tem perature or at an interm ediate tem perature.For example, single-com ponent varicella vaccine th at is stored frozen m ust be discarded after 72 hours o f storage at refrigerator tem perature.Vaccine trans p o rt betw een the storage site and the adm inistration clinic is discouraged unless the cold chain is m aintained, and vaccine tran sp o rt by th e p a tie n t (e.g., tra n sp o rtin g zoster vaccine from a p harm acy to a clinic) is particularly discouraged.A n expiration w indow also applies to vaccines th a t have been reconstituted.For example, after reconstitution, M M R vac cine should be k ept at refrigerator tem perature and m ust be adm inistered w ithin 8 hours.Doses o f expired vaccines that are adm inistered inadvertently generally should n o t be counted as valid and should be repeated.Inactivated vaccines should be repeated as soon as possible.Live vaccines should be repeated after a 28-day interval from the invalid dose to reduce the risk for interference from interferon on the subsequent doses.A dditional inform ation about expiration dates is available at w w .cdc.gov/ vaccines/recs/storage. # Multidose Vials C ertain vaccines (i.e., quadrivalent m eningococcal poly saccharide vaccine , PPSV, TIV, IPV, and yellow fever) are available in m ultidose vials.Because several doses are w ithdraw n from the sam e vial, p roper technique m ust be followed to prevent contam ination.For m ultidose vials that do n o t require reconstitution, doses th at rem ain after w ith drawal of a dose can be adm inistered until the expiration date p rin ted on the vial or vaccine packaging if the vial has been stored correctly and the vaccine is n o t visibly contam inated, unless otherwise specified by the m anufacturer.M ultidose vials that require reco n stitu tio n m ust be used w ith in the interval specified by the m anufacturer.A fter reconstitution, the new expiration date should be w ritten on the vial. # Altered Im m unocom petence # General Principles A ltered im m u n o co m p eten ce, a term often used synony m ously w ith im m unosuppression and im m unocom prom ise, can be classified as prim ary or secondary.Prim ary im m unodefi ciencies generally are inherited and include conditions defined by an absence or quantitative deficiency o f cellular or hum oral com ponents or both that provide im m unity.Examples include congenital im m unodeficiency diseases such as X -linked agam m aglobulinem ia, severe com bined im m unodeficiency disease, and chronic granulom atous disease.Secondary im m unodefi ciency generally is acquired and is defined by loss or qualitative deficiency in cellular or hum oral im m u n e com ponents that occurs as a result o f a disease process or its therapy.Examples o f sec o n d a ry im m u n o d e fic ie n c y in c lu d e H IV in fe c tio n , hem atopoietic m alignancies, treatm en t w ith radiation, and treatm ent w ith im m unosuppressive drugs including alkylating agents and antim etabolites.T h e degree to w hich im m u n o su p pressive drugs cause clinically significant im m unodeficiency generally is dose related and varies by drug.Prim ary and sec ondary im m unodeficiencies m ight include a com bination o f deficits in both cellular and hum oral im m unity.In this report, the general term altered im m unocom petence also is used to include conditions such as asplenia and chronic renal disease, and treatm ents w ith therapeutic m onoclonal antibodies (spe cifically, the tu m o r necrosis factor inhibitors) (127-132) and prolonged adm inistration o f high-dose corticosteroids. D eterm in atio n o f altered im m un o co m p eten ce is im p o r tan t to the vaccine provider because incidence or severity o f som e vaccine-preventable diseases is higher in persons w ith altered im m unocom petence; therefore, certain vaccines (e.g., inactivated influenza vaccine and pneum ococcal vaccines) are recom m ended specifically for persons w ith these diseases (28,68).Vaccines m ight be less effective during the period o f altered im m unocom petence.Live vaccines m ight need to be deferred u n til im m une function has im proved.Inactivated vaccines adm inistered during the period o f altered im m u n o com petence m ight need to be repeated after im m une function has im proved.In ad d itio n , persons w ith altered im m u n o com petence m ight be at increased risk for an adverse reaction after adm inistration o f live, attenuated vaccines because o f uninhibited replication. T he degree o f altered im m unocom petence in a patient should be determ ined by a physician.T h e challenge for clinicians and other health-care providers is assessing the safety and effective ness o f vaccines for conditions associated w ith prim ary or sec ondary im m unodeficiency, especially w hen new therapeutic modalities are being used and inform ation about the safety and effectiveness o f vaccines has not been characterized fully in persons receiving these drugs (Table 13).Laboratory studies can be useful for assessing the effects o f a disease or drug on the im m une system.Tests useful to assess hum oral im m unity include im m unoglobulin (and im m unoglobulin subset) levels and spe cific antibody levels (e.g., tetanus and diphtheria).Tests that dem onstrate the status o f cellular im m unity include lymphocyte num bers (i.e., a com plete blood count with differential), a test that delineates concentrations and proportions o f lymphocyte subsets (i.e., B and T lymphocytes, C D 4 + T versus C D 8+ T lym phocytes), and tests th at measure T-cell proliferation in response to specific or nonspecific stimuli (e.g., lym phocyte proliferation assays) (133,134).T he ability to characterize a drug or disease condition as affecting cellular or hum oral im m unity is only the first step; using this inform ation to draw inferences about w hether particular vaccines are indicated or w hether cau tion is advised w ith use o f live or inactivated vaccines is more com plicated and m ight require consultation w ith an infectious disease or im m unology specialist.

# Altered Im m unocom petence as an Indication to Receive a Vaccine # Vaccination with Inactivated Vaccines All inactivated vaccines can be adm inistered safely to per sons w ith altered im m unocom petence w hether the vaccine is a killed w hole-organism or a recom binant, subunit, toxoid, polysaccharide, or polysaccharide protein-conjugate vaccine.If inactivated vaccines are indicated for persons w ith altered im m unocom petence, the usual doses and schedules are rec om m ended.However, the effectiveness o f such vaccinations m ight be suboptim al. Except for inactivated influenza vaccine, vaccination during chem otherapy or radiation therapy should be avoided if pos sible because antibody response m ight be suboptim al.Patients vaccinated w ithin 14 days before starting im m unosuppressive therapy or while receiving im m unosuppressive therapy should be considered unim m unized and should be revaccinated at least 3 m onths after therapy is discontinued if im m une com petence has been restored. # Vaccination with Live, Attenuated Viral and Bacterial Vaccines Severe # Recipients of Hematopoietic Cell Transplants A hem atopoietic cell transplant (H C T ) results in im m u nosuppression because o f the hem atopoietic ablative therapy adm inistered before the transplant, drugs used to prevent or treat graft-versus-host disease, and, in som e cases, from the underlying disease process necessitating transplantation (152)(153)(154) # Conditions or Drugs that Might Cause Im m unodeficiencies Asplenia and use o f corticosteroids or certain drugs have the potential to be im m unosuppressive and are presum ed to cause som e degree o f altered im m unocom petence. # A natom ic or Functional Asplenia Persons w ith anatom ic asplenia (e.g., surgical removal or congenital absence o f the spleen) or functional asplenia (as occurs in persons w ith sickle cell disease) are at increased risk for infection by encapsulated bacteria, especially by S. Pneumococcal, m eningococcal, and H ib vaccinations should be adm inistered at least 14 days before elective splenectomy, if possible.If the vaccinations are n o t adm inistered before surgery, they should be adm inistered after the procedure as soon as the p atien t's condition is stable. # Corticosteroids T he am ount o f systemically absorbed corticosteroids and the duration o f adm inistration needed to suppress the im m une system o f an otherw ise im m u n o co m p eten t person are n o t well defined.C orticosteroid therapy usually is n o t a contraindica tion to adm inistering live-virus vaccine w hen adm inistration is 1) short term (i.e., 2 m g/kg o f body w eight or >20 m g/day o f prednisone or equivalent for persons w ho weigh >10 kg w hen adm inistered for >14 days as sufficiently im m unosuppressive to raise concern about the safety o f vaccination w ith live-virus vaccines (154).C orticosteroids used in greater than physiologic doses also can reduce the im m une response to vaccines.Vaccination providers should defer live-virus vaccination for at least 1 m o n th after discon tin u atio n of high-dose systemically absorbed corticos teroid therapy adm inistered for >14 days. # Other Immunosuppressive Drugs W h e n feasible, clinicians should adm inister all indicated vac cines to all persons before initiatio n o f chem otherapy, before treatm en t w ith oth er im m unosuppressive drugs, and before radiation or splenectom y. Persons receiving chem otherapy or radiation for leukem ia and other hem atopoietic m alignancies, for solid tum ors, or after solid organ tran sp lan t should be assumed to have altered im m unocom petence. # S pecial Situations # Concurrent Administration of Antimicrobial Agents and Vaccines W ith a few exceptions, use o f an antim icrobial agent is not a contraindication to vaccination.A ntibacterial agents have no effect on the response to live, attenuated vaccines, except live o ra lT y 2 la typhoid vaccine, and have no effect on inactivated, recom binant subunit, or polysaccharide vaccines or toxoids.T y 2 la typhoid vaccine should not be adm inistered to persons receiving antim icrobial agents until 24 hours after the last dose o f antim icrobial (14).I f feasible, to avoid a possible reduction in vaccine effectiveness, antibacterial drugs should n o t be started or resum ed until 1 week after the last dose ofT y21a. A n tiv ira l d ru g s used for tre a tm e n t o r p ro p h y lax is o f influenza virus infections have no effect on the response to inactivated influenza vaccine (68).However, live, attenuated influenza vaccine should n o t be adm inistered u n til 48 hours after cessation o f therapy w ith antiviral influenza drugs.If feasible, to avoid possible reduction in vaccine effectiveness, antiviral m edication should n o t be adm inistered for 14 days after LAIV adm inistration (68).A ntiviral drugs active against herpesviruses (e.g., acyclovir or valacyclovir) m ight reduce the efficacy o f live, attenuated varicella and zoster vaccines (4,55).These drugs should be discontinued at least 24 hours before adm inistration o f vaccines containing varicella zoster virus, including zoster vaccine, if possible.D elay use or resum ption o f antiviral therapy for 14 days after vaccination.N o data exist to suggest that com m only used antiviral drugs have an effect on rotavirus vaccine or M M R . # Tuberculosis Screening and Skin Test Reactivity Measles illness, severe acute or chronic infections, H IV infection, and m aln u tritio n can create a relatively anergic state during w hich the tuberculin skin test (TST) m ight have a falsenegative reaction (156-158).A lthough any live, attenuated measles vaccine theoretically can suppress T S T reactivity, the degree o f suppression is likely less th an that occurring from acute infection from wild-type measles virus.A lthough routine T S T screening o f all children is no longer recom m ended, T S T screening is som etim es needed (e.g., for well child care, school entrance, or employee health reasons) at the same tim e as adm inistration o f a m easles-containing vaccine. T h e T S T and m easles-containing vaccine can be adm in istered at the same visit (preferred option).Sim ultaneously adm inistering the T S T and m easles-containing vaccine does n o t interfere w ith reading the T S T result at 4 8 -7 2 hours and ensures that the person has received measles vaccine. I f th e m easles-containing vaccine has been adm inistered recently, T S T screening should be delayed for at least 4 weeks after vaccination.A delay in perform ing the T S T removes the concern o f any theoretical b u t transient suppression o f T S T reactivity from the vaccine. T S T screening can be perform ed and read before adm inis tration of the m easles-containing vaccine.T h is o p tion is the least favored because it delays receipt o f the m easles-containing vaccine.If a person is suspected to have tuberculosis, n o t only should the M M R vaccine be w ithheld before the TST, it should be w ithheld u n til after treatm en t has been initiated because a person w ith active tuberculosis w ho is m oderately or severely ill should n o t receive M M R vaccine.In a general screening situation in w hich tuberculosis is n o t suspected, a T S T may be adm inistered sim ultaneously w ith live vaccines or should be deferred for 28 days after vaccination. N o data exist regarding the poten tial degree o f T S T sup pression that m ight be associated w ith other live, attenuated virus vaccines (e.g., varicella or yellow fever).However, in the absence o f data, following guidelines for m easles-containing vaccine w hen scheduling T S T screening and adm inistering other live, attenuated virus vaccines is p ru d en t. I f the oppor tu n ity to vaccinate m ight be missed, vaccination should not be delayed only because o f these theoretical considerations. # Because o f sim ilar concerns about sm allpox vaccine and T S T suppression, a T S T should n o t be perform ed until 4 weeks after sm allpox vaccination ( 1.59). A m ore specific test for diagnosis o f tuberculosis or latent tuberculosis infection was licensed in 2005-T h e interferon gam m a release assay (IGRA) requires only one visit to com plete and is less sensitive to the effects o f previous B C G vaccination (160).T h e same tim in g guidelines that apply to the interval betw een a live vaccine and T S T apply to IG R A (i.e., 28 days betw een live vaccine and IG R A if they do n o t occur on the same day), because IG R A (like T S T ) m ig h t be suppressed th ro u g h im m unologic m echanism s. T h e p o tential for T S T to cause boosting o f results should be considered in adults w ho m ight have latent tuberculosis and have a negative in itia lT S T (160).T h e tw o-step tuberculin test is recom m ended for certain situations (160).Because this test consists o f two TSTs (or a T S T followed by IGRA) separated by an interval o f 1-3 weeks, there is a greater w indow o f tim e during which live vaccine replication could suppress reactivity.If a live vaccine is adm inistered, the first dose o f a two-step T S T should be delayed for 4 weeks, and if additional doses of live vaccines are indicated thereafter, they should be delayed until the second T S T (or the IG R A after an initial T ST ). T S T or IG RA reactivity in the absence o f tuberculosis disease is n o t a contraindication to adm inistration o f any vaccine, including live, attenuated virus vaccines.Tuberculosis disease is n o t a contraindication to vaccination, unless the person is m oderately or severely ill.A lthough no studies have reported on the effects o f M M R vaccine on persons w ith untreated tuberculosis, a theoretical basis exists for concern that measles vaccine m ight exacerbate tuberculosis disease (2).As a result, before adm inistering M M R to persons w ith untreated active tuberculosis, initiating antituberculosis therapy is advisable (2).C onsidering w hether concurrent im m unosuppression (e.g., im m unosuppression caused by H IV infection) is a concern before adm inistering live, attenuated vaccines also is prudent. # Severe Allergy to Vaccine Com ponents Vaccine co m ponents can cause allergic reactions am ong certain recipients.T hese reactions can be local or systemic and can include anaphylaxis or anaphylactic-like responses (e.g., generalized urticaria or hives, wheezing, swelling o f the m outh and throat, dyspnea, hypotension, and shock).Allergic reactions m ight be caused by the vaccine antigen, residual anim al protein, antim icrobial agents, preservatives, stabiliz ers, or o th er vaccine com ponents (161).C hildren w ho have had an apparent severe allergic reaction to a vaccine should be evaluated by an allergist to determ ine the responsible allergen and to m ake recom m endations regarding future vaccination.C o m ponents o f each vaccine are listed in the respective pack age insert.A n extensive list o f vaccine com ponents and their use, as well as the vaccines th at contain each com ponent, has been published (162) and also is available from C D C (h ttp :// www.cdc.gov/ vaccines). T h e m ost com m on anim al p rotein allergen is egg protein, w hich is found in influenza and yellow fever vaccines because they are prepared using em bryonated chicken eggs.Ordinarily, persons w ho are able to eat eggs or egg products safely can receive these vaccines; persons w ho have had an anaphylactic or anaphylactic-like allergy to eggs or egg proteins generally should n o t receive these vaccines.Asking persons if they can eat eggs w ith o u t adverse effects is a reasonable way to determ ine w hich persons m ight be at risk for allergic reactions from yel low fever and influenza vaccines.A regim en for adm inistering influenza vaccine to children w ith egg hypersensitivity and severe asthm a has been developed (163,164) # Latex Allergy Latex is sap from the com m ercial rubber tree.Latex contains naturally occurring im purities (e.g., plant proteins and pep tides) th at m ight be responsible for allergic reactions.Latex is processed to form natural rubber latex and dry, natural rubber.N atural rubber latex and dry, natural rubber m ight contain the same plant im purities as latex b u t in lesser am ounts.N atural ru b b er latex is used to p ro d u ce m edical gloves, catheters, and other products.Dry, natural rubber is used in the tip o f syringe plungers, the tip on prefilled syringes, vial stoppers, and injection ports on intravascular tubing.Synthetic rubber and synthetic latex also are used in m edical gloves, syringe plungers, and vial stoppers.Synthetic rubber and synthetic latex do n o t contain natural rubber or natural latex and do n o t contain im purities linked to allergic reactions.Latex or dry, natural rubber used in vaccine packaging generally is noted in the m anufacturers' package inserts. T he most com m on type o f latex sensitivity is a contact-type (type 4) allergy, usually as a result o f prolonged contact w ith latex-containing gloves (176).However, latex allergies associated w ith injection procedures have been described am ong patients w ith diabetes mellitus (177-179)-Allergic reactions (including anaphylaxis) after vaccinations are rare.A review o f reports to VAERS identified only 28 cases o f possible im m ediate-type anaphylactic reactions among more than 160,000 vaccine adverse event reports (180). If a person reports a severe (anaphylactic) allergy to latex, vaccines supplied in vials or syringes th at co ntain natural rubber latex should n o t be adm inistered unless the benefit o f vaccination clearly outweighs the risk for a potential allergic reaction.In these cases, providers should be prepared to treat patients w ho are having an allergic reaction.For latex allergies other th an anaphylactic allergies (e.g., a history o f contact allergy to latex gloves), vaccines supplied in vials or syringes th at contain dry, natural rubber or natural rubber latex may be adm inistered. # Vaccination of Preterm Infants In the m ajority o f cases, preterm infants (infants born before 37 weeks' gestation), regardless o f b irth w eight, should be vaccinated at the same chronological age and according to the same schedule and using the same precautions as for full-term I f a child aged at least 6 weeks has been in the hospital since birth, deferral o f rotavirus vaccine is recom m ended until the tim e of discharge (136).T h e rotavirus vaccine series should n o t be initiated for infants aged >15 weeks, 0 days. # Breastfeeding and Vaccination N eith er inactivated n o r live-virus vaccines adm inistered to a lactating w om an affect the safety o f breastfeeding for w om en or their infants.A lthough live viruses in vaccines can replicate in vaccine recipients (i.e., the m other), the m ajority o f live viruses in vaccines have been d em onstrated n o t to be excreted in hu m an milk.Varicella vaccine virus has n o t been found in h u m an m ilk (190).A lthough rubella vaccine virus m ight be excreted in h u m a n m ilk, the virus usually does n o t infect the infant.If infection does occur, it is well tolerated because the virus is attenuated (191).Inactivated, recom binant, subunit, polysaccharide, and conjugate vaccines, as well as toxoids, pose no risk for m others w ho are breastfeeding or for their infants.Breastfeeding is a contraindication for sm allpox vaccination o f the m o th er because o f the theoretical risk for contact trans m ission from m o th er to infant.Yellow fever vaccine should be avoided in breastfeeding w om en (19).However, w hen nursing m others can n o t avoid or postpone travel to areas endem ic for yellow fever in w hich risk for acquisition is high, these w om en should be vaccinated. Lim ited data indicate that breastfeeding can enhance the response to certain vaccine antigens (192).T here are no data to suggest th at passive transfer o f antibodies in h u m a n m ilk can affect the efficacy o f live-virus vaccines.Breastfed infants should be vaccinated according to the recom m ended schedule (1 9 3 -1 9 5 ). # Vaccination During Pregnancy Risk to a developing fetus from vaccination o f the m other during pregnancy is theoretical.N o evidence exists o f risk to the fetus from vaccinating pregnant w om en w ith inactivated virus or bacterial vaccines or toxoids (196,197).

Live vaccines adm inistered to a pregnant w om an pose a theoretical risk to the fetus; therefore, live, attenuated virus and live bacterial vac cines generally are contraindicated during pregnancy.Benefits o f vaccinating pregnant w om en usually outw eigh potential risks w hen the likelihood o f disease exposure is high, w hen infection would pose a risk to the m other or fetus, and w hen the vaccine is unlikely to cause harm .R ecom m endations for vaccination d u rin g pregnancy are developed using A C IP 's G uiding Principles fo r Development o fA C IP Recommendations fo r Vaccination D uring Pregnancy a n d Breastfeeding (198).Because vaccinating against influenza before the season begins is critical, and because predicting exactly w hen the season will begin is im possible, routine influenza vaccination is recom m ended for all w om en w ho are or will be pregnant (in any trim ester) durin g influenza season, w hich in the U nited States is usually early O cto b er th ro u g h late M arch (68). IPV can be adm inistered to p regnant w om en who are at risk for exposure to w ild -ty p e poliovirus in fectio n (201).H epatitis A, pneum ococcal polysaccharide, m eningococcal conjugate, and m eningococcal polysaccharide vaccines should be considered for w om en at increased risk for those infections (49,51,202).Pregnant w om en w ho m ust travel to areas where the risk for yellow fever is high should receive yellow fever vaccine because the lim ited theoretical risk from vaccination is outw eighed substantially by the risk for yellow fever infec tion (19,203).H epatitis B vaccine is n o t contraindicated in pregnancy and should be given to a pregnant w o m an w ho has an indication for hepatitis B vaccine (26,204). Pregnancy is a contraindication for sm allpox (vaccinia) vac cine and measles-, m um ps-, rubella-, and varicella-containing vaccines.Sm allpox vaccine is the only vaccine know n to harm a fetus w hen adm inistered to a pregnant w om an.In addition, sm allpox vaccine should n o t be adm inistered to a household contact o f a preg n an t w om an (159).However, antibody testing was perform ed by using a hem ag glutination assay, w hich tends to underestim ate protection and cannot directly be com pared w ith antibody concentration (210).D ata are likely to rem ain lim ited for areas other than the People's Republic o f C hina, Russia, and E astern Europe.Health-care providers should ensure that household contacts o f international adoptees are vaccinated adequately, particularly for measles, hepatitis A, and hepatitis B (211). H ealth-care providers m ay use one o f m ultiple approaches if the im m unogenicity o f vaccines adm inistered to persons outside the U nited States is in question.Repeating the vaccina tions is an acceptable o p tio n that usually is safe and prevents the need to obtain and interp ret serologic tests.If avoiding unnecessary injections is desired, judicious use o f serologic testing m ight help determ ine w hich vaccinations are needed. For som e vaccines, the m ost readily available serologic tests cannot d o cu m en t protection against infection.These recom m endations provide guidance on possible approaches to evalu ation and revaccination for each vaccine recom m ended in the U nited States (Table 14).b u t w aning antibody; serologic testing can be repeated after a booster dose if the vaccination provider w ants to avoid revac cination w ith a com plete series. # DTaP Vaccine A lternately, for a child whose records indicate receipt o f >3 doses, a single booster dose can be adm inistered followed by serologic testing after 1 m o n th for specific IgG antibody to both diphtheria and tetanus toxins.I f the child has a protective concentration, the recorded doses are considered valid, and the vaccination series should be com pleted as age appropriate.C hildren w ith an indeterm inate concentration after a booster dose should be revaccinated w ith a com plete series. # Hepatitis A Vaccine # Poliovirus Vaccine T h e sim plest approach to vaccinating w ith poliovirus vaccine is to revaccinate persons aged <18 years w ith IPV according to the U.S. schedule.Adverse events after IP V are rare {201).C hildren appropriately vaccinated w ith 3 doses o f O P V in econom ically developing countries m ig h t have suboptim al seroconversion, including to type 3 poliovirus {201).Serologic testing for neutralizing antib o d y to poliovirus types 1, 2, and 3 can be obtained com m ercially and at certain state health departm en t laboratories.Persons w ith protective titers against all three types do n o t need to repeat doses b u t should com plete the schedule as age appropriate. # Rotavirus Vaccine Rotavirus vaccination should not be initiated for infants aged >15 weeks, 0 days.Infants w ho began the rotavirus vaccine series outside the U n ited States b u t who did n o t com plete the series and w ho are still aged <8 m onths, 0 days, should follow the routine schedule and receive doses to com plete the series.I f the brand o f a previously adm inistered dose is RV5 or unknow n, a total o f 3 doses o f rotavirus vaccine should be do cu m en ted for series com pletion.All doses should be adm inistered by age 8 m onths, 0 days. # Td and Tdap Vaccines C hildren aged >7 years w ho need the prim ary series doses o f tetanus-toxoid-containing vaccine should receive T d or T dap as age appropriate. # Varicella Vaccine # Varicella vaccine is n o t available in the m ajority o f countries.A person w ho lacks reliable evidence o f varicella im m u n ity should be vaccinated as age appropriate {4,20). # Zoster Vaccine Zoster vaccination is recom m ended for all persons aged >60 years who have no contraindications, including persons who report a previous episode o f zoster or who have chronic medical conditions.T he vaccine should be offered at the patients first clinical encounter w ith the health-care provider.T h e vaccine is administered as a single 0.65-m L subcutaneous dose.Zoster vac cination is not indicated to treat acute zoster, to prevent persons with acute zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia.Before adm inistration o f zoster vaccine, patients do not need to be asked about their history o f varicella or to have serologic testing conducted to determ ine zoster immunity. # Vaccinating Persons with Bleeding Disorders Because o f the risk for hem atom a form ation after injections, intram uscular injections are often avoided am ong persons w ith bleeding disorders by using the subcutaneous or intraderm al routes for vaccines th a t norm ally are adm inistered intram us cularly.In one study, hepatitis B vaccine was adm inistered intram uscularly to 153 persons w ith hem ophilia.T h e vac cination was adm inistered w ith a 23-gauge or sm aller caliber needle, followed by application o f steady pressure to the site for 1-2 m inutes.T h e vaccinations resulted in a low (4%) bruising rate, and no patients required factor supplem entation {213).W h e th er antigens that produce m ore local reactions (e.g., pertussis) w ould produce an equally low rate o f bruising is unknow'n.W h en hepatitis B or any other intram uscularly adm inistered vaccine is indicated for a p atien t w ith a bleeding disorder, the vaccine should be adm inistered intram uscularly if a physician fam iliar w ith the p atien ts bleeding risk determ ines th at the vaccine can be adm inistered by this ro u te w ith reasonable safety I f the patien t receives antihem ophilia or sim ilar therapy intram uscularly adm inistered vaccinations can be scheduled shortly after such therapy is adm inistered.A fine-gauge needle (23 gauge or smaller caliber) should be used for the vaccina tion, followed by firm pressure on the site, w ith o u t rubbing, for at least 2 m inutes.T h e p atien t or family should be given in form atio n o n the risk for h em ato m a from the injection.Patients receiving anticoagulation therapy presum ably have the same bleeding risk as patients w ith clotting factor disor ders and should follow the sam e guidelines for intram uscular adm inistration.tered, the vaccine m anufacturer, the vaccine lot num ber, and the nam e, address, and title of the person adm inistering the vaccine.In addition, the provider is required to record the edition date of the V IS distributed and the date those m ateri als were provided.T h e act considers a health-care provider to be any licensed health-care professional, organization, or institutio n , w hether private or public (including federal, state, and local departm ents and agencies), und er w hose authority a specified vaccine is adm inistered.T his inform ation should be kept for all vaccines, n o t just for those required by the act.Providers and staff m em bers also should system atically update patient's perm anent medical records to reflect any docum ented episodes of adverse events after vaccination and any serologic test results related to vaccine-preventable diseases (e.g., those for rubella screening and antib o d y to HBsAg). # Vaccination R ecords # Records of Health-Care Providers # Personal Records of Patients Official childhood vaccination records have been adopted by every state and territory and the D istrict o f C o lum bia to encourage u n iform ity o f records and to facilitate assessment o f vaccination status by schools and child-care centers.T h e records also are key tools in vaccination education program s aim ed at increasing parental and patient awareness o f the need for vaccines.A perm an en t vaccination record card should be established for each new born infant and m aintained by the parent or guardian.T h e parent or guardian should be educated about the im portance o f keeping the record up to date and instructed to keep the record indefinitely as part o f the child's perm anent medical record.These cards should be distributed to new m others before discharge from the hospital.Using vaccina tion record cards for adolescents and adults also is encouraged.Standardized adult vaccination records are available at h ttp :// w w w .im m unize.org. # Immunization Information Systems # Vaccination of Children and Adolescents Physicians and other pediatric vaccination providers should adhere to the standards for child and adolescent vaccination practices (8).T hese standards were published by the N ational Vaccine A dvisory C o m m ittee and define appropriate vaccina tion practices for both public and private sectors.T h e standards provide guidance on practices that elim inate barriers to vaccina tion, including elim inating unnecessary prerequisites for receiv ing vaccinations, elim inating missed opportunities to vaccinate, im proving procedures to assess vaccination needs, enhancing knowledge about vaccinations am ong parents and providers, and im proving m anagem ent and reporting of adverse events.In addition, the standards address the im portance o f recall and rem inder systems and using assessments to m o n ito r clinic or office vaccination coverage levels.E nsuring adolescents receive rou tin e and catch-up vaccina tion and increasing vaccination coverage in this age group pres ent challenges.In general, adolescents do n o t visit health-care providers frequently.H ealth-care providers should prom ote annual preventive visits (217), including one specifically for adolescents aged 11 and 12 years.T h e annual visits should be used as o pportunities to provide routinely recom m ended vac cine doses, additional catch-up doses needed for lapsed vaccine series, vaccines recom m ended for high-risk groups, additional doses th at m ight have been recently recom m ended, and other recom m ended health-care services. All vaccine doses should be adm inistered according to A C IP vaccine-specific statem ents and w ith the m ost recent schedules for b o th routine and catch-up vaccination.Before leaving any visit for m edical care, adolescents should be encouraged to schedule retu rn visits for any additional vaccine doses needed.D u rin g visits that occur outside o f influenza season, providers should discuss and recom m end seasonal influenza vaccination and m ake explicit plans for vaccination, including tim ing and anticipated setting (e.g., health-care provider's office, school, or pharm acy).C atch-up vaccination w ith m ultidose adolescent vaccines generally can occur according to the rou tine dosing schedule for these vaccines, although in some circumstances the clinician or health-care provider m ight use m in im u m intervals for vaccine doses.T hese circum stances include an outbreak th at increases risk for disease o r the likelihood th at doses will be missed in the future (e.g., because o f an im pending loss o f health-care coverage or tran sp o rtatio n challenges).Because o f lack o f efficacy data for H P V vaccine adm inistration using m inim um intervals, providers are encouraged, w h en possible, to use routine dosing intervals for females aged 11-26 years w ho have n o t yet received 3 H P V vaccine doses as recom m ended (20,28). O n e o f the challenges o f adolescent vaccination is ensur ing that current, com plete vaccination histories are available.Insurers, covered services, or reim bursem ent levels can change, and these changes m ight affect reim bursem ent for vaccine doses and vaccination services directly w hile also causing disruptions in an adolescent's access to vaccination providers or venues.In circum stances in w hich a vaccination record is unavailable, vaccination providers should attem p t to obtain this inform a tio n from various sources (e.g., parent, previous providers, or school records).M ore detail about how to obtain these records is available at from C D C at w w .cdc.gov/vaccines/ recs/im m uniz-records.htm .W ith the exception o f influenza and pneum ococcal polysaccharide vaccines, if d o cu m en ta tio n o f a vaccine dose is n o t available, the adolescent should be considered unvaccinated for th at dose.Regardless o f the venue in w hich an adolescent receives a dose o f vaccine, that vaccine dose should be docum ented in the p atien t's chart or in an office log, and the inform ation should be entered into an IIS.T h e adolescent also should be provided w ith a record card th at docum ents the vaccination history. # Adult Vaccination T h e incidence o f vaccine-preventable diseases in adults in the U nited States is high.A pproxim ately 4 5,000 adults die each year from vaccine-preventable diseases, the m ajority from influenza (222).In 2008, an estim ated 44,000 cases ofinvasive pneum ococcal disease were reported w ith approxim ately 4,500 deaths, the m ajority occurring am ong persons aged >35 years ( w w .cdc.gov/abcs/survreports/spneu08.htm ).Because o f recent licensure o f new vaccines approved for ad ults and new A C IP recom m endations for the use o f m any vaccines in adults, providers o f adult health care now share a greater responsibility for p u tting these recom m endations into practice.In 2009, an estim ated 4,070 deaths were caused by infection w ith the H P V strains causing the m ajority o f cervical cancers in this co untry th at are preventable w ith H P V vaccine and routine Papanicolaou sm ear testing ( w w .cancer.org/ docroot/hom e/index.asp).H erpes zoster causes considerable m orbidity in adults aged >50 years (55).A painful com plica tion o f herpes zoster infection is postherpetic neuralgia, w hich is characterized by severe pain that can persist for up to a year after the herpes zoster rash has subsided.A vaccine to prevent herpes zoster was licensed in 2006. In Vaccination w ith vaccines recommended for all adults or for those in specific age groups is generally cost-effective, if n o t costsaving, for society.T h e N ational Com m ission on Prevention Priorities (N CPP) ranked clinical preventive services based on clinically preventable disease effects and cost-effectiveness (223) In the N C P P report, influenza vaccination for adults aged >50 years and pneumococcal vaccination for adults aged >65 years ranked high, w ith 8 o f 10 possible points in the scoring system used.M ost other studies have found influenza vaccination reduces or minimizes health care, societal, and individual costs or the pro ductivity losses and absenteeism associated w ith influenza illness {224-226).Economic analyses am ong adults aged >65 years have found influenza vaccination to be cost-effective (225)(226)(227). A 2008 study o f the cost-effectiveness o f PPSV dem onstrated that vaccination resulted in a gain o f $3,341 per quality-adjusted life year; the result is sensitive to vaccine uptake assumptions (228).PPSV administered at ages 50-65 years m ight be clini cally favorable and, depending on cost-effectiveness criteria used, economically favorable (228).

H epatitis B vaccine is n o t recom m ended routinely for all adults.However, m ultiple studies have established the costeffectiveness o f providing hepatitis B vaccinations at counseling and testing sites for H IV and other sexually tran sm itted dis eases, correctional institutions, drug-abuse treatm en t centers, and other settings serving adults at risk for hepatitis B virus infection (229-230). Four studies have estim ated the cost-effectiveness o f a rou tine herpes zoster vaccination program o f im m u n o com petent persons aged >60 years (231-234).At a vaccine cost o f $150 per dose, the societal costs o f ro utinely vaccinating im m u n o com p eten t persons aged >60 years range from $27,000 to $ 112,000 per quality-adjusted life year gained (231-234).T he estim ated cost per quality-adjusted life year for zoster vaccina tion covers a wide range th at appears acceptable com pared with either standard thresholds or oth er established interventions b u t is at the interm ediate to high end o f that range. Vaccination rates in adults are considered suboptimal (235-238).Healthy People 2010 goals for adult vaccination coverage with influenza and pneumococcal polysaccharide vaccines are 90% for each vaccine.For the 2007-2008 season, influenza vaccination coverage am ong adults aged 50-64 years was 34% , and cover age am ong adults aged >65 years was 66% (67).In 2008, 60% o f adults aged >65 years received a dose o f PPSV ( w w cdc.gov/nchs/data/hestat/vaccine_coverage.htm ).N ew Healthy People2 0 2 0 goals for influenza and pneumococcal polysaccharide vaccines include specific subsets o f adults, including institutional ized adults aged >18 years (for both influenza and pneumococcal polysaccharide vaccines) and noninstitutionalized adults at high risk aged >18 years (for pneumococcal polysaccharide vaccine) ( ?id=30&topicarea=immunization+and+infectious+diseases). T h e m ost substantial barrier to vaccination coverage is lack o f knowledge about these vaccines am ong adult patients and adult A com m on challenge for health-care providers is vaccinating adults w ith unknow n vaccination records.In general (except for influenza and pneum ococcal polysaccharide vaccines), adults should receive a vaccine dose if the dose is recom m ended and no record o f previous adm inistration exists.If an adult has a record of military service and does n o t have records available, providers can assume that the person has received all vaccines recom m ended by the military at the time o f service entry.Serologic testing m ight be helpful in clarifying im m une status if questions remain because at different times and depending on military assignments, there m ight be interservice and individual differences. 15). # Evidence-Based Interventions to Increase Vaccination Coverage In 1997, the task force categorized as a recom m ended strat egy vaccination requirem ents for child care, school, and college (236).W hen appropriate, health agencies should take necessary steps to develop and enforce these requirem ents.Since 1995, all states receiving federal funds for vaccination program s have been required to cond u ct annual assessments of vaccination rates both in public health clinics and in pri vate provider offices.Prim arily to aid local and state health departm ents in their efforts to cond u ct assessments and assist providers, C D C has developed num erous software applications to m easure vaccination rates in provider practices. # Other General Programmatic Issues P ro g ram m atic challenges, evolving issues, and effective in te rv e n tio n s related to a d u lt and adolescent v accination program s have been described by oth er advisory groups and expert groups.Ad ditional evidence-based approaches are being developed for certain issues (e.g., settings for adolescent vac cination delivery) th ro u g h ongoing research and evaluation.A m ong current program m atic challenges, vaccine financing is especially difficult because certain problem s and solutions differ m arkedly from one state to another.Practitioners interested in beginning or contin u in g to provide vaccinations to patients are encouraged to consult w ith local and state public health vaccination program s to learn about publicly funded program s th at m ight be available in their areas for patients w ho need vac cination but have insufficient health insurance coverage and no financial resources.I f n o t already participating, providers wrho care for adolescents and children aged <19 years should enroll in the Vaccines for C hild ren Program ( w w .cdc.gov/ vaccines/program s/vfc/default.htm ).T h ro u g h this program 's provision o f A C IP-recom m ended, federally purchased vaccines, participating providers are able to fully vaccinate eligible chil dren w hose parents m ight n o t otherw ise be able to afford the vaccinations.Interested providers are encouraged to w ork w ith insurers, state and specialty-specific medical organizations, vac cine m anufacturers, and other stakeholders to address financial barriers to achieving high vaccination coverage.W ith avail ability o f safe and effective vaccines for 17 vaccine-preventable diseases, the capacity for realizing the potential benefits o f these products in the U nited States depends on reaching children, adolescents, and adults through dedicated, knowledgeable vac cination providers and efficient, strong vaccination program s at local, state, and federal levels. # V accine Information S ources In addition to these general recom m endations, the following sources contain specific and updated vaccine inform ation. # CDC-INFO Contact Center T h e C D C -IN F O contact center is supported by C D C and provides public health-related inform ation, including vaccina tion inform ation, for health-care providers and the public, 24 hours a day, 7 days a week (telephone : 800-232-4636; telephone : 800-232-6348). # CDC's National Center for immunization and Respiratory Diseases # American Academy of Family Physicians (AAFP) Inform ation from the professional organization o f family physicians is available at w w .aafp.org. # Immunization Action Coalition # National Network for Immunization Information # Vaccine Education Center Located at the C h ild re n 's H o sp ital o f P h iladelphia, the Vaccine E ducation C en ter provides p atien t and provider vac cine inform ation ( w w .vaccine.chop.edu). # Institute for Vaccine Safety Located at Johns H o p k in s U niversity S chool o f Public H ealth, the In stitute for Vaccine Safety provides inform ation about vaccine safety concerns and objective and tim ely infor m ation to physicians and health-care providers and parents ( w w .vaccinesafety.edu). # Group on Immunization Education of the Society of Teachers of Family Medicine # State and Local Health Departments # TABLE 1. (Continued) R ecom m en ded and m in im u m ages a n d intervals b e tw e e n vaccine doses'1 ' Abbreviations: DTaP = diphtheria and tetanus toxoids and acellular pertussis; HepA = hepatitis A; HepB = hepatitis B; Hib = Haemophilus influenzae type b; IHPV = human papillomavirus; IPV = inactivated poliovirus; LAIV= live, attenuated influenza vaccine; MCV4 = quadrivalent meningococcal conjugate vaccine; MMR = measles, mumps, and rubella; MMRV= measles, mumps, rubella, and varicella; MPSV4 = quadrivalent meningococcal polysaccharide vaccine; PCV= pneumococcal conjugate vaccine; PPSV = pneumococcal polysaccharide vaccine; PRP-OMB = polyribosylribitol phosphate-meningococcal outer membrane protein conjugate; Td = tetanus and diphtheria toxoids;TIV = trivalent inactiated influenza vaccine;Tdap = tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; Var = varicella vaccine. -Combination vaccines are available.Use o f licensed combination vaccines is generally preferred to separate injections o f their equivalent com ponent vaccines.When administering combination vaccines, the minim um age for administration is the oldest age for any o f the individual components; the m inimum interval between doses is equal to the greatest interval o f any o f the individual components.f Information on travel vaccines, including typhoid, Japanese encephalitis, and yellow fever, is available at .Information on other vaccines that are licensed in the United States but not distributed, including anthrax and smallpox, is available at .5 Combination vaccines containing the hepatitis B component are available (see Table 2).These vaccines should not be administered to infants aged 7 months require fewer doses to complete the series.1111 If PRP-OMP (Pedvax-Hib, Merck Vaccine Division) was administered at ages 2 and 4 months, a dose at age 6 months is not necessary. *A fourth dose is not needed if the third dose was administered at >4 years and at least 6 months after the previous dose. - Although MMR, DTaP, DT,Td, and Tdap are combination vaccines, they are not included on this list because they are not available in the United States as single-antigen products.f A dash ( -) between vaccine products indicates that products are supplied in their final form by the manufacturer and do not require mixing or reconstitution by the user.A slash ( / ) indicates that the products must be mixed or reconstituted by the user. # TABLE 3.G uidelines for spacing o f live and ina c tiv ate d antigen s Antigen com bination Recomm ended m inim um interval betw een doses Two or more inactivated- May be administered simultaneously or at any interval between doses Inactivated and live May be administered simultaneously or at any interval between doses Two or more live injectable1 28 days m inimum interval, if not administered simultaneously Source: American Academy o f Pediatrics.Pertussis.In: Pickering LK, Baker, CJ, Kimberlin DW, Long SS, eds.Red book: 2009 report o f the Committee on Infectious Diseases.28th ed.Elk Grove Village, IL: American Academy o f Pediatrics; 2009:22. -Certain experts suggest a 28-day interval between tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine and tetravalent meningococcal conjugate vaccine if they are not administered simultaneously.T Live oral vaccines (e.g.,Ty2la typhoid vaccine and rotavirus vaccine) may be administered simultaneously or at any interval before or after inactivated or live inject able vaccines. # TABLE 4 .G uidelines for ad m in is te rin g a n tib o d y -c o n ta in in g p ro d u cts - and vaccines Type o f adm inistration Products adm inistered Recomm ended m inim um interval betw een doses Simultaneous (during the same office visit) # Nonsimultaneous Antibody-containing products and inactivated antigen Antibody-containing products and live antigen # Adm inistered first Antibody-containing products Inactivated antigen Antibody-containing products Live antigen # Adm inistered second # Inactivated antigen Antibody-containing products Live antigen Antibody-containing products Can be administered simultaneously at different anatomic sites or at any tim e interval between doses Should not be administered simultaneously.1 ' If simultaneous administration o f measles-containing vaccine or varicella vaccine is unavoidable, administer at different sites and revaccinate or test for seroconversion after the recommend ed interval (see Table 5) # No interval necessary No interval necessary Dose related1-5 2 weeks1 " - Blood products containing substantial amounts o f immune globulin include intramuscular and intravenous immune globulin, specific hyperimmune globulin (e.g., hepatitis B immune globulin, tetanus immune globulin, varicella zoster immune globulin, and rabies immune globulin), whole blood, packed red blood cells, plasma, and platelet products.1 Yellow fever vaccine; rotavirus vaccine; oralTy2la typhoid vaccine; live, attenuated influenza vaccine; and zoster vaccine are exceptions to these recommendations. These live, attenuated vaccines can be administered at any tim e before or after or simultaneously with an antibody-containing product.5 The duration o f interference o f antibody-containing products with the immune response to the measles com ponent o f measles-containing vaccine, and possibly varicella vaccine, is dose related (see Table 5). - Events or conditions listed as precautions should be reviewed carefully.Benefits o f and risks for administering a specific vaccine to a person under these circum stances should be considered.If the risk from the vaccine is believed to outweigh the benefit, the vaccine should not be administered.If the benefit o f vaccination is believed to outweigh the risk, the vaccine should be administered.Whether and when to administer DTaP to children w ith proven or suspected underlying neurologic disorders should be decided on a case-by-case basis.I HIV-infected children may receive varicella and measles vaccine if CD4+ T-lymphocyte count is >15%. (Source: Adapted from American Academy o f Pediatrics. # TABLE 5.R ecom m en ded intervals b e tw e e n a d m in is tra tio n o f a n tib o d y -c o n ta in in g p roducts and m easles-or varicella-con tain ing vaccine, by p ro d u ct and ind icatio n for vaccination Passive immunization.In: Pickering LK, ed.Red book: 2009 report o f the comm ittee on infectious diseases.28th ed.Elk Grove Village, IL: American Academy of Pediatrics: 2009.)5 MMR and varicella vaccines can be administered on the same day.If not administered on the same day, these vaccines should be separated by at least 28 days.II Substantially immunosuppressive steroid dose is considered to be >2 weeks o f daily receipt o f 20 mg or 2 m g/kg body weight o f prednisone or equivalent. See text and Table 5 for details.t f Measles vaccination m ight suppress tuberculin reactivity temporarily.Measles-containing vaccine can be administered on the same day as tuberculin skin testing. If testing cannot be performed until after the day o f MMR vaccination, the test should be postponed for >4 weeks after the vaccination.If an urgent need exists to skin test, do so w ith the understanding that reactivity m ight be reduced by the vaccine.55 Hepatitis B vaccination should be deferred for infants weighing <2,000 g if the mother is documented to be HBsAg-negative at the tim e o f the infant's birth. Vaccination can commence at chronological age 1 month or at hospital discharge.For infants born to HBsAg-positive women, hepatitis B immune globulin and hepatitis B vaccine should be administered w ithin 12 hours after birth, regardless o f weight.1111 Vaccine should be deferred for the appropriate interval if replacement im mune globulin products are being administered (see Table 5).R e co m m e n d a tio n s a nd Reports # TABLE 7.C onditions com m o nly m isperceived as con traind ication s to vaccination Vaccine # Conditions com m only misperceived as contraindications (i.e., vaccination may be adm inistered under these conditions) General for all vaccines, including Mild acute illness w ith or w ithout fever DTaP, pediatric DT, adult Td, Mild-to-moderate local reaction (i.e., swelling, redness, soreness); low-grade or moderate fever after previous dose adolescent- - Antibacterial drugs m ight interfere w ith Ty21a oral typhoid vaccine, and certain antiviral drugs m ight interfere with varicella-containing vaccines and LAIV.+ Hepatitis B vaccination should be deferred for infants weighing <2,000 g if the mother is documented to be HBsAg-negative at the tim e o f the infant's birth. Vaccination can commence at chronological age 1 month or at hospital discharge.For infants born to HBsAg-positive women, hepatitis B immune globulin and hepatitis B vaccine should be administered w ithin 12 hours after birth, regardless o f weight.5 MMR and varicella vaccines can be administered on the same day.If not administered on the same day, these vaccines should be separated by at least 28 days. HIV-infected children should receive im mune globulin after exposure to measles.HIV-infected children can receive varicella and measles vaccine if CD4+T-lymphocyte count is >15%.If testing cannot be performed until after the day o f MMR vaccination, the test should be postponed for at least 4 weeks after the vaccination.If an urgent need exists to skin test, do so with the understanding that reactivity m ight be reduced by the vaccine.f t If a vaccinee experiences a presumed vaccine-related rash 7-25 days after vaccination, the person should avoid direct contact with im munocompromised persons for the duration o f the rash. J M e d V ir o l 1 9 8 6 ;1 9 :3 0 7 -1 1 . 18.S tefano I, Sato H K , P a n n u ti CS, e t al.R ecent im m u n iz a tio n against measles does n o t inte rfere w ith the sero-response to y e llo w fever vaccine. V a ccine 1 9 9 9 ;1 7 :1 0 4 2 -6 . # G lossary Adverse event.An untoward event that occurs after a vaccination that might be caused by the vaccine product or vaccination process.Adverse events include those that have the following characteristics: 1) vaccine induced (caused by the intrinsic characteristic of the vaccine preparation and the individual response of the vaccinee): these events would not have occurred w ithout vaccination (e.g., vaccine-associated paralytic poliomyelitis); 2) vaccine potentiated: the events would have occurred anyway but were precipitated by the vaccination (e.g., first febrile seizure in a predisposed child); 3) programmatic error: the event was caused by technical errors in vaccine preparation, handling, or administration; and 4) coin cidental: the event was associated temporally with vaccination by chance or caused by underlying illness.Special studies are needed to determine whether an adverse event is a reaction to the vaccine or the result of another cause (Sources: Chen RT.Special m eth odological issues in pharmacoepidemiology studies o f vaccine safety.In: Strom BL, ed.Pharmacoepidemiology.3rd ed.Sussex, England: John Wiley & Sons; 2000:707-32; and Fenichel GM, Lane DA, Livengood JR, Horwitz SJ, Menkes JH , Schwartz JF.Adverse events following immunization: assessing probability of causation.Pediatr Neurol 1989;5:287-90). Adverse reaction.

An undesirable medical condition that has been demonstrated to be caused by a vaccine.Evidence for the causal relation is usually obtained through randomized clinical trials, controlled epidemiologic studies, isolation of the vaccine strain from the pathogenic site, or recurrence of the condition with repeated vaccination (i.e., rechallenge); synonyms include side effect and adverse effect. A djuvant.A vaccine com ponent distinct from the antigen that enhances the immune reponse to the antigen. A ntitoxin.A solution of antibodies against a toxin.Antitoxin can be derived from either hum an (e.g., tetanus im m une globulin) or animal (usually equine) sources (e.g., diphtheria and botulism antitoxin).Antitoxins are used to confer passive im m unity and for treatment. H y p e rim m u n e g lo b u lin (sp e c ific ).Special preparations obtained from blood plasma from donor pools preselected for a high antibody content against a specific antigen (e.g., hepatitis B immune globulin, varicella-zoster immune globulin, rabies immune globulin, tetanus im m une globulin, vaccinia immune globulin, cytomegalovirus im mune globulin, botulism im m une globulin). Im m u n e globulin.A sterile solution containing antibodies, which are usually obtained from hum an blood.It is obtained by cold ethanol fractionation of large pools of blood plasma and contains 15%-18% protein.Intended for intramuscular adminis tration, immune globulin is primarily indicated for routine main tenance of im m unity among certain immunodeficient persons and for passive protection against measles and hepatitis A. Im m u n o b io lo g ic.Antigenic substances (e.g., vaccines and toxoids) or antibody-containing preparations (e.g., globulins and antitoxins) from hum an or animal donors.These prod ucts are used for active or passive immunization or therapy.Examples of im m u nobiologies include antitoxin, immune globulin and hyperimmune globulin, monoclonal antibodies, toxoids, and vaccines. Intravenous im m une globulin.A product derived from blood plasma from a donor pool similar to the imm une globulin pool, but prepared so that it is suitable for intravenous use.Intravenous im m une globulin is used primarily for replacement therapy in primary antibody-deficiency disorders, for treatment of Kawasaki disease, imm une thrombocytopenic purpura, hypogammaglobu linemia in chronic lymphocytic leukemia, and certain cases of hum an immunodeficiency virus infection (Table 5). M onoclonal antibody.An antibody product prepared from a single lymphocyte clone, which contains only antibody against a single antigen. S im ultaneous.In the context of vaccine timing and spacing, occurring on the same clinic day, at different anatomic sites, and not combined in the same syringe. Toxoid.A modified bacterial toxin that has been made nontoxic, but retains the ability to stimulate the formation of antibodies to the toxin. Vaccination and im m unization.The terms vaccine and vaccina tion are derived from rncca, the Latin term for cow.Vaccine was the term used by Edward Jenner to describe material used (i.e., cowpox virus) to produce im m unity to smallpox.The term vaccination was used by Louis Pasteur in the 19th century to include the physical act of administering any vaccine or toxoid.Immunization is a more inclusive term, denoting the process of ind ucing or providing im m unity by administering an immunobiologic.Immunization can be active or passive.Active immunization is the production of antibody or other immune responses through administration of a vaccine or toxoid.Passive immunization means the provi sion of temporary im m unity by the administration of preformed antibodies.Although persons often use the terms vaccination and immunization interchangeably in reference to active immunization, the terms are not synonymous because the administration of an immunobiologic cannot be equated automatically with develop m ent of adequate immunity. Vaccine.A suspension of live (usually attenuated) or inactivated microorganisms (e.g., bacteria or viruses) or fractions thereof administered to induce im m unity and prevent infectious disease or its sequelae.Some vaccines contain highly defined antigens (e.g., the polysaccharide of Haemophilus influenzae type b or the surface antigen of hepatitis B); others have antigens that are complex or incompletely defined (e.g., Bordetella pertussis antigens or live, attenuated viruses). # Advisory Committee on Immunization # TABLE 14.Approaches to evalu atio n a n d vaccination o f persons vaccinated o utsid e th e U n ite d States w h o have no (or q uestio nab le) vaccina tio n records

For more than 20 years, the occupational safety and health community has relied on skin notations from the National Institute for Occupational Safety and Health (NIOSH) to warn workers about the health hazards of skin exposures to chemicals.These notations have proved to be useful risk management tools for occupational health professionals concerned about protecting workers from injuries and illnesses caused by skin contact with chemicals.However, according to the definition, a NIOSH skin notation may be assigned to a chemical only if that substance has been scientifically determined to be dermally absorbed.The current, widespread practice of using a skin notation to indicate that a substance poses other health effects, such as skin irritation, following any kind of skin exposure is inaccurate and misleading.NIOSH adopted the skin notations for 142 chemicals as part of its 1988 testimony to the Occupational Safety and Health Administration's (OSHA) proposed rule on Air Contaminants (Permissible Exposure Limit update).The skin notations for these chemicals are listed in the NIOSH Pocket Guide to Chemical Hazards by the symbol .Despite the usefulness of the skin notations as a risk management tool, NIOSH has identified several conceptual difficulties with the ways in which skin notations have been assigned:# iii # Foreword The National Institute for Occupational Safety and Health (NIOSH) has estimated that workplace skin diseases account for 15%-20% of all reported occupational diseases in the United States, with estimated total annual costs (including lost workdays and lost productivity) up to $1 billion.Skin exposures to chemicals can cause a wide array of injuries and illness including contact dermatitis, immunemediated responses, and irreversible damage to the skin.Despite the relatively high incidence of contact dermatitis and other workplace skin diseases, the impact and risk of skin contact with chemicals and other hazardous agents are not well known, hampering the recognition and prevention of these disorders.Additionally, skin contact represents a significant route of exposure for chemicals that have the potential to be percutaneously absorbed and subsequently cause systemic effects including, but not limited to, acute toxicity, cancers, neurotoxicity, and effects on the reproductive system. NIOSH has long recognized the hazards of skin contact with chemicals in the workplace and the importance of quality research and policies to prevent such exposures.In 1999, NIOSH launched an Interdisciplinary Cross-Sectional Research Program as part of the National Occupational Research Agenda (NORA).This Dermal Exposure Research Program (DERP) was established to promote the identification and control of skin exposures to hazardous agents and conditions in the workplace.The focus of DERP was to expand the current knowledge base through laboratory and field research and to apply scientific decision-making processes for policy development.NIOSH has entered the second decade of NORA and, through its Immunological and Dermal Cross-Sector Program, continues to investigate methods for protecting workers from hazardous skin exposures and for reducing the prevalence of occupational skin diseases. NIOSH skin notations are hazard warnings used worldwide to alert workers and employers to the health risks of skin exposures to chemicals in the workplace.This Current Intelligence Bulletin (CIB) provides the rationale for assigning new NIOSH skin notations.The new system reflects the current state of scientific knowledge and involves critical evaluation of scientific data so that scientists can assign multiple skin notations that distinguish between the systemic, direct, and sensitizing effects of skin exposures to chemicals.This new strategy is a form of hazard identification that advances our understanding of the hazards posed by skin exposures to chemicals.Such improved understanding will enable us to implement better risk management practices and controls for the prevention of workplace skin diseases 1.The current NIOSH system relies on a single skin notation that is intended to warn against the potential for a chemical to be dermally absorbed and contribute substantially to systemic toxicity.This skin notation is not intended to be applied to chemicals that would cause direct effects to the skin or to chemicals that have the potential to act as a sensitizer.2.The NIOSH skin notation has not been assigned on the basis of a standardized methodology.As a result, chemicals have been improperly assigned a skin notation as a warning for nonsystemic effects, such as skin irritation and corrosion, thereby causing confusion about what types of risk-management practices should be undertaken to prevent skin exposure.3.The NIOSH skin notation does not reflect the contemporary state of scientific knowledge or recommendations made in NIOSH criteria documents since the 1988 Permissible Exposure Limit update. # New Strategy for Assigning NIOSH Skin Notations vi strategic framework outlined within this document is a form of hazard identification that has been designed to do the following: - Ensure that the assigned skin notations reflect the contemporary state of scientific knowledge - Provide transparency behind the assignment process - Communicate the hazards of chemical exposures of the skin - Meet the needs of health professionals, employers, and other interested parties in protecting workers from chemical contact with the skin This strategy involves the assignment of multiple skin notations for distinguishing systemic (SYS), direct (DIR), and sensitizing (SEN) effects caused by exposure of skin (SK) to chemicals.Chemicals that are highly or extremely toxic and may be potentially lethal or life-threatening following exposures of the skin are designated with the systemic subnotation (FATAL).Potential irritants and corrosive chemicals are indicated by the direct effects subnotations (IRR) and (COR), respectively.Thus with the new strategy, chemicals labeled as SK: SYS are recognized to contribute to systemic toxicity through dermal absorption.Chemicals assigned the notation SK: SYS (FATAL) have been identified as highly or extremely toxic and have the potential to be lethal or life-threatening following acute contact with the skin.Substances identified to cause direct effects (i.e., damage or destruction) to the skin limited to or near the point of contact are labeled SK: DIR, and those resulting in skin irritation and corrosion at the point of contact are labeled as SK: DIR (IRR) and SK: DIR (COR), respectively.The SK: SEN notation is used for substances identified as causing or contributing to allergic contact dermatitis (ACD) or other immune-mediated responses, such as airway hyper reactivity (asthma).Candidate chemicals may be assigned more than one skin notation when they are identified to cause multiple effects resulting from skin exposure.For example, if a chemical is identified as corrosive and also contributes to systemic toxicity, it will be labeled as SK: SYS-DIR (COR).When scientific data for a chemical indicate that skin exposure does not produce systemic, direct, or sensitizing effects, the compound will be assigned the notation (SK).The ID (SK) notation is assigned to indicate that insufficient data on the health hazards associated with skin exposure to a substance exist at the time of the review to determine whether the chemical has the potential to act as a systemic, direct, or sensitizing agent.The ND notation indicates that a chemical has not been evaluated by the strategy outlined in this CIB and that the health hazards associated with skin exposure are unknown. The new skin notation strategy is a form of health hazard identification that standardizes the method for deriving skin notations.Assignment of the new NIOSH skin notations to chemicals relies on a critical assessment of the following: - A substance's physicochemical properties - Reports of human exposures and health effects - Empirical data from in vivo and in vitro laboratory testing vii - Considerations provided by computational techniques, such as predictive algorithms (e.g., QSAR) and mathematical models (e.g., skin permeation) A weight-of-evidence approach is applied in evaluating the quality and constituency of the scientific data when conflicting findings are reported.Figure 1 illustrates an overview of the process used to assign skin notations. The new strategy for assigning the NIOSH skin notations was designed to preserve the conventional wisdom about them and also to address the issues associated with their historic misuse-including their assignment to nonsystemic effects.This system provides a framework for assigning multiple skin notations that incorporates the current scientific database on workplace chemicals and dermal toxicity.The new system warns users about the direct, systemic, and sensitizing effects of exposures of the skin to chemicals.The labeling of a chemical with a hazard-specific skin notation (and in some cases multiple notations) will greatly enhance the quality of hazard communication and the associated risk management process.The new strategy outlined in this CIB also corresponds with the classification strategy adopted in the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) developed by the United Nations (see Appendix G.2).This CIB will be updated as new scientific data becomes available. Historically, skin notations have been published in the NIOSH Pocket Guide to Chemical Hazards.This practice will continue with the NIOSH skin notation assignments for each evaluated chemical being integrated as they become available.A support document called a Skin Notation Profile (see Appendix F) will be developed for each evaluated chemical.The Skin Notation Profile for a chemical will provide information supplemental to the skin notation, including a summary of all relevant data used to aid in determining the hazards associated with skin exposures. viii # ICSC International Chemical Safety Cards ID (SK) skin notation indicating that a chemical has been evaluated, but insufficient data exist to accurately assess the hazards of skin exposure (IRR) subnotation of SK: DIR indicating the potential for a chemical to be a skin irritant following exposure to the skin Isomers-Molecules that exhibit unique physical structures, but consist of the same elemental composition and weight that may result in significant difference in toxic potency. K Photocarcinogenesis-The elicitation or increase of a carcinogenic response after skin exposure to a photo reactive chemical and subsequent exposure to sunlight. Phototoxicity-The elicitation or increase of a toxic response after skin exposure to a photo reactive chemical and subsequent exposure to sunlight. Sensitization-A specific immune-mediated response that develops following exposure to a chemical, which, upon re-exposure, can lead to allergic contact dermatitis (ACD) or other immune-mediated diseases such as asthma, depending on the site and route of re-exposure. # Substance-A chemical. Systemic effects-Systemic toxicity associated with skin absorption of chemicals after exposure of the skin. xvi 1 # Introduction The skin - is the largest organ of the human body and accounts for more than 10% of the body's mass.It enables the body to readily interact with the environment and also serves as a general defense system.It also represents a potentially significant exposure pathway for many chemicals because of the large surface area available for contact to any one of the innumerable potentially toxic substances in the workplace.The health and economic impacts of such exposures are not fully understood because of the inherent difficulties in differentiating between the contribution of dermal absorption of a chemical and other routes of entry (i.e., inhalation and ingestion) to total body burden and subsequent onset of a specific disease or disorder.Additionally, less attention is often given to characterizing occupational and environmental exposures of the skin to chemicals than is given to other exposure pathways.These limitations potentially leave exposed workers susceptible to a wide spectrum of adverse health outcomes including dermatoses, systemic toxicity, and, in extreme cases, death. August 1, 1988.Despite the usefulness of the notation as a risk management tool, it provides little guidance about a chemical other than warning of its possible absorption through the skin. The assignment of skin notations has several inconsistencies and limitations: 1.The skin notation is based in theory on the potential contribution a chemical makes to systemic toxicity when it is absorbed by the skin .However, the notation has not been consistently assigned according to this principle.Many skin notations are based only on the potential or reported transdermal penetration of chemicals-with no consideration of the causality between dermal absorption and overall toxicity.The system preserves the conventional wisdom for assigning skin notations to chemicals that pose a hazard from skin contact.In addition, this system attempts to prevent possible misclassifications by assigning a notation that specifies potential adverse effects.The skin notation classification scheme presented within this CIB is as follows: - SYS indicates the potential for a chemical to contribute substantially to systemic toxicity through dermal absorption. -(FATAL), a subnotation of SYS, indicates that a chemical is highly or extremely toxic, and may be potentially lethal or life-threatening following skin exposures. - DIR indicates non-immune mediated direct effect(s) of a chemical on the skin at or near the point of contact, including corrosion, primary irritation, bleaching (blanching), staining, and reduction/disruption of the skin barrier integrity. -(IRR), a subnotation of DIR, indicates that a chemical is a skin irritant. -(COR), a subnotation of DIR, indicates that a chemical is a corrosive. - SEN indicates that skin exposure to a chemical may cause or contribute to the onset of allergic contact dermatitis (ACD) or other immune-mediated responses, such as airway hyper reactivity (asthma). - SK indicates that the reviewed data identified no health hazard associated with skin exposure and did not support assignment of the SYS, DIR, or SEN notation. - ID (SK) indicates that insufficient data were available at time of evaluation to determine the hazards associated with dermal contact to a candidate chemical substance. - ND indicates that a chemical has not been evaluated by the improved skin notation strategy, and the health hazards associated with skin exposure are unknown. The new system also permits the assignment of several skin notations for a chemical when multiple skin hazards exist.For example, if health data indicate that the chemical causes systemic toxicity when absorbed by the skin and is also corrosive, the notation assigned to the chemical would be SK: SYS-DIR (COR). The skin notations may be modified or additional skin notations may be added when improved scientific data on test methods and increased understanding about the toxicological mechanisms of skin injuries become available. Also, current criteria for assigning skin notations may be revised to enhance the usefulness of the notations for selecting exposure prevention strategies.Hazard categories that are added later may follow the current scheme, which makes skin corrosives a subnotation under the DIR notation and acute lethality a subnotation under the SYS notation. It should be noted that the strategy and skin notations outlined in this CIB are not intended to provide a risk-based exposure value for skin exposures to chemicals and should not be used to infer toxic potency for evaluated chemicals. Other issues associated with skin notations include their application to chemical mixtures, the health effects of contaminants within neat substances, and isomeric variations of a chemical.Because of the complexity of assessing the hazards of chemical interactions associated with complex mixtures or because of the presence of contaminants, the skin notations are intended to apply to neat chemicals and may not be health protective against additional effects associated with complex mixtures (see Appendix G.1).Also, assigned skin notations are applicable only to the specified forms of an evaluated compound and may not provide adequate warnings about unique hazards of the nonspecified isomeric forms of the chemical (see Appendix G.1). # Criteria for Assigning Skin Notations The critical step in assigning skin notations to a chemical is determining its hazard potentialthat is, its potential for causing adverse health effects as a result of skin exposure.This determination involves a health hazard identification process that assesses the following: - Scientific data on the physicochemical properties of a chemical - Human exposures and health effects - Empirical data from in vivo and in vitro laboratory testing - The use of computational techniques, including predictive algorithms and mathematical models that describe a selected process (e.g., skin permeation) using analytical or numerical methods. A weight-of-evidence approach is applied when available data are inconsistent.Figure 2 illustrates the hierarchy of scientific data used for assigning skin notations. Computational techniques, such as mathematical models and predictive algorithms, represent alternative methods to expensive in vivo and in vitro toxicity testing methods.These approaches are increasingly applied to estimate the potential of chemicals to act as skin irritants and sensitizers and their potential to be absorbed (i.e., skin permeation).The performance and reliability of these computational techniques remain unclear.For this reason, predications from computational techniques, such as QSARs and the skin dose to inhalation dose ratio (SI ratio) (see Appendix B), should not be used as the primary basis for the assignment of a skin notation.Instead, they are intended only to serve as additional supportive data sources when limited data are available for the assignment of skin notations.As the computational techniques become more reliable and validated, NIOSH will reassess their use within the assignment of skin notations.If it is determined that the computational techniques accurately predict the effects of skin exposures to chemicals, they may become a primary basis for the assignment of skin notations. The following sections discuss the skin notation assignments in each category.Exceptions to this approach are also described.This strategy for assigning skin notations has been developed to correspond with the classification strategy adopted in the # SYS The SYS notation is assigned to chemicals that are absorbed through the skin and contribute to systemic toxicity.The (FATAL) subnotation is assigned to chemicals identified as highly or extremely toxic and potentially lethal or lifethreatening following skin exposure.Experimental toxicity studies using these protocols frequently result in quantitative data that can be used in assigning skin notations. The SYS notation is assigned to a chemical when one or more of the following criteria are met: - Credible evidence indicates that systemic effects in workers result from skin exposure to a chemical in the absence of significant inhalation or oral exposures. - Data from experimental animal studies indicate--Systemic effects occurred from skin exposures. -Fatalities or health effects in exposed animals were not associated with skin damage by the chemical or the vehicle containing the chemical. -Skin exposure results for animals included data on acute toxicity, repeat-dose toxicity, subchronic toxicity, chronic toxicity, carcinogenicity, or biologic system/ function-specific effects.

Appendix A describes the study protocols used and the criteria selected for assigning the SYS notation and its subnotations. - Studies of scientific merit that followed protocols other than those previously identified and demonstrated systemic effects from skin exposure to a chemical.The protocols may be modifications of the standardized protocols with variations in the evaluation procedures, or they may be designs allowing for examination of health endpoints other than those the standardized protocols allow for.Examples of the latter studies include the following: - Both conditions must be satisfied to assign a SYS notation. - When no acceptable-quality empirical data exist on the systemic effects of skin exposure, the potential for dermal absorption and consequent systemic toxicity of the chemical may be mathematically estimated via computational techniques. To mathematically determine the risk for systemic toxicity (e.g., predictive algorithm), the following information is needed: (1) skin permeation rate, (2) chemical dose calculated to be absorbed through skin (skin dose), (3) reference dose representing the threshold of acceptable body accumulation (a chemical dose to be absorbed via inhalation during the same period of exposure), and (4) comparison of the skin dose to the reference dose (which indicates the significance of skin absorption and its potential contribution to systemic toxicity). Appendix B presents an algorithm that can be used for determining the potential for systemic toxicity.When the predictive algorithm is used as the basis for identification, a positive result indicates that a chemical is capable of producing systemic toxicity from skin exposure and should be assigned the SYS notation.If the predictive algorithm indicates no potential for systemic toxicity from dermal absorption, the chemical should be further evaluated with accepted tests.The results of the predictive algorithm should not be used as the sole basis of the assignment of a SYS notation. Indicates that insufficient data were identified to accurately assess the systemic hazards or potential for dermal absorption associated with contact of the skin with a specified chemical. adverse effects accompanied by pain or discomfort, such as tissue lesions or blisters, and burns of varying degrees at or near the point of contact.Skin irritants that are identified to cause corrosion will be assigned only the SK: DIR (COR) notation to ensure that the most hazards endpoint is recognized. Immune-mediated responses of the skin associated with exposures of the skin to chemicals, such as ACD and allergic urticaria, are not assigned the DIR notation.These immunemediated responses would be assigned the SEN notation if data are supportive and are addressed within Section 2.4. An SK: DIR notation is assigned when one or more of the following criteria are met: - Credible evidence indicates that immediate, prolonged, or repeated contact of skin with the chemical produces direct effects on the skin of exposed workers.The direct effects reported were based on incidents of worker exposures.The effects consist of the following: -Primary irritation, including irritant contact dermatitis (macroscopically manifested as erythema and edema) -Corrosion (manifested as ulceration, visible necrosis of epidermis/dermis, bleeding, eschar formation, and discoloration) -Changed pigmentation -Chloracne caused by chemicals such as halogenated aromatic hydrocarbons -Defatting/drying of skin -Skin cancer at or near the point of contact Predictive patch tests conducted on human volunteers (e.g., the acute dermal irritation study in human volunteers) may also yield information about acute or cumulative irritation of human skin .Such information will be considered when assigning skin notations. - Data from laboratory tests indicate direct effects on skin as a result of chemical exposures.These data include in vivo animal studies reporting the acute irritancy, corrosivity, and carcinogenicity of chemicals, in vitro assays identifying corrosivity potentials, and in vitro evaluations examining alteration in the barrier properties of skin as a result of skin exposure to chemicals.Appendix A describes protocols and the criteria that can be used for deriving SK: DIR notations. - Relevant scientific data not generated using the study protocols previously described can be used if they provide adequate qualitative data on the direct effects on skin as a result of skin exposure to a chemical.Protocols may be modifications of standardized protocols (e.g., the research protocols introduced in Appendix A) with variations in the evaluation procedures or study design that examine health endpoints other than those evaluated by the standardized protocols.Examples of the latter include reports of histopathological examinations indicating impairment of skin tissues, disintegration of skin components (e.g., defatting and discoloration), or the presence of neoplastic lesions or tumors in the epidermis and dermis in association with changes in the transdermal penetration of chemicals. - When no acceptable-quality empirical data exist on the direct effects of skin exposure to a chemical, information from the structure-activity-relationship (SAR)-based analysis and the physicochemical properties and reactivity of the chemical may be used as alternative methods for identifying hazards .Examples of SAR analysis are the clinical and/or experimental observations of the adverse effects occurring at the site of exposure to a structurally related or similar chemical in question. Physicochemical properties such as extreme pH and buffering capacity can be used to estimate the corrosivity potential of acidic or alkaline chemicals on the skin.See Appendix C for further discussion about using pH and acid/alkali reserves for assigning SK: DIR notations.When the algorithm is used as the basis of identification, a positive result is sufficient to classify a chemical as capable of provoking direct effects on the skin and assigning an SK: DIR notation. # SEN Skin exposure to a chemical may cause or contribute to the onset of ACD or other immunemediated responses, such as airway hyper reactivity (asthma).Occupationally, the most commonly recognized immune-mediated responses following skin exposure is ACD.For ACD, the skin-sensitizing potential of the chemical is typically evaluated by two endpoints-the immunologic induction of sensitization and the elicitation of ACD.The SEN notation may be assigned to the following types of immunemediated responses caused by or contributed to exposures of the skin: - ACD - Systemic allergic reactions - Immune-mediated respiratory diseases Immune-mediated responses are commonly associated with two immune mechanisms: the immediate hypersensitivity response (which, in a previously sensitized person, normally occurs within minutes of exposure) and the delayed hypersensitivity response (which occurs 24-72 hours following exposure).Immediate responses are primarily mediated by immunoglobulin E antibodies when the chemical-specific antibodies in systemic circulation contact antigens such as exogenous proteinaceous molecules. In the immediate hypersensitivity reaction, the respiratory tract, in addition to the skin, may respond after dermal exposure to the causative agent.Delayed hypersensitivity response is a T-cell-mediated immune response that requires a procession of cellular events within the body (the induction phase) leading up to the inflammatory response (the elicitation phase).This procession includes (1) association of antigens (haptens) with proteins, (2) presentation of the protein-hapten conjugates to the regional lymph nodes, (3) recognition of the conjugates by specific T cells, and (4) proliferation of the specific T cells in draining lymph nodes. Results of animal and human studies support a link between exposures of the skin to certain chemical allergens, systemic sensitization, and the subsequent development of lung allergic responses following inhalational exposures .Animal studies in several species have shown that skin exposure to isocyanates followed by inhalational challenge is highly effective at inducing asthmatic lung responses. .Human studies, although more limited, suggest a similar role following skin exposure to certain sensitizing chemicals .Despite decreased inhalation exposures to isocyanates and beryllium within various occupational settings, immune-mediated respiratory diseases associated with these compounds continue to occur, frequently in settings with opportunities for skin exposure .Together, the human and animal data suggest that skin contact with certain chemical allergens may contribute to the development of immune-mediated respiratory diseases, such as asthma or chronic beryllium disease . In laboratory testing, chemical allergens are largely identified in vivo using the conventional guinea pig sensitization test or the more innovative murine local lymph node assay (LLNA).Data relevant for determining whether the chemical may cause an immune-mediated response include the following : - Analytical or descriptive epidemiologic studies - Observational case reports from health surveillance programs and/or poison control centers - Clinical studies Note-The main purpose of clinical tests with human volunteers is to confirm the safety of test materials or preparations rather than to identify skin sensitization hazards. The SEN notation is assigned when one or more of the following criteria are met: - Credible evidence indicates the occurrence of ACD or sensitization as a result of chemical exposure of the skin.Skin sensitization among workers is often characterized clinically by immunologically mediated cutaneous reactions such as pruritus, erythema, edema, papules, vesicles, bullae, or a combination of these findings.Information about human immune-mediated reactions from skin exposure may also be used from the results of predictive patch tests conducted on human volunteers (e.g., the human repeat insult patch test ).Such information will be considered when assigning skin notations. - When human data are used as the basis of identification, one of the following types of evidence is sufficient to classify a substance as a sensitizer: -Studies in which sensitization is evident from valid clinical investigations (e.g., patch testing or antigen-specific immune responses, such as antibody responses or lymphocyte proliferation) -Confirmed case reports describing several subjects in more than one independent study -Epidemiologic evidence establishing a causal relationship between exposure and sensitization When only isolated episodes of ACD are observed, supporting evidence should be obtained (including data available from animal tests and an appropriate SAR) before the chemical is recognized as a contact allergen . - Animal data indicate the potential for ACD or other immune-mediated responses associated with skin exposure.Such animal data include the guinea pig sensitization tests identifying sensitization or ACD, LLNA, mouse ear swelling test, and relevant animal models of asthma.Appendix A describes protocols and criteria that can be used in assigning the SEN notation. - Scientific data other than those previously described may be used to demonstrate sensitization as a result of skin exposure to a chemical.Such protocols include those that may be modifications of the standardized protocols (e.g., the research protocols introduced in Appendix A) with variations in the evaluation procedures or study designs that examine health endpoints other than those evaluated by the standardized protocols.An example is studies that evaluate the induction of antigen-mediated responses following skin exposure. - When no empirical data of acceptable quality exist, the occurrence of ACD or other immune-mediated responses as a result of skin exposure to a chemical, information from the SAR-based analysis, and other computational techniques can be used as alternative methods for identifying hazards.An example of a SAR analysis is the use of the knowledge-based expert system Deductive Estimation of Risk from Existing Knowledge (DEREK™) to evaluate the relationship between the molecular structure of the chemical and its allergenic properties.Appendix C describes the DEREK™ expert system for identifying sensitizers.When the algorithm is used as the basis of identification, a positive result is sufficient to classify a chemical as an agent capable of provoking ACD or sensitization from skin exposure and assigning the SEN notation. # SK The SK notation is assigned to indicate that a chemical underwent a critical assessment, based on the criteria described above, of the scientific data and was not identified as a systemic, direct, or sensitizing health risk from skin exposure.It should be noted that for a chemical to be assigned the SK notation, the scientific data must be classified as sufficient based on the criteria outlined in Appendix E. # ID (SK) The ID (SK) notation indicates that insufficient data exist on the health hazards associated with skin exposures to a substance to determine if the chemical has the potential to act as a systemic, direct, or sensitizing agent.Assignment of this notation will be determined through an assessment of a chemical's creditable scientific data identified during an extensive search of published literature (see Appendix E).Chemicals designated with the ID (SK) notation may represent a significant health hazard following contact with the skin, and proper controls should be applied to prevent or minimize occupational exposures.Despite the absence of sufficient data to assign the SYS, DIR, or SEN notation, a Skin Notation Profile (see Appendix F) will be drafted for all chemicals assigned ID (SK) to document that the substance has been previously evaluated. # ND The ND notation signifies that a chemical has not been evaluated by the strategy outlined in this CIB, and the associated health hazards of skin exposure are unknown.The ND notation will be included within future NIOSH publications, including the NIOSH Pocket Guide to Chemical Hazards.This appendix presents the experimental protocols used in laboratory studies of the systemic effects, direct effects on skin, and sensitization potentials of chemicals resulting from skin exposure using animal models or alternative methods (e.g., in vitro bioassays).The protocols included have generally been standardized and validated by various regulatory agencies and research institutes in the United States and Europe.For each protocol, the introduction contains (1) concise discussions of the underlying principles and methods and (2) criteria for assigning skin notations based on results of studies that followed the protocol. As the investigative methods are developed or improved, other protocols with scientific merit may become available.Depending on their status, additional protocols may be selected to develop criteria for assigning skin notations. # A.1 Experimental protocols for investigating systemic effects of skin exposure and derived criteria for assigning the SYS notations # A.1.1 Dermal absorption Dermal absorption is the transport of chemicals from the outer surface of the skin both into the skin and into systemic circulation.This process is often described using the terms penetration, permeation, and resorption.Experimental techniques used to estimate the potential for absorption include in vivo and in vitro toxicity studies and computational techniques. In vivo and in vitro test methods have been developed to estimate both the rate and percentage of an applied dose of a substance absorbed (i.e., penetration or permeation) through the skin .In vivo studies use a physiologically and metabolically active system in the form of human volunteers or test animals, such as rats, to assess the skin penetration, permeation, and resorption of test chemicals .In vitro dermal absorption tests generally rely on the application of a radiolabelled test substance to a sample of nonviable or metabolically active excised skin suspended between two chambers of a diffusion cell and are used to measure the rates of penetration and permeation .In both in vivo and in vitro experimental studies, the applied dose and the vehicle may directly influence the absorption of the substance across the skin. Computational techniques, such as QSARs and QSPR, have been developed to offer a relatively inexpensive method for determining skin penetration of chemicals [Moss et al.2002 # A.1.8 Assignment of the SYS notation based on alternative exposure pathways Toxicity data associated with alternative exposure pathways (i.e., ingestion, inhalation, and injection) may be considered during the assignment of the SYS notation.The primary criteria applied for determining the appropriateness of the use of toxicity data associated from alternative exposure pathways are as follows: 1.No quality dermal toxicity data were identified. 2.Toxicokinetics data clearly demonstrate that the chemical has a high potential to be dermally absorbed and contributes significantly to systemic dose (see Section A.1.1). 3.The critical health endpoint(s) being investigated must be systemic in nature. 4.The critical systemic endpoint(s) is independent of the route of exposure. # A.2 Experimental protocols for investigating direct effects of skin exposure and derived criteria for assigning the DIR notations # A.2.1 In vivo animal tests for acute irritancy and corrosivity Most research protocols available for in vivo testing for skin irritation and corrosion follow the Draize procedure, with modifications in exposure duration, test animal species and number, and intervals between observations.In the standardized protocols [U.S. EPA 1998j; OECD 2002a], a single dose of the test chemical is applied to the skin of albino rabbits, normally for 4 hours unless corrosion is observed.The animals are examined for signs of erythema and edema, and the responses are scored at intervals over 72 hours.These procedures are also used to examine and grade any persistent or delayed effects that may occur within 14 days after exposure and to fully evaluate the reversibility of observed effects.A chemical that induces reversible inflammation, dryness, or redness with minor pain or discom fort of the skin is considered an irritant and is assigned the (IRR) notation.The (COR) subnotation will be assigned when a chemical is known to cause irreversible adverse effects accompanied by pain or discomfort, such as tissue lesions or blisters, and burns of varying degrees at or near the point of contact. # A.2.2 In vitro tests for corrosivity using human or animal skin models In vitro methods using human or animal skin models are used as alternatives to conventional in vivo tests for assessing the corrosivity of chemicals. -The rat skin transcutaneous electrical resistance (TER) assay The Corrositex® assay evaluates the pH-sensitive destruction of a reconstituted, collagen-based biobarrier and determines the corrosivity potential by measuring the time required for the test material to pass through the biobarrier membrane (i.e., the breakthrough time) and produce a visually detectable change in the Chemical Detection System.Chemicals of high acid/alkaline reserves (Category I materials) and those of low acid/alkaline reserves (Category II materials) are considered corrosive when their breakthrough times are less than 4 hours and 1 hour, respectively .The EPISKIN™ and EpiDerm™ models evaluate the corrosivity potential of a test substance by measuring the decreased viability of human skin cells in reconstructed epidermis/dermis after exposure.In EPISKIN™, a test substance is identified as potentially corrosive when it induces at least a 35% decrease in cell viability.In EpiDerm™, the substance is classified as corrosive if it induces at least a 50% decrease in relative cell viability after 3 minutes of exposure or at least an 85% decrease after 60 minutes.

The TER assay measures the reduction of inherent TER on the skin of young rats caused by the loss of normal stratum corneum integrity and barrier function.A test substance is considered potentially corrosive and assigned the (COR) notation if it reduces the TER to a threshold below 5 kilohms. # A.2.3 Carcinogenicity # A.2.4 In vitro tests of skin integrity using human donor skin Examples of in vitro methods for evaluating skin integrity include those for measuring the movement of a standard compound such as tritiated water through the stratum corneum, the transepidermal water loss from the stratum corneum, and the electrical resistance of skin to an alternating current at up to 2 volts . # A.3 Experimental protocols for investigating sensitization from skin exposure and derived criteria for assigning the SEN Notation # A.3.1 Identifying skin sensitization or ACD with guinea pig test methods Standardized guinea pig test methods include the guinea pig maximization test and the Buehler test .In these tests, the animals are initially exposed to the test substance by intradermal injection and/or epidermal application to induce an immune response.After 10-14 days, the animals receive a challenge exposure to the test substance to establish whether a hypersensitive state has been induced.The disease-analogous skin reactions (e.g., local irritation in the forms of erythema/ edema) following the challenge exposure are measured and graded (usually 24 and 48 hours post challenge) to determine the degree of skin sensitization or ACD.A chemical that induces allergic skin reactions is considered a sensitizer and is assigned the SEN notation. # A.3.2 Identifying skin sensitization potential with the murine local lymph node assay The murine LLNA has been peer-reviewed by ICCVAM and the NICEATM panel and recommended for regulatory acceptance .OECD and U.S. EPA have adopted this assay as a standard test method for evaluating the skin sensitization potential for chemicals.The LLNA determines the induction of skin sensitization by identifying cell proliferation in the lymph node that drains the site of chemical application.The LLNA also provides quantitative data for assessing the dose-response relationship.In the test, cellular proliferation is measured as a function of in vivo radioisotope incorporation into the deoxyribonucleic acid (DNA) of dividing lymphocytes.The ratio of lymphocyte proliferation in treated groups to that in vehicular controls (stimulation index) is determined to serve as a quantitative criterion.A substance is considered a sensitizer and assigned the SEN notation if it has a statistically significant stimulation index greater than or equal to 3 and is supported by a fitting dose-response relationship. # A.3.3 Identifying skin sensitization potential with the mouse ear swelling test The mouse ear swelling test (MEST) # B.1 Algorithm for estimating and evaluating skin exposure hazards Appendix B presents a predictive algorithm for estimating and evaluating the health hazards of skin exposure to chemicals.The algorithm is designed to evaluate the potential for a chemical agent to penetrate the skin and induce systemic toxicity.The goals for incorporating this algorithm into the proposed strategy for assigning SYS notation are as follows: - Provide an alternative method to evaluate chemicals for which no clinical reports or animal toxicity studies exist or for which empirical data are insufficient to determine systemic effects - Use the algorithm evaluation results to determine whether a chemical poses a skin absorption hazard and should be labeled with the SYS notation The algorithm evaluation includes three steps: 1.Determining a skin permeation coefficient for the chemical 2.Estimating chemical uptake by the dermal and respiratory absorption routes 3.Evaluating whether the chemical poses a skin exposure hazard. The algorithm is flexible in the data requirement and can operate entirely on the basis of the physicochemical properties of a chemical and the relevant exposure parameters.Thus, the algorithm is independent of the need for biologic data.Or, it can function using both the physicochemical properties and the experimentally determined permeation coefficients when the latter data are available and appropriate to use. # B.1.1 Step 1: Determining the skin permeation coefficient The first step in the evaluation is to determine the skin permeation coefficient (K p ) for the chemical to describe the transdermal penetration rate of the substance.The K p determined for a chemical is expressed in cm/hr and represents the overall diffusion of the substance through the stratum corneum and into the blood capillaries of the dermis.This value may be determined from laboratory tests or by QSPR or QSAR. Experimentally, the permeation of chemicals through human skin can be determined in vitro using diffusion cell techniques such as those described in the protocols standardized by OECD Exercising caution is important when a QSPR is used in the derivation of K p .Many of the empirical QSPRs, which are constrained by the experimental data used in the development and validation, are subject to limitations in the types of chemicals to which the models may apply.These QSPRs may not provide reliable K p estimates for inorganic substances, ionized substances, very high-MW chemicals, small hydrophilic molecules, or highly volatile substances.Chemicals in the first three categories are not readily absorbed through the skin, and their experimental K p values are often not readily available for model validation.Hydrophilic substances of small MW tend to penetrate hair follicles and sweat glands and, therefore, are not sufficiently covered in the assumed pathway of penetration by many models.Also, with a few exceptions, the QSPRs typically do not account for the evaporation of chemicals from the skin; as a result, the predicted K p for volatile substances could be overstated. # B.1.2 Step 2: Estimating chemical uptake from skin and inhalation exposures Step 2 in the evaluation (as initially proposed by the Toxic Substances Control Act Interagency Testing Committee ) is to calculate the biologic uptake of the chemical from skin absorption (skin dose) and inhalation (inhalation dose) during the same period of exposure.The inhalation dose represents a critical presence of the examined substance in the body.Beyond this dose, bioaccumulation of the substance is a cause for concern for health effects.The skin and inhalation doses provide quantifiable measures for absorption of the chemical by different routes.These doses serve as the basis for determining whether the substance constitutes a skin absorption hazard. The skin dose is calculated as a mathematical product of the K p acquired in Step 1, the water solubility (S W ) of the chemical, the exposed skin surface area, and the duration of exposure.In the calculation, the transdermal flux of the substance is assumed to originate from a saturated aqueous solution.Assuming that the skin exposure continues for 8 hours to unprotected skin on both palms (a surface area of 360 cm 2 ), The inhalation dose is derived on the basis of the occupational exposure limit (OEL) of the substance-if the OEL is developed to prevent the occurrence of systemic effects rather than sensory/irritant effects or direct effects on the respiratory tract.Assuming a continuous exposure of 8 hours, an inhalation volume of 10 m 3 in 8 hours, and a factor of 75% for the retention of the airborne substance in the lungs during respiration (retention factor, RF), # Inhalation dose = OEL × Inhalation volume × RF = OEL (mg/m 3 ) × 10 m 3 × 0.75 In the above equation, a default value of 0.75 is used for the RF to represent the respiratory retention of chemicals.The percentage value for the absorption of xenobiotics via the lungs is commonly assumed to be 75%-100% , and the default RF of 0.75 is selected to avoid underestimating skin absorption as a significant route of biologic uptake because complete absorption is unlikely to occur for most chemicals inhaled into the lungs.When scientifically justified, chemical-specific RFs may be used in place of the default value, especially for chemicals with systemic bioavailability lower than the default value (e.g., because of the extensive metabolism of substances in the lungs or accumulation in the blood leading to absorption that is no longer perfusion limited). # B.1.3 Step 3: Evaluating the skin exposure hazard The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of skin dose to inhalation dose (the SI ratio).This ratio quantitatively indicates (1) the significance of dermal absorption as a route of occupational exposure to the substance and (2) the contribution of dermal uptake to systemic toxicity.If a chemical has an SI ratio greater than or equal to 0.1, it is considered a skin absorption hazard. # B.2 Criterion for assigning the SYS notations The SYS notation will be assigned to a chemical when the mathematical evaluation indicates an SI ratio of at least 0.1 and when no data of scientific merit suggest that the potential health effects exclude systemic effect(s).An SI ratio of 0.1 is selected as the reference level based on a recent examination of chemicals recognized as skin absorption hazards by NIOSH.In this examination, SI ratios were calculated for 108 chemicals; all chemicals had assigned NIOSH skin notations, and the literature suggested them to be agents of systemic toxicity following skin exposure.Approximately 76% of the examined substances had SI ratios greater than 0.1.This result suggests that a chemical be treated as a skin absorption hazard when its dermal uptake exceeds 10% of its uptake by inhalation.The result also supports an SI ratio of 0.1 as the threshold value for assigning SYS notation.For the 24% of examined substances predicted to have an SI ratio less than 0.1, the preliminary analysis indicates that two factors may have contributed significantly to the low ratio: - The OELs used to calculate inhalation dose were initially developed with a small safety margin compared with the OELs for substances having an SI ratio greater than 0.1. - The health effects basis for skin notations may not be adequate. These factors are being further investigated as a part of the ongoing NIOSH effort to reevaluate the health effects of skin exposure to these chemicals using scientifically up-to-date data.Results of these analyses will be used to improve the NIOSH skin notations. This criterion agrees with the findings from similar research conducted by other international occupational safety and health organizations.One example is the proposal of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) to recommend skin notations based on a semiquantitative approach .The algorithm proposed by ECETOC is similar to the one intended for assigning NIOSH SK: SYS notations.The ECETOC algorithm determines the skin exposure hazard posed by a chemical agent by comparing its dermal uptake to its systemic absorption from inhalation.ECETOC concluded that a skin notation should be assigned to a chemical when the amount of chemical absorbed by both hands and forearms in 1 hour could exceed 10% of the amount absorbed by inhalation when airborne concentrations are at the OEL for 8 hours.This comparison shows that for any chemical where the modeling approach may be applied, the SI ratio determined using the algorithm for assigning the SYS notation is approximately the same as the SI ratio generated by following the assumptions made in the algorithm proposed by ECETOC.Similarly, in both methods, the criteria for determining the health hazard of a skin exposure are based on essentially the same level of skin absorption. In view of these findings, dermal absorption of a chemical is considered a systemic toxicity hazard if the substance is evaluated by the algorithm as demonstrated in this appendix and is shown to have an SI ratio greater than 0.1.The SYS notation will be assigned accordingly.For these substances, additional toxicological evaluations are recommended to clinically or experimentally verify the adverse systemic effect(s). Note that in the context of Appendix B, the predictive algorithm is intended to serve as a hazard identification tool for determining whether skin exposure to a chemical agent is inherently capable of provoking systemic toxicity and is supportive of assigning the SYS notation.The SI ratio of 0.1 was determined as the threshold level by modeling chemicals that currently carry NIOSH skin notations.To provide a consistent basis for comparing modeling results, the following exposure parameters were treated as constants during the investigation (with assumptions made for reasonably representing the conditions of skin exposures): (1) concentration of the chemical on the skin surface, (2) surface area of exposed skin, and (3) exposure duration.If exposure conditions are not known, these parameters will remain as constants when the algorithm is used to estimate the SI ratio for assigning the SYS notation.Note that in actual workplace situations, these exposure parameters are likely to vary from the values assumed here, depending on the chemicals and the industrial processes or tasks involved.Before using the predictive algorithm to assess the risk of a given chemical exposure during a specific task, an exposure assessment should be conducted to sufficiently characterize all relevant information.The mathematical model described here may be improved and updated as more dermal absorption data become available and other facets of dermal penetration are incorporated into the model. # C.1 Using pH and acid/alkali reserve to identify skin corrosives In A Sequential Testing Strategy for Dermal Irritation and Corrosion, the supplement to the OECD Guideline for Testing of Chemicals 404 , the OECD recommends using a weight-of-evidence analysis on existing relevant data before undertaking in vivo testing to evaluate skin corrosion.Relevant data encompass data generated from methods alternative to biologic testing, including "evidence of corrosivity/irritation of one or more structurally related substances or mixtures of such substance" and "data demonstrating strong acidity or alkalinity of the substance. "The OECD Guideline also specifies that the acid/alkali reserve (or buffering capacity) be considered if a chemical is recognized as a skin corrosive on the basis of its extreme pH. Using pH and acid/ alkali reserve to identify potential skin corrosives is in accordance with the approach adopted in the GHS .In this system, the appropriate evaluation of extreme pH values (≤ 2.0 or ≥ 11.5) (including acid/alkaline reserve capacity) is accepted as a decision logic for recognizing corrosive agents. When a chemical is evaluated for potential skin corrosivity based on pH and buffering capacity, the substance is to be recognized as corrosive following the outlined predictive models : - pH ≤ 2.0 or ≥ 11.5 - pH − (acid reserve ÷ 6) ≤ 1 or - pH + (alkali reserve ÷ 12) ≥ 14.5 where the acid reserve of a substance is the amount in grams of sodium hydroxide required to bring 100 g of a test substance (in a 10% solution or suspension) to a pH of 4, and the alkali reserve is the amount in grams of sulfuric acid required to bring 100 g of a test substance to a pH of 10. (See Young et al. for details about the generation and use of acid/alkali reserve measurements.) # C.2 Using structural alerts implemented in the DEREK™ expert system to identify sensitizers The knowledge-based DEREK™ expert system contains algorithms to predict the toxicity of chemical mixtures based on a series of structure-activity rules (also known as structural rules or structural alerts).These rules describe the substructures of chemical molecules potentially responsible for adverse health effects .As part of the DEREK™ expert system architecture, a rule base for APPENDIX C - Identifying skin corrosives and sensitizers using physicochemical properties and structure activity relationship-based analysis identifying potential contact allergens was derived using results of the guinea pig maximization test conducted for 294 substances classified as strong or moderate sensitizers .The rule base initially consisted of 40 structural rules and has been continuously updated since its inception.Workshop 19 of the European Centre for the Validation of Alternative Methods discussed the DEREK™ skin sensitization rule base as an alternative to skin sensitization testing.The Workshop recommended that QSAR predictions and expert systems serve as screens for identifying positive substances . Zinke et al. assessed the effectiveness of these structural alerts for identifying the skinsensitizing properties of chemicals.The researchers evaluated the 40 originally published structural alerts against a database developed in the German Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV).The BgVV database contained data submitted under its procedure for notification about new chemicals within the European Union and data on the skin-sensitization potentials of 1,039 substances .Zinke et al. reported that among the structural alerts examined, eight could be used to identify contact allergens without further refinement.These alerts are for acid halides, acid anhydrides, isocyanates, isothiocyanates, β-lactams, aldehydes, epoxides, and quaternary ammonium cation. These structural alerts will be used to evaluate substances for their potential as skin sensitizers when no human or biologic testing data are available.As the DEREK™ structural rules continue to be refined, it is anticipated that additional alerts will be validated and available to identify hazards and facilitate the assignment of SK: SEN notations. Zinke S, Gerner I, Schlede E .Evaluation of a rule base for identifying contact allergens by using a regulatory database: comparison of data on chemicals notified in the European Union with "structural alerts" used in the DEREK™ expert system.Altern Lab Animals 30:285-298. NIOSH CIB 61 - Skin Notations # D.1 Selecting chemicals for evaluation Chemicals can be identified and selected for evaluation based on the strategic framework outlined in this CIB through three primary pathways: # D.2 Selecting and prioritizing candidate chemicals found within the NIOSH Pocket Guide to Chemical Hazards The NIOSH Pocket Guide to Chemical Hazards lists 142 chemicals assigned the skin notation , which indicates the potential for dermal absorption.These substances have been selected to be the first evaluated through the strategic framework outlined in this CIB.As part of this process, a hierarchal ranking scheme that applies a binominal hazard-ranking approach has been developed to aid in the ranking of the many candidate chemicals.

Parameters addressed within the hierarchal scheme of prioritizing the candidate chemicals include the following: - Potential health hazards - Potential for occupational exposure - Annual production volume - OELs recommended by both governmental and nongovernmental organizations. An array of information resources containing data related to the outlined parameters were assessed to aid in ranking the chemicals to be classified according to the new strategy.The following information resources were applied within this scheme: # F.2 Systemic toxicity from skin exposure Toxicokinetic studies of phenol have been identified.Dermal absorption of phenol by human subjects has been reported to range from 4%-23% of the applied dose, depending on the period of exposure and the concentration of phenol .In male volunteers, the rate of absorption of an aqueous phenol solution (2.5, 5.0, or 10.0 g/L from a 2 mL reservoir) applied directly to the forearm (15.6 cm 2 ) was found to be concentration-dependent, with the rate ranging from 0.079 mg/ cm 2 /hr at the low concentration to 0.301 mg/ cm 2 /hr at the high concentration .In this study, the total amount of phenol absorbed-but not the rate of absorption-at the low concentration increased with time, with 12.6% and 22.7% of the applied dose absorbed in 30 and 60 minutes, respectively.Feldman and Maibach reported the degree of dermal absorption as 4.4% of the administered dose following a single topical application of 4 µg/cm 2 phenol on 13 cm 2 of the unprotected ventral forearm of human adults.Phenol vapors are also reported to readily penetrate the skin with absorption efficiency equal to that of inhalation, thus contributing to the total skin exposure .In a whole-body skin exposure study in which unclothed and lightly clothed volunteers were exposed to phenol vapors at concentrations from 1.3-6.5 ppm for 6 hours, but were breathing clean air by mask, reported that absorption increased proportionately with air concentration .These studies generally demonstrated that phenol can be absorbed through the human skin. The potential of phenol to be absorbed through the skin has also been evaluated in laboratory animals.Hughes and Hall reported a 120-hour cumulative dermal absorption of 66%-80% in young rats (29-day-old female rat). In an earlier study, the same authors reported that approximately 85% of the dose of phenol was absorbed in 72 hours in 90-day-old female rats after dermal administration of phenol.In vitro studies using laboratory animal tissues also indicate that phenol is absorbed through the skin.For example, in an in vitro system using dermatomed rat skin, Hughes et al. reported a 72-hour dermal absorption of phenol of 95% of the applied dose.Brooks and Riviere considered a recent study that evaluated dermal absorption of phenol in acetone and water under nonoccluded and occluded applications using isolated perfused porcine skin.The authors reported absorption, penetration into tissues, and total recoveries of phenol to be greater under occluded than nonoccluded conditions and that for each solvent, the absorption percentage was higher with the low-dose (4 μg/cm 2 ) compared to the high-dose (40 μg/cm 2 ), suggesting saturation of absorption or other nonlinear kinetics under some conditions of exposure.Depending on the solvent and dose, Brooks and Riviere reported that dermal absorption ranged from 9.24%-14.62% under occluded conditions at the low dose and 2.90%-5.45% under nonoccluded condition.In vitro permeability coefficients for phenol were found to increase with increasing concentration of aqueous phenol applied to mouse skin , with a 12-fold increase in mean coefficient (0.007-0.085 cm / hour) resulting from doubling the concentration from 20 g/L to 40 g/L, and a value of 0.169 cm/hr noted when 60 g/L was applied .The authors concluded that phenol concentrations exceeding 20 g/L may destroy a diffusion barrier normally provided by the intact stratum corneum, permitting increased dermal absorption.Results from animal studies in vivo and studies using animal skin in vitro also demonstrated that phenol is absorbed through the skin of animals.The potential of phenol to pose a skin absorption hazard was also evaluated using the NIOSH predictive algorithm for estimating and evaluating the health hazards of skin exposure to substances. Based on this algorithm, the ratio of the skin dose to the inhalation dose (SI ratio) of 11 was calculated for phenol.This ratio is significantly higher than the SI ratio of greater than or equal to 0.1 indicating that skin absorption may substantially contribute to the overall body burden of a chemical.For this reason, phenol is considered to be absorbed through the skin following dermal contact.The result from the predictive algorithm supports the results from human and animal studies in vivo and from in vitro studies. - Application of Appendix A.1.1: Dermal absorption.The results of studies using human subjects have reported that dermal absorption of phenol range from 4%-23% of the applied dose.The studies indicate that phenol may be readily absorbed in liquid or vapor forms.Animal studies using different protocols report dermal absorption range from 9%-85% of the applied dose in multiple species.For this reason, phenol is identified as having a high potential to be absorbed following contact with the skin in liquid and vapor forms. Several case reports of humans dermally exposed to varying doses of phenol have been identified .In these reports, accidental exposure of phenol to intact skin or intentional (therapeutic) application of phenol to the skin has resulted in fatalities (from, e.g., respiratory depression and cardiac arrest), but the doses were not known with any accuracy, precluding estimation of a lethal dermal dose for humans.In animals, the dermal LD 50 values (the dose resulting in 50% mortality in the exposed animals) range from 0.5 mL/kg body weight to 0.68 mL/kg (corresponding to 669-1,500 mL / kg body weight) in rats under both occlusive and nonocclusive conditions and 1400 mg/kg in rabbits .The Conning and Hayes study reported severe muscular tremors, twitching, generalized convulsions with loss of consciousness, and prostration occurring within 10 minutes of skin exposure to phenol in water; subjects developed severe hemoglobinuria from 45-90 minutes.Brown et al. reported hematuria and convulsions as clinical signs of phenol toxicity.Because the reported acute dermal LD 50 values for the rat and rabbit are both lower than the critical dermal LD 50 value of 2 g / kg body weight that identifies substances with the potential for acute dermal toxicity , phenol is considered systemically toxic by the acute dermal route.No standard toxicity or specialty studies evaluating biologic-system/function-specific effects (including reproductive and developmental effects and immunotoxicity) following skin exposure to phenol were identified in humans or animals. - Application of Appendix A.1.7: Toxic effects of exposures of the skin on organ systems or biologic functions.No evidence was identified that evaluated the effects of phenol on organ systems or biologic functions.The SYS notation would not be assigned to phenol based on the criteria outlined in this section. Although a literature search identified no epidemiologic studies that allowed for evaluation of the carcinogenic potential of phenol, a limited number of studies in animals involving repeated application of phenol in benzene or in acetone in two-stage carcinogenicity protocols in mice indicated that phenol has promoting activity.Studies conducted by Boutwell and Bosch in several strains of mice also suggested that phenol in benzene or dioxane is a tumor promoter and possibly a complete carcinogen (i.e., having both promoting and initiating activity).In the latter study, phenol elicited skin tumors in mice even in the absence of a tumor-initiating agent (i.e., 9,10-dimethyl-1,2-benzanthracene).These studies are inadequate for the evaluation of the carcinogenic potential of phenol because of the following: - The short duration of exposures applied in the studies - The lack of appropriate controls , and/or # F.3 Direct effect(s) on the skin The available information indicates that phenol is corrosive to the skin.For example, skin Other effects, such as erythema, inflammation, discoloration, eczema, redness, and severe edema have been reported on contact of the skin with solid or liquid phenol .The effects of phenol on the skin have been attributed to its ability to impair the barrier function of the stratum corneum and produce coagulation necrosis by denaturing and precipitating proteins.Although the structure-activity-relationship model, DEREK™, predicts that phenol is nonirritating to the skin, which indicates that the chemical does not have structural alerts for skin irritation, several studies in humans and animals show that phenol is corrosive to the skin or is a skin irritant depending on the concentration. # F.4 Sensitization Few studies have been identified that evaluated the potential of phenol to cause skin sensitization in both humans and animals.In one study using 24 volunteers, phenol produced negative results in skin sensitization tests .The Magnussen and Kligman skin sensitization test in guinea pigs also gave negative results for phenol .Predictions using structure-activity-relationship models provide some information regarding this endpoint.Based on the chemical structure, phenol is predicted by DEREK™ as negative for sensitization, indicating that the chemical does not have structural alerts for skin sensitization.This prediction of negative sensitization potential is consistent with the absence of published reports of sensitization in workers handling phenol and the limited empirical evidence. The limited information available indicates that phenol is not likely to be a skin sensitizer.Therefore, this assessment does not assign a SK: SEN notation for phenol. - Application of Appendix A.3: Experimental protocols for investigating sensitization from skin exposure and derived criteria for assigning the SK: SEN Notations and Appendix C.2: Using structural alerts implemented in the DEREK™ expert system to identify sensitizers.This section reviews the assembled data set for phenol to assess the potential for sensitization following skin exposures.The identified data set provided insufficient information to assign the SEN notation.This decision is supported by the inclusion of the DEREK™ negative prediction for phenol to cause sensitization. # F.5 Summary There is sufficient information from toxicokinetics , acute dermal toxicity studies , and repeatdose dermal toxicity studies to indicate that phenol is absorbed through the skin and is acutely toxic and induces systemic effects (e.g., central nervous system effects, effects on body weight and survival) following skin exposure.Information from human experience and animal studies is sufficient to demonstrate that phenol is corrosive and that more dilute solutions are irritating to the skin.The limited information available indicates that phenol is not a skin sensitizer.Therefore, this assessment recommends the composite skin notation of SK: SYS-DIR (COR) for phenol. Phenol has also been classified as being harmful and toxic upon contact with the skin and corrosive by the European Commission (EC) .ACGIH , NIOSH # G.1 Contaminants and isomers Skin notations are intended to provide warnings and salient facts about the adverse health effects associated with skin exposures to a neat chemical or mixture.Commercial-grade chemicals may contain a contaminant, which has been defined as the following: 1.A chemical that is unintentionally present within a neat substance or mixture having a concentration less than 1.0% or 2.A chemical that is recognized as a potential carcinogen present within a neat substance or mixture having a concentration less than 0.1% Contaminants may be discussed within the supporting documentation for a specific compound, but the skin notations apply solely to the neat substance or mixture because of the potential for the contaminant to represent a unique occupational hazard.If a contaminant is deemed to represent a substantial health hazard for workers following contact of the skin, it may be independently evaluated to determine whether assignment of skin notations is appropriate. Isomers are molecules that exhibit unique physical structures, despite having the same elementary composition and weight.Variations within the chemical properties of isomers of a molecule may result in substantial differences in toxic potency.Unless otherwise noted, skin notations derived for a chemical that displays isomerism apply strictly to the structural arrangements specified within the supporting documentation of the compound. # G.2 Globally Harmonized System of Classification and Labeling of Chemicals GHS is an international classification and labeling system for chemicals adopted by the U.N. # G.3 Cancer Cancer refers to any one of a group of diseases that occurs when cells in the body become abnormal and grow or multiply out of control. Exposure of the skin to some chemicals has been demonstrated to contribute to the development of (1) cancers within internal organ systems beyond the point of contact and (2) cancers of the skin at or near the point of contact.To ensure consistency in the assignment of the skin notations, the following paradigm has been developed: - Cancers occurring within an internal organ system or tissue beyond the point of contact are defined as systemic effects and warrant the assignment of the SYS notation. - Cancers occurring at or near the point of contact on the skin are defined as direct effects and warrant the assignment of the DIR notation. The weight-of-evidence approach described within this CIB will be applied to assess the potential for a chemical to act as a carcinogen following exposures of the skin and the subsequent assignment of the SYS and DIR notations when appropriate.In addition, the Skin Notation Profiles (see Appendix F) will summarize the data associated with carcinogenic potential of a chemical, including cancer designations provided by NIOSH, NTP, U.S. EPA, IARC, and ACGIH. # G.4 Nanoparticles and the skin Nanotechnology is a system of innovative methods to control and manipulate matter at nearatomic scale (1-100 nanometers) to produce new materials, structures, and devices.Examples of nanoparticles include carbon-based materials (i.e., nanotubes and fullerenes), metal-based materials (i.e., quantum dots, metal oxides, nanogold, and nanosilver), nanocomposites, and dendrimers.Because of their small size and relatively large surface area, engineered nanoparticles may have chemical, physical, and biologic properties distinctly different from and greater than fine particles of similar chemical composition .These variations may result in unique health hazards for workers employed to manufacture or use products containing nanomaterials. Limited information is currently available to accurately assess the health hazards of skin exposures to nanoparticles.The results from in vitro studies using primary or cultured human skin cells show that single-walled and multi-walled carbon nanotubes are able to enter cells and cause the release of proinflammatory cytokines, oxidative stress, and decreased viability . More recent studies have reported the ability of quantum dots and fullerenes to penetrate the stratum corneum by passive diffusion and to induce inflammatory response and cytotoxicity within skin fibroblasts and keratinocytes .Factors including size, shape, water solubility, and surface coating may directly affect a nanoparticle's potential to penetrate the skin . The occupational health hazards of exposing skin to the different forms of nanoparticles are unclear.For this reason, skin notations derived from neat substances or mixtures with similar chemical composition to a specific form of nanoparticles may not be applicable because of the different physicochemical properties and toxic potential.As new data become available, the skin notations and supporting documentation will address the toxic potential of 57

This report updates and consolidates all previous PHS recommendations for the management of health-care workers (HCWs) who have occupational exposure to blood and other body fluids that may contain human immunodeficiency virus (HIV); it includes recommendations for HIV postexposure prophylaxis (PEP) and discusses the scientific rationale for PEP.The decision to recommend HIV postexposure prophylaxis must take into account the nature of the exposure (e.g., needlestick or potentially infectious fluid that comes in contact with a mucous membrane) and the amount of blood or body fluid involved in the exposure.Other considerations include pregnancy in the HCW and exposure to virus known or suspected to be resistant to antiretroviral drugs.Assessments of the risk for infection resulting from the exposure and of the infectivity of the exposure source are key determinants of offering PEP.Systems should be in place for the timely evaluation and management of exposed HCWs and for consultation with experts in the treatment of HIV when using PEP.Recommendations for PEP have been modified to include a basic 4-week regimen of two drugs (zidovudine and lamivudine) for most HIV exposures and an expanded regimen that includes the addition of a protease inhibitor (indinavir or nelfinavir) for HIV exposures that pose an increased risk for transmission or where resistance to one or more of the antiretroviral agents recommended for PEP is known or suspected.An algorithm is provided to guide clinicians and exposed health-care workers in deciding when to consider PEP.Occupational exposures should be considered urgent medical concerns to ensure timely administration of PEP.Health-care organizations should have protocols that promote prompt reporting and facilitate access to postexposure care.Enrollment of HCWs in registries designed to assess side effects in HCWs who take PEP is encouraged.#INTRODUCTION Although preventing blood exposures is the primary means of preventing occupationally acquired human immunodeficiency virus (HIV) infection, appropriate postexposure management is an important element of workplace safety.In January 1990, CDC issued a statement on the management of HIV exposures that included considerations for zidovudine (ZDV) use for postexposure prophylaxis (PEP) (1 ).At that time, data were insufficient to assess the efficacy of ZDV as a prophylactic agent in humans or the toxicity of this drug in persons not infected with HIV.Although there are still only limited data to assess safety and efficacy, additional information is now available that is relevant to this issue. In December 1995, CDC published a brief report of a retrospective case-control study of health-care workers (HCWs) from France, the United Kingdom, and the United States exposed percutaneously to HIV; the study identified risk factors for HIV transmission and documented that the use of ZDV was associated with a decrease in the risk for HIV seroconversion (2 ).This information, along with data on ZDV efficacy in preventing perinatal transmission (3 ) and evidence that PEP prevented or ameliorated retroviral infection in some studies in animals (4 ), prompted a Public Health Service (PHS) interagency working group*, with expert consultation (5 ), in June 1996 to issue provisional recommendations for PEP for HCWs after occupational HIV exposure (6 ). Since the provisional recommendations were released, several new antiretroviral drugs have been approved by the Food and Drug Administration (FDA), and more information is available about the use and safety of antiretroviral agents in exposed HCWs (7)(8)(9)(10).In addition, questions have been raised about the use of chemoprophylaxis in situations not fully addressed in the 1996 recommendations, including when not to offer PEP, what to do when the source of exposure or the HIV status of the source person is unknown, how to approach PEP in HCWs who are or may be pregnant, and considerations for PEP regimens when the source person's virus is known or suspected to be resistant to one or more of the antiretroviral agents recommended for PEP. In May 1997, a meeting of expert consultants, convened by CDC to consider the new information, prompted a PHS interagency working group † decision to issue updated recommendations.This document addresses the management of occupational exposure to HIV, including guidance in assessing and treating exposed HCWs, updates previous recommendations for occupational postexposure chemoprophylaxis, and updates and replaces all previous PHS guidelines and recommendations for occupational HIV exposure management for HCWs.Included in this document is an algorithm to guide decisions regarding the use of PEP for HIV exposures.The algorithm and these recommendations together address most issues that may be encountered during postexposure follow-up.As relevant information becomes available, updates of these recommendations will be published.Recommendations for nonoccupational (e.g., sexual or pediatric) exposures are not addressed in these guidelines. # DEFINITIONS OF HEALTH-CARE WORKERS AND EXPOSURE In this report, "health-care worker" (HCW) is defined as any person (e.g., an employee, student, contractor, attending clinician, public-safety worker, or volunteer) whose activities involve contact with patients or with blood or other body fluids from patients in a health-care or laboratory setting.An "exposure" that may place an HCW at risk for HIV infection and therefore requires consideration of PEP is defined as a *This interagency working group comprised representatives of CDC, the Food and Drug Administration, the Health Resources and Services Administration, and the National Institutes of Health. †This interagency working group comprised representatives of CDC, FDA, and the National Institutes of Health.Information included in these recommendations may not represent FDA approval or approved labeling for the particular product or indications in question.Specifically the terms "safe" and "effective" may not be synonymous with the FDA-defined legal standards for product approval.percutaneous injury (e.g., a needlestick or cut with a sharp object), contact of mucous membrane or nonintact skin (e.g., when the exposed skin is chapped, abraded, or afflicted with dermatitis), or contact with intact skin when the duration of contact is prolonged (i.e., several minutes or more) or involves an extensive area, with blood, tissue, or other body fluids.Body fluids include a) semen, vaginal secretions, or other body fluids contaminated with visible blood that have been implicated in the transmission of HIV infection (11,12 ); and b) cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids, which have an undetermined risk for transmitting HIV (11 ).In addition, any direct contact (i.e., without barrier protection) to concentrated HIV in a research laboratory or production facility is considered an "exposure" that requires clinical evaluation and consideration of the need for PEP. Although one nonoccupational episode of HIV transmission has been attributed to contact with blood-contaminated saliva (13 ), this incident involved intimate kissing between sexual partners and is not similar to contact with saliva that may occur during the provision of health-care services.Therefore, in the absence of visible blood in the saliva, exposure to saliva from a person infected with HIV is not considered a risk for HIV transmission; also, exposure to tears, sweat, or nonbloody urine or feces does not require postexposure follow-up.- Human breast milk has been implicated in perinatal transmission of HIV.However, occupational exposure to human breast milk has not been implicated in HIV transmission to HCWs.Moreover, the contact HCWs may have with human breast milk is quite different from perinatal exposure and does not require postexposure follow-up. # BACKGROUND The rationale is provided here for the postexposure management and prophylaxis recommendations given at the end of the document.Additional details concerning the risk for occupational HIV transmission to HCWs and management of occupational HIV exposures are available elsewhere (16)(17)(18). # Risk for Occupational Transmission of HIV to HCWs Prospective studies of HCWs have estimated that the average risk for HIV transmission after a percutaneous exposure to HIV-infected blood is approximately 0.3% (95% confidence interval =0.2%-0.5%) (16 ) and after a mucous membrane exposure is 0.09% (95% CI=0.006%-0.5%) (19 ).Although episodes of HIV transmission after skin exposure have been documented (20 ), the average risk for transmission by this route has not been precisely quantified because no HCWs enrolled in prospective studies have seroconverted after an isolated skin exposure.The risk for transmission is estimated to be less than the risk for mucous membrane exposures (21 ).The risk for *Although exposure to these body substances generally is not considered a risk for occupational HIV transmission, this does not negate the importance of handwashing and appropriate glove use when contacting these body substances.Handwashing and appropriate glove use are part of standard precautions for infection control to prevent transmission of nosocomial and community-acquired pathogens and are required for compliance with the Occupational Safety and Health Administration bloodborne pathogen standard (14,15 ).In addition, postexposure evaluation for hepatitis B (and possibly hepatitis C) should be provided if contact with saliva includes a possible portal of entry (i.e., nonintact skin, mucous membrane, or percutaneous injury). transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified.As of June 1997, CDC has received reports of 52 U.S. HCWs with documented HIV seroconversion temporally associated with an occupational HIV exposure.An additional 114 episodes in HCWs are considered possible occupational HIV transmissions; these workers reported that their infection was occupationally acquired and no other risk for HIV infection was identified, but transmission of infection after a specific exposure was not documented (22 ).Of the 52 documented episodes, 47 HCWs were exposed to HIV-infected blood, one to a visibly bloody body fluid, one to an unspecified fluid, and three to concentrated virus in a laboratory.Forty-five exposures were percutaneous, and five were mucocutaneous; one HCW had both a percutaneous and a mucocutaneous exposure.The route of exposure for one person exposed to concentrated virus is uncertain.Of the percutaneous exposures, the objects involved included a hollow-bore needle (41), a broken glass vial (two), a scalpel (one), and an unknown sharp object (one) (CDC, unpublished data, 1998). Epidemiologic and laboratory studies suggest that several factors may affect the risk for HIV transmission after an occupational exposure.The one retrospective casecontrol study of HCWs who had percutaneous exposure to HIV found that the risk for HIV transmission was increased with exposure to a larger quantity of blood from the source patient as indicated by a) a device visibly contaminated with the patient's blood, b) a procedure that involved a needle placed directly in a vein or artery, or c) a deep injury (23 ). (A laboratory study that demonstrated that more blood is transferred by deeper injuries and hollow-bore needles lends further support for the observed variation in risk related to blood quantity ).The risk also was increased for exposure to blood from source patients with terminal illness, possibly reflecting either the higher titer of HIV in blood late in the course of AIDS or other factors (e.g., the presence of syncytia-inducing strains of HIV).It was estimated that the risk for HIV transmission from exposures that involve a larger volume of blood, particularly when the source patient's viral load is probably high, exceeds the average risk of 0.3% (23 ). The utility of viral load measurements from a source patient as a surrogate for estimating the viral titer for assessing transmission risk is not known.Plasma viral load measurement (e.g., HIV RNA) reflects only the level of cell-free virus in the peripheral blood.This measurement does not reflect the level of cell-associated virus in the peripheral blood or the level of virus in other body compartments (e.g., lymphatic tissue).Although a lower viral load, or results that are below the limits of viral quantification, in the peripheral blood probably indicates a lower titer exposure, it does not rule out the possibility of transmission; HIV transmission from persons with a plasma viral load below the limits of viral quantification (based on the assay used at the time) has been reported in instances of mother-to-infant transmission (25,26 ) and in one HCW seroconversion (J.L. Gerberding, San Francisco General Hospital, unpublished data, May 1997). There is some evidence that host defenses also may influence the risk for HIV infection.In one small study, HIV-exposed but uninfected HCWs demonstrated an HIV-specific cytotoxic T-lymphocyte (CTL) response when peripheral blood mononuclear cells were stimulated in vitro with HIV mitogens (27 ).Similar CTL responses have been observed in other populations with repeated HIV exposure without resulting infection (28)(29)(30)(31)(32)(33).Among several possible explanations for this observation, one is that the host immune response sometimes may be able to prevent establishment of HIV infection after a percutaneous exposure; another is that the CTL response simply may be a marker for exposure. # HIV Seroconversion in HCWs Data on the timing and clinical characteristics of seroconversion in HIV-exposed HCWs are limited by the infrequency of infection following occupational exposure, variations in postexposure testing intervals, and differences over time in the sensitivity of HIV-antibody testing methods.Among the HCWs with documented seroconversions reported to CDC for whom data are available, 81% experienced a syndrome compatible with primary HIV infection a median of 25 days after exposure (CDC, unpublished data, 1998).In a recent analysis of 51 seroconversions in HCWs, the estimated median interval from exposure to seroconversion was 46 days (mean: 65 days); an estimated 95% seroconverted within 6 months after the exposure (34 ).These data suggest that the time course of HIV seroconversion in HCWs is similar to that in other persons who have acquired HIV through nonoccupational modes of transmission (35 ). Three instances of delayed HIV seroconversion occurring in HCWs have been reported; in these instances, the HCWs tested negative for HIV antibodies >6 months postexposure but were seropositive within 12 months after the exposure (36,37; J.L. Gerberding, San Francisco General Hospital, unpublished data, May 1997).DNA sequencing confirmed the source of infection in one instance.Two of the delayed seroconversions were associated with simultaneous exposure to hepatitis C virus (HCV) (37; J.L. Gerberding, San Francisco General Hospital, unpublished data, May 1997).In one case, co-infection was associated with a rapidly fatal HCV disease course (37 ); however, it is not known whether HCV directly influences the risk for or course of HIV infection or is a marker for other exposure-related factors. # Rationale for PEP Considerations that influence the rationale and recommendations for PEP include the pathogenesis of HIV infection, particularly the time course of early infection; the biologic plausibility that infection can be prevented or ameliorated by using antiretroviral drugs and direct or indirect evidence of the efficacy of specific agents used for prophylaxis; and the risk/benefit of PEP to exposed HCWs.The following discussion considers each of these issues. # Role of Pathogenesis in Considering Antiretroviral Prophylaxis Information about primary HIV infection indicates that systemic infection does not occur immediately, leaving a brief "window of opportunity" during which postexposure antiretroviral intervention may modify viral replication.Data from studies in animal models and in vitro tissue studies suggest that dendritic cells in the mucosa and skin are the initial targets of HIV infection or capture and have an important role in initiating HIV infection of CD4+ T-cells in regional lymph nodes (38 ).In a primate model of simian immunodeficiency virus (SIV) infection, infection of dendritic-like cells occurred at the site of inoculation during the first 24 hours following mucosal exposure to cell-free virus.During the subsequent 24-48 hours, migration of these cells to regional lymph nodes occurred, and virus was detectable in the peripheral blood within 5 days (39 ).HIV replication is rapid (generation time: 2.5 days) and results in bursts of up to 5,000 viral particles from each replicating cell (40; M.S. Saag, University of Alabama, personal communication, September 1997).The exponential increase in viral burden continues unless controlled by the immune system or other mechanisms (e.g., exhaustion of available target CD4+ T-cells).Theoretically, initiation of antiretroviral PEP soon after exposure may prevent or inhibit systemic infection by limiting the proliferation of virus in the initial target cells or lymph nodes. # Efficacy of Antiretrovirals for PEP Studies in animals and humans provide direct and indirect evidence of the efficacy of antiretroviral drugs as agents for postexposure prophylaxis.In human studies and in most animal studies, ZDV was the antiretroviral agent used for prophylaxis (26,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54).However, in more recent animal studies, newer agents also have been reported to be effective (55,56 ). Data from animal studies have been difficult to interpret, in part because of problems identifying a comparable animal model for humans.Most studies use a higher inoculum for exposure than would be expected in needlestick injuries.Among the animal studies, differences in controlled variables (e.g., choice of viral strain , inoculum size, route of inoculation, time of prophylaxis initiation, and drug regimen) make attempts to apply these results to humans difficult.In the animal studies that showed efficacy of pre-exposure and/or postexposure prophylaxis, reported outcomes (4,57 ) have included a) suppression of viremia or delayed antigenemia (41-47 ); b) drug-facilitated vaccine-type response (i.e., chemoprophylaxis sufficiently inhibited viral replication to permit formation of a long-lasting, protective cellular immune response) (48)(49)(50)(51)(52)(53)(54)(55)(56); and c) definitive prevention of infection (i.e., chemoprophylactic efficacy) (41,(52)(53)(54).More recent refinements in methodology have enabled studies more relevant to humans; in particular, the viral inocula used in animal studies have been reduced to levels more analogous to human exposures (54,56 ).The results of these studies provide additional evidence of postexposure chemoprophylactic efficacy. In studies of HIV-2 or SIV in nonhuman primates in which ZDV or 3'-fluorothymidine was used, suppression or delay of antigenemia was the most common outcome; prevention of infection was infrequent (43,52,(58)(59)(60).However, two other antiretroviral agents, 2',3'-dideoxy-3'-hydroxymethyl cytidine (BEA-005) and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), used to study PEP in primates have been more effective in preventing infection.When PMPA was administered 48 hours before, 4 hours after, or 24 hours after intravenous SIV inoculation to long-tailed macaques, a 4-week regimen prevented infection in all treated animals (55 ).A 3-day regimen of BEA-005 prevented SIV infection in 12 of 12 pigtailed macaques when administered 1-8 hours after intravenous inoculation; infection also was prevented in four of four animals that received 3 days of BEA-005 within 10 minutes after HIV-2 inoculation (56 ) .

Animal studies have demonstrated that early initiation of PEP and small inoculum size are correlates of successful PEP.ZDV initiated 1 hour or 24 hours after intravenous exposure to a rapidly lethal variant of SIV in pigtailed macaques prevented infection in one of three animals and modified SIV disease in three of six animals, respectively; PEP initiated at 72 hours had no effect (54 ).In macaques administered ZDV or BEA-005 1 to 72 hours after SIV intravenous challenge, earlier initiation of PEP was correlated with delayed onset and peak of antigenemia, decreased duration of antigenemia, and reduction in SIV serum titer; the most potent effect was evident when PEP was initiated within 8 hours of exposure (43,56 ).Studies in primates and murine and feline animal models have demonstrated that larger inocula decrease prophylactic efficacy (47,48,53,60 ).In addition, delaying initiation, shortening the duration, or decreasing the antiretroviral dose of PEP, individually or in combination, decreased prophylactic efficacy (42,43,45,47,50,55 ). There is little information with which to assess the efficacy of PEP in humans.Seroconversion is infrequent after an occupational exposure to HIV-infected blood; therefore a prospective trial would need to enroll many thousands of exposed HCWs to achieve the statistical power necessary to directly demonstrate PEP efficacy.During 1987-1989, the Burroughs-Wellcome Company sponsored a prospective placebocontrolled clinical trial among HCWs to evaluate 6 weeks of ZDV prophylaxis; however, this trial was terminated prematurely because of low enrollment (61 ).Because of current indirect evidence of PEP efficacy, it is unlikely that a placebo-controlled trial in HCWs would ever be feasible. In the retrospective case-control study of HCWs, after controlling for other risk factors for HIV transmission, the risk for HIV infection among HCWs who used ZDV as PEP was reduced by approximately 81% (95% CI=43%-94%) (23 ).In addition, in a randomized, controlled, prospective trial (AIDS Clinical Trial Group protocol 076) in which ZDV was administered to HIV-infected pregnant women and their infants, the administration of ZDV during pregnancy, labor, and delivery and to the infant reduced transmission by 67% (3 ).Only 9%-17% (depending on the assay used) of the protective effect of ZDV was explained by reduction of the HIV titer in the maternal blood, suggesting that ZDV prophylaxis in part involves a mechanism other than the reduction of maternal viral burden (26 ). The limitations of all of these studies must be considered when reviewing evidence of PEP efficacy.The extent to which data from animal studies can be extrapolated to humans is largely unknown, and the exposure route for mother-to-infant HIV transmission is not similar to occupational exposures; therefore these findings may not reflect a similar mechanism of ZDV prophylaxis in HCWs.Although the results of the retrospective case-control study of HCWs suggest PEP efficacy, the limitations of that study include the small number of cases studied and the use of cases and controls from different cohorts. Failure of ZDV PEP to prevent HIV infection in HCWs has been reported in at least 14 instances (62-64; G. Ippolito, AIDS Reference Center, Rome, Italy, and J. Heptonstall, Communicable Disease Surveillance Center, London, United Kingdom, personal communication, 1997).Although eight of the 13 source patients had taken ZDV, laboratory assessment for ZDV resistance of the virus from the source patient was performed in only three instances, two of which demonstrated reduced susceptibility to ZDV.In addition to possible exposure to a ZDV-resistant strain of HIV, other factors that may have contributed to the apparent failures in these instances may include a high titer and/or large inoculum exposure, delayed initiation and/or short duration of PEP, and possible factors related to the host (e.g., cellular immune system responsive-ness) and/or to the source patient's virus (e.g., presence of syncytia-forming strains) (62 ). # Antiretroviral Agents for PEP Several antiretroviral agents from at least three classes of drugs are available for the treatment of HIV disease.These include the nucleoside analogue reverse transcriptase inhibitors (NRTIs), nonnuceloside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) (See Appendix).Among these drugs, ZDV (an NRTI) is the only agent shown to prevent HIV transmission in humans (2,3 ).Although there are theoretical concerns that the increased prevalence of resistance to ZDV may diminish its utility for PEP (65 ), no data are available to assess whether this is a factor for consideration.Clinical data from the ACTG protocol 076 study documented that despite genotypic evidence of maternal ZDV resistance, ZDV prevented perinatal transmission (66 ).Thus, based on the available information, it is still reasonable that ZDV should continue to be the first drug of choice for PEP regimens. There are no data to directly support the addition of other antiretroviral drugs to ZDV to enhance the effectiveness of the PEP regimen.However, in HIV-infected patients, combination regimens have proved superior to monotherapy regimens in reducing HIV viral load (67,68 ).Thus, theoretically a combination of drugs with activity at different stages in the viral replication cycle (e.g., NRTIs with a PI) could offer an additive preventive effect in PEP, particularly for occupational exposures that pose an increased risk for transmission. Determining which agents and how many agents to use or when to alter a PEP regimen is largely empiric.Guidelines for the treatment of early HIV infection recommend the use of three drugs (two NRTIs and a PI) (69 ); however, the applicability of these recommendations to PEP remains unknown.In addition, the routine use of three drugs for all occupational HIV exposures may not be needed.Although the use of a highly potent regimen can be justified for exposures that pose an increased risk for transmission, it is uncertain whether the potential additional toxicity of a third drug is justified for lower-risk exposures.For this reason, the recommendations at the end of this report provide guidance for two-and three-drug PEP regimens that are based on the level of risk for HIV transmission represented by the exposure. NRTIs that can be considered for use with ZDV for PEP are lamivudine (3TC), didanosine (ddI), and zalcitabine, each of which has been included in recommended regimens that include ZDV (69 ).In previous CDC recommendations, 3TC was recommended as a second agent for PEP based on greater antiretroviral activity of the ZDV/3TC combination and its activity against many ZDV-resistant HIV strains without substantially increased toxicity (6 ).Also, data suggest that ZDV-resistant mutations develop more slowly in patients receiving the ZDV/3TC combination than those receiving ZDV alone (70 ), and in vitro studies indicate that the mutation associated with 3TC resistance may be associated with reversal of ZDV phenotypic resistance (71 ).No additional information has emerged to warrant altering the original recommendation of 3TC as the second agent for PEP.In addition, because ZDV and 3TC are available in a combination formulation (Combivir TM , manufactured by Glaxo Wellcome, Inc., Research Triangle Park, NC), the use of 3TC may be more convenient for HCWs.However, individual clinicians may prefer other NRTIs or combinations of other antiretroviral agents based on local knowledge and experience in treating HIV infection and disease. The addition of a PI as a third drug for PEP following high-risk exposures is based on the site of activity in the replication cycle (i.e., after viral integration has occurred) and demonstrated effectiveness in reducing viral burden.Previously, indinavir (IDV) was recommended as the PI for PEP because of its increased bioavailability when compared with saquinavir and its more favorable immediate toxicity profile compared with ritonavir (72 ).In addition, requirements for dose escalation when initiating ritonavir make it less practical for use in PEP.Since the 1996 PEP recommendations were published, nelfinavir (NEL) was approved for use by FDA and is now included in regimens recommended for the treatment of primary HIV infection (69 ).Also, FDA recently approved a soft-gel formulation of saquinavir (Fortovase TM , manufactured by Hoffmann-LaRoche, Inc., Nutley, New Jersey) that has improved bioavailability relative to its hard-gel formulation (Invirase TM , manufactured by Hoffmann-LaRoche, Inc.).However, the recommended dose of soft-gel saquinavir (1200 mg three times a day) is twice that of the hard-gel formulation (600 mg three times a day) and necessitates taking 18 pills a day, a factor that may influence HCW compliance if used for PEP.Based on these considerations, either IDV or NEL is recommended as first choice for inclusion in an expanded PEP regimen.If saquinavir is preferred by the prescribing physician, the soft-gel formulation (Fortovase TM ) should be used.Also, differences in the side effects associated with IDV and NEL, discussed below, may influence which of these agents is selected in a specific situation. The NNRTIs (i.e., nevirapine and delavirdine) have not been included in these recommended regimens for PEP.As a class of antiretroviral agents, the NNRTIs are fast-acting and very potent, making them appealing in concept for PEP.In addition, there is some evidence of prophylactic efficacy (73 ).However, concerns about side effects and the availability of alternative agents argue against routinely using this class of drugs for initial PEP, although with expert consultation, an NNRTI might be considered. # Side Effects and Toxicity of Antiretroviral Agents An important goal of PEP is to encourage and facilitate compliance with a 4-week PEP regimen.Therefore, the toxicity profile of antiretroviral agents, including the frequency, severity, duration, and reversibility of side effects, is a relevant consideration.All of the antiretroviral agents have been associated with side effects (See Appendix).However, studies of adverse events have been reported primarily for persons with advanced disease (and longer treatment courses) and therefore may not reflect the experience of persons with less advanced disease or those who are uninfected (74 ).Side effects associated with many of the NRTIs (e.g., ZDV or ddI) are chiefly gastrointestinal (e.g., nausea or diarrhea), and in general the incidence of adverse effects has not been greater when these agents are used in combination (72 ). All of the approved PIs may have potentially serious drug interactions when used with certain other drugs, requiring careful evaluation of concomitant medications being used by an HCW before prescribing a PI and close monitoring for toxicity when an HCW is receiving one of these drugs (See Appendix).PIs may inhibit the metabolism of nonsedating antihistamines and other hepatically metabolized drugs; NEL and ritonavir may accelerate the clearance of certain drugs, including oral contraceptives (requiring alternative or additional contraceptive measures for women taking these drugs).The use of PIs also has been associated with new onset of diabetes mellitus, hyperglycemia, diabetic ketoacidosis, and exacerbation of pre-existing diabetes mellitus (75)(76)(77).Nephrolithiasis has been associated with IDV use (including in HCWs using the drug for PEP) (8 ); however, the incidence of this potential complication may be limited by drinking at least 48 oz (1.5 L) of fluid per 24-hour period (e.g., six 8 oz glasses of water throughout the day) (72 ).Rare cases of hemolytic anemia also have been associated with the use of IDV.NEL, saquinavir, and ritonavir have been associated with the development of diarrhea; however, this side effect usually responds to treatment with antimotility agents that can be prescribed for use, if necessary, at the time any one of these drugs is prescribed for PEP.The manufacturer's package insert should always be consulted for questions about potential drug interactions. Among HCWs receiving ZDV PEP, usually at doses of 1,000-1,200 mg per day (i.e., higher than the currently recommended dose), 50%-75% reported one or more subjective complaints and approximately 30% discontinued the drug because of symptoms (7,78,79 ).Common symptoms included nausea, vomiting, malaise or fatigue, headache, or insomnia.Mild decreases in hemoglobin and absolute neutrophil count also were observed.All side effects were reversed when PEP was discontinued. Preliminary information about HCWs receiving combination drugs for PEP (usually ZDV plus 3TC with or without a PI) suggests that approximately 50%-90% of HCWs report subjective side effects that caused 24%-36% to discontinue PEP (8-10 ).One study documented that combination regimens that included ZDV at a lower dose (600 mg per day) were better tolerated than high-dose ZDV used alone (1,000-1,200 mg per day) (10 ).However, serious side effects, including nephrolithiasis, hepatitis, and pancytopenia, have been reported with the use of combination drugs for PEP (9,80; J.L. Gerberding, San Francisco General Hospital, personal communication, May 1997). # Resistance to Antiretroviral Agents Known or suspected resistance of the source virus to antiretroviral agents, particularly to one or more agents that might be included in a PEP regimen, is a concern for those making decisions about PEP.Resistance of HIV has been reported with all available antiretroviral agents (65 ).However, the relevance of exposure to a resistant virus is not understood.Although transmission of resistant strains has been reported (81-85 ), in the perinatal clinical trial that studied vertical HIV transmission (ACTG protocol 076), ZDV prevented perinatal transmission despite genotypic resistance of HIV to ZDV in the mother (66 ).In addition, patients generally take more than one antiretroviral drug and, unless testing is performed, often it is difficult to know to which drug(s) resistance exists.The complexity of this issue is further compounded by the frequency of cross-resistance within drug classes. Resistance should be suspected in source patients when there is clinical progression of disease or a persistently increasing viral load and/or a decline in CD4 T-cell count despite therapy, or a lack of virologic response to a change in therapy.Nevertheless, in this situation it is unknown whether a modification in the PEP regimen is necessary or will influence the outcome of an occupational exposure. # Antiretroviral Drugs in Pregnancy Considerations for the use of antiretroviral drugs in pregnancy include their potential effect on the pregnant woman and on her fetus or neonate.The pharmacokinetics of antiretroviral drugs has not been completely studied in pregnant women.Some of the antiretroviral drugs are known to cross the placenta, but data for humans are not yet available for others (particularly the PIs).In addition, data are limited on the potential effects of antiretroviral drugs on the developing fetus or neonate (86 ).Decisions on the use of specific drugs in pregnancy also are influenced by whether a drug has specific adverse effects or might further exacerbate conditions associated with pregnancy, (e.g., drugs that cause nausea may be less tolerated when superimposed on the nausea normally associated with pregnancy). There are data on both ZDV and 3TC from clinical trials in HIV-infected pregnant women.The most extensive experience has been with the use of ZDV after 14 weeks of gestation in pregnant HIV-infected women in phase I studies and the perinatal ACTG protocol 076 (4,87 ).The dose of ZDV for pregnant women is the same as that in nonpregnant persons, and ZDV appears safe and well tolerated in both women and their infants who have had a follow-up period of several years (88)(89)(90).Data from the Antiretroviral Pregnancy Registry have not documented an increased risk for birth defects in infants with in utero exposure to ZDV (91 ).There are limited data on use of 3TC alone or in combination with ZDV in late gestation in pregnant HIV-infected women.As with ZDV, the pharmacokinetics and dose of 3TC appear to be similar to those for nonpregnant persons.The drug appears safe during pregnancy for women and infants, although long-term safety is not known (92,93 ). Carcinogenicity and/or mutagenicity is evident in several in vitro screening tests for ZDV and all other FDA-licensed nucleoside antiretroviral drugs.In some in vivo rodent studies, high-dose lifetime continuous ZDV exposure (94 ) or very high dose in utero ZDV exposure has been associated with the development of tumors in adult females or their offspring (95,96 ).The relevance of these animal data to humans is unknown.However, in 1997 an independent panel reviewed these data and concluded that the known benefits of ZDV in preventing perinatal transmission, where the risk for transmission without ZDV is 25%-30%, outweigh the hypothetical concerns about transplacental carcinogenesis (97 ). No data are available regarding pharmacokinetics, safety, or tolerability of any of the PIs in pregnant women.The use of PIs in HIV-infected persons has been associated with hyperglycemia; it is unknown whether the use of these agents during pregnancy will exacerbate the risk for pregnancy-associated hyperglycemia.Therefore, close monitoring of glucose levels and careful instruction regarding symptoms related to hyperglycemia are recommended for pregnant HCWs receiving a PI for PEP.IDV is associated with infrequent side effects in adults (i.e., hyperbilirubinemia and renal stones) that could be problematic for the newborn.As the half-life of IDV in adults is short, these concerns may be relevant only if the drug is administered shortly before delivery. # RECOMMENDATIONS FOR THE MANAGEMENT OF POTENTIALLY EXPOSED HCWs Health-care organizations should make available to their workers a system that includes written protocols for prompt reporting, evaluation, counseling, treatment, and follow-up of occupational exposures that may place HCWs at risk for acquiring any bloodborne infection, including HIV.Employers also are required to establish exposure-control plans, including postexposure follow-up for their employees, and to comply with incident reporting requirements mandated by the Occupational Safety and Health Administration (15 ).Access to clinicians who can provide postexposure care should be available during all working hours, including nights and weekends.Antiretroviral agents for PEP should be available for timely administration (i.e., either by providing access to PEP drugs on site or creating links with other facilities or providers to make them available offsite).Persons responsible for providing postexposure counseling should be familiar with evaluation and treatment protocols and the facility's procedures for obtaining drugs for PEP. HCWs should be educated to report occupational exposures immediately after they occur, particularly because PEP is most likely to be effective if implemented as soon after the exposure as possible (41,55,56 ).HCWs who are at risk for occupational exposure to HIV should be taught the principles of postexposure management, including options for PEP, as part of job orientation and ongoing job training.

# Exposure Report If an occupational exposure occurs, the circumstances and postexposure management should be recorded in the HCW's confidential medical record (usually on a form the facility designates for this purpose).Relevant information includes - date and time of exposure; - details of the procedure being performed, including where and how the exposure occurred, and if the exposure was related to a sharp device, the type of device and how and when in the course of handling the device the exposure occurred; - details of the exposure, including the type and amount of fluid or material and the severity of the exposure (e.g., for a percutaneous exposure, depth of injury and whether fluid was injected; or for a skin or mucous-membrane exposure, the estimated volume of material and duration of contact and the condition of the skin ); - details about the exposure source (i.e., whether the source material contained HIV or other bloodborne pathogen), and if the source is an HIV-infected person, the stage of disease, history of antiretroviral therapy, and viral load, if known; and - details about counseling, postexposure management, and follow-up. # Exposure Management # Treatment of an Exposure Site Wounds and skin sites that have been in contact with blood or body fluids should be washed with soap and water; mucous membranes should be flushed with water.There is no evidence that the use of antiseptics for wound care or expressing fluid by squeezing the wound further reduces the risk for HIV transmission.However, the use of antiseptics is not contraindicated.The application of caustic agents (e.g., bleach) or the injection of antiseptics or disinfectants into the wound is not recommended. # Assessment of Infection Risk After an occupational exposure, the source-person and the exposed HCW should be evaluated to determine the need for HIV PEP.Follow-up for hepatitis B virus and hepatitis C virus infections also should be conducted in accordance with previously published CDC recommendations (98,99 ). Evaluation of exposure.The exposure should be evaluated for potential to transmit HIV based on the type of body substance involved and the route and severity of the exposure.Exposures to blood, fluid containing visible blood, or other potentially infectious fluid (including semen; vaginal secretions; and cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids) or tissue through a percutaneous injury (i.e., needlestick or other penetrating sharps-related event) or through contact with a mucous membrane are situations that pose a risk for bloodborne transmission and require further evaluation (Figure 1).In addition, any direct contact (i.e., personal protective equipment either was not used or was ineffective in protecting skin or mucous membranes) with concentrated HIV in a research laboratory or production facility is considered an exposure that requires clinical evaluation to assess the need for PEP. For skin exposures, follow-up is indicated if it involves direct contact with a body fluid listed above and there is evidence of compromised skin integrity (e.g., dermatitis, abrasion, or open wound).However, if the contact is prolonged or involves a large area of intact skin, postexposure follow-up may be considered on a case-by-case basis or if requested by the HCW. For human bites, the clinical evaluation must consider possible exposure of both the bite recipient and the person who inflicted the bite.HIV transmission only rarely has been reported by this route (100,101;CDC, unpublished data, 1998).If a bite results in blood exposure to either person involved, postexposure follow-up, including consideration of PEP, should be provided. Evaluation and testing of an exposure source.The person whose blood or body fluids are the source of an occupational exposure should be evaluated for HIV infection.Information available in the medical record at the time of exposure (e.g., laboratory test results, admitting diagnosis, or past medical history) or from the source person may suggest or rule out possible HIV infection.Examples of information to consider when evaluating an exposure source for possible HIV infection include laboratory information (e.g., prior HIV testing results or results of immunologic testing ), clinical symptoms (e.g., acute syndrome suggestive of primary HIV infection or undiagnosed immunodeficiency disease), and history of possible HIV exposures (e.g., injecting-drug use, sexual contact with a known HIV-positive partner, unprotected sexual contact with multiple partners , or receipt of blood or blood products before 1985). If the source is known to have HIV infection, available information about this person's stage of infection (i.e., asymptomatic or AIDS), CD4+ T-cell count, results of viral load testing, and current and previous antiretroviral therapy, should be gathered for consideration in choosing an appropriate PEP regimen.If this information is not immediately available, initiation of PEP, if indicated, should not be delayed; changes in the PEP regimen can be made after PEP has been started, as appropriate.If the source or, in the case of an unknown source, the setting where the exposure occurred suggests a possible risk for HIV exposure and the EC is 2 or 3, consider PEP basic regimen. Basic regimen is four weeks of zidovudine, 600 mg per day in two or three divided doses, and lamivudine, 150 mg twice daily. Expanded regimen is the basic regimen plus either indinavir, 800 mg every 8 hours, or nelfinavir, 750 mg three times a day.No PEP needed A source is considered negative for HIV infection if there is laboratory documentation of a negative HIV antibody, HIV polymerase chain reaction (PCR), or HIV p24 antigen test result from a specimen collected at or near the time of exposure and there is no clinical evidence of recent retroviral-like illness. A source is considered infected with HIV (HIV positive) if there has been a positive laboratory result for HIV antibody, HIV PCR, or HIV p24 antigen or physician-diagnosed AIDS. Examples are used as surrogates to estimate the HIV titer in an exposure source for purposes of considering PEP regimens and do not reflect all clinical situations that may be observed.Although a high HIV titer (HIV SC 2) in an exposure source has been associated with an increased risk for transmission, the possibility of transmission from a source with a low HIV titer also must be considered. # FIGURE 1.Determining the need for HIV postexposure prophylaxis (PEP) after an occupational exposure- -Continued If the HIV serostatus of the source person is unknown, the source person should be informed of the incident and, if consent is obtained, tested for serologic evidence of HIV infection.If consent cannot be obtained (e.g., patient is unconscious), procedures should be followed for testing source persons according to applicable state and local laws.Confidentiality of the source person should be maintained at all times. HIV-antibody testing of an exposure source should be performed as soon as possible.Hospitals, clinics, and other sites that manage exposed HCWs should consult their laboratories regarding the most appropriate test to use to expedite these results.An FDA-approved rapid HIV-antibody test kit should be considered for use in this situation, particularly if testing by enzyme immunoassay (EIA) cannot be completed within 24-48 hours.Repeatedly reactive results by EIA or rapid HIV-antibody tests are considered highly suggestive of infection, whereas a negative result is an excellent indicator of the absence of HIV antibody.Confirmation of a reactive result by Western blot or immunofluorescent antibody is not necessary for making initial decisions about postexposure management but should be done to complete the testing process. If the source is HIV seronegative and has no clinical evidence of acquired immunodeficiency syndrome (AIDS) or symptoms of HIV infection, no further testing of the source is indicated.It is unclear whether follow-up testing of a source who is HIV negative at the time of exposure, but recently (i.e., within the last 3-6 months) engaged in behaviors that pose a risk for HIV transmission, is useful in postexposure management of HCWs; HCWs who become infected generally seroconvert before repeat testing of a source would normally be performed. If the exposure source is unknown, information about where and under what circumstances the exposure occurred should be assessed epidemiologically for risk for transmission of HIV.Certain situations, as well as the type of exposure, may suggest an increased or decreased risk; an important consideration is the prevalence of HIV in the population group (i.e., institution or community) from which the contaminated source material is derived.For example, an exposure that occurs in a geographic area where injecting-drug use is prevalent or on an AIDS unit in a health-care facility would be considered epidemiologically to have a higher risk for transmission than one that occurs in a nursing home for the elderly where no known HIV-infected residents are present.In addition, exposure to a blood-filled hollow needle or visibly bloody device suggests a higher-risk exposure than exposure to a needle that was most likely used for giving an injection.Decisions regarding appropriate management should be individualized based on the risk assessment. HIV testing of needles or other sharp instruments associated with an exposure, regardless of whether the source is known or unknown, is not recommended.The reliability and interpretation of findings in such circumstances are unknown. # Clinical Evaluation and Baseline Testing of Exposed HCWs Exposed HCWs should be evaluated for susceptibility to bloodborne pathogen infections.Baseline testing (i.e., testing to establish serostatus at the time of exposure) for HIV antibody should be performed.If the source person is seronegative for HIV, baseline testing or further follow-up of the HCW normally is not necessary.If the source person has recently engaged in behaviors that are associated with a risk for HIV transmission, baseline and follow-up HIV-antibody testing (e.g., 3 and/or 6 months postexposure) of the HCW should be considered.Serologic testing should be made available to all HCWs who are concerned that they may have been exposed to HIV. For purposes of considering HIV PEP, the evaluation also should include information about medications the HCW may be taking and any current or underlying medical conditions or circumstances (i.e., pregnancy, breast feeding, or renal or hepatic disease) that may influence drug selection.Pregnancy testing should be offered to all nonpregnant women of childbearing age whose pregnancy status is unknown. # HIV PEP The following recommendations apply to situations where an HCW has had an exposure to a source person with HIV or where information suggests that there is a likelihood that the source person is HIV-infected.These recommendations are based on the risk for HIV infection after different types of exposure and limited data regarding efficacy and toxicity of PEP.Because most occupational HIV exposures do not result in the transmission of HIV, potential toxicity must be carefully considered when prescribing PEP.When possible, these recommendations should be implemented in consultation with persons having expertise in antiretroviral therapy and HIV transmission. # Explaining PEP to HCWs Recommendations for chemoprophylaxis should be explained to HCWs who have sustained occupational HIV exposures (Figure 1).For exposures for which PEP is considered appropriate, HCWs should be informed that a) knowledge about the efficacy and toxicity of drugs used for PEP are limited; b) only ZDV has been shown to prevent HIV transmission in humans; c) there are no data to address whether adding other antiretroviral drugs provides any additional benefit for PEP, but experts recommend combination drug regimens because of increased potency and concerns about drugresistant virus; d) data regarding toxicity of antiretroviral drugs in persons without HIV infection or in pregnant women are limited for ZDV and not known regarding other antiretroviral drugs; and e) any or all drugs for PEP may be declined by the HCW.HCWs who have HIV occupational exposures for which PEP is not recommended should be informed that the potential side effects and toxicity of taking PEP outweigh the negligible risk of transmission posed by the type of exposure. # Factors in Selection of a PEP Regimen Selection of the PEP regimen should consider the comparative risk represented by the exposure and information about the exposure source, including history of and response to antiretroviral therapy based on clinical response, CD4+ T-lymphocyte counts, viral load measurements, and current disease stage.Most HIV exposures will warrant only a two-drug regimen, using two NRTIs, usually ZDV and 3TC.The addition of a third drug, usually a PI (i.e., IDV or NEL), should be considered for exposures that pose an increased risk for transmission or where resistance to the other drugs used for PEP is known or suspected. # Timing of PEP Initiation PEP should be initiated as soon as possible.The interval within which PEP should be started for optimal efficacy is not known.Animal studies have demonstrated the importance of starting PEP within hours after an exposure (43,54,56 ).To assure timely access to PEP, an occupational exposure should be regarded as an urgent medical concern and PEP started as soon as possible after the exposure (i.e., within a few hours rather than days).If there is a question about which antiretroviral drugs to use, or whether to use two or three drugs, it is probably better to start ZDV and 3TC immediately than to delay PEP administration.Although animal studies suggest that PEP probably is not effective when started later than 24-36 hours postexposure (42,55,5 6 ) , the interval after which there is no benefit from PEP for humans is undefined.Therefore, if appropriate for the exposure, PEP should be started even when the interval since exposure exceeds 36 hours.Initiating therapy after a longer interval (e.g., 1-2 weeks) may be considered for exposures that represent an increased risk for transmission; even if infection is not prevented, early treatment of acute HIV infection may be beneficial (69 ).The optimal duration of PEP is unknown.Because 4 weeks of ZDV appeared protective in HCWs (2 ) , PEP probably should be administered for 4 weeks, if tolerated. # PEP if Serostatus of Source Person is Unknown If the source person's HIV serostatus is unknown at the time of exposure (including when the source is HIV negative but may have had a recent HIV exposure), use of PEP should be decided on a case-by-case basis, after considering the type of exposure and the clinical and/or epidemiologic likelihood of HIV infection in the source (Figure 1).If these considerations suggest a possibility for HIV transmission and HIV testing of the source is pending, it is reasonable to initiate a two-drug PEP regimen until laboratory results have been obtained and later modify or discontinue the regimen accordingly. # PEP if Exposure Source is Unknown If the exposure source is unknown, use of PEP should be decided on a case-by-case basis.Consideration should include the severity of the exposure and the epidemiologic likelihood that the HCW was exposed to HIV. # PEP for Pregnant HCWs If the HCW is pregnant, the evaluation of risk and need for PEP should be approached as with any other HCW who has had an HIV exposure.However, the decision to use any antiretroviral drug during pregnancy should involve discussion between the woman and her health-care provider regarding the potential benefits and potential risks to her and her fetus. # Follow-up of HCWs Exposed to HIV Postexposure Testing HCWs with occupational exposure to HIV should receive follow-up counseling, postexposure testing, and medical evaluation regardless of whether they receive PEP.HIV-antibody testing should be performed for at least 6 months postexposure (e.g., at 6 weeks, 12 weeks, and 6 months).It is unclear whether an extended follow-up period (e.g., 12 months) is indicated in certain circumstances.Although rare instances of delayed HIV seroconversion have been reported (36,37, J.L. Gerberding, San Francisco General Hospital, unpublished data, May 1997), the infrequency of this occurrence does not warrant adding to HCWs' anxiety by routinely extending the duration of postexposure follow-up.Circumstances for which extending the duration of follow-up have been suggested include the use of highly potent antiretroviral regimens (i.e., more than two drugs) because of theoretical concerns that HIV seroconversion could be delayed, or simultaneous exposure to HCV.Data are insufficient for making a general recommendation in these situations.However, this should not preclude a decision to extend follow-up in an individual situation based on the clinical judgement of the HCW's health-care provider.HIV testing should be performed on any HCW who has an illness that is compatible with an acute retroviral syndrome, regardless of the interval since exposure.HIV-antibody testing using EIA should be used to monitor for seroconversion.The routine use of direct virus assays (e.g., HIV p24 antigen EIA or polymerase chain reaction for HIV RNA) to detect infection in exposed HCWs generally is not recommended (34 ).Although direct virus assays may detect HIV infection a few days earlier than EIA, the infrequency of HCW seroconversion and increased costs of these tests do not warrant their routine use in this setting.Also, HIV RNA is approved for use in established HIV infection; its reliability in detecting very early infection has not been determined. # Monitoring and Management of PEP Toxicity If PEP is used, drug-toxicity monitoring should be performed at baseline and again 2 weeks after starting PEP.Clinical judgement, based on medical conditions that may exist in the HCW and any toxicity associated with drugs included in the PEP regimen, should determine the scope of testing.Minimally these should include a complete blood count and renal and hepatic chemical function tests.Monitoring for evidence of hyperglycemia should be included for HCWs whose regimen includes any PI; if the HCW is receiving IDV, monitoring for crystalluria, hematuria, hemolytic anemia, and hepatitis also should be included.If toxicity is noted, modification of the regimen should be considered after expert consultation; further diagnostic studies may be indicated. HCWs who fail to complete the recommended regimen often do so because of the side effects they experience (e.g., nausea and diarrhea).These symptoms often can be managed without changing the regimen by prescribing antimotility and antiemetic agents or other medications that target the specific symptoms.

In other situations, modifying the dose interval (i.e., administering a lower dose of drug more frequently throughout the day, as recommended by the manufacturer), may help promote adherence to the regimen. # Counseling and Education Although HIV infection following an occupational exposure occurs infrequently, the emotional impact of the exposure often is substantial (102,103 ).In addition, HCWs are given seemingly conflicting information.Although HCWs are told that there is a low risk for HIV transmission, a 4-week regimen of PEP is recommended and they are asked to commit to behavioral measures (i.e., sexual abstinence or condom use) to prevent secondary transmission, all of which influence their lives for several weeks to months (102 ).Therefore, access to persons who are knowledgeable about occupational HIV transmission and who can deal with the many concerns an HIV exposure may raise for the HCW is an important element of postexposure management. HIV-exposed HCWs should be advised to use the following measures to prevent secondary transmission during the follow-up period, especially during the first 6-12 weeks after the exposure when most HIV-infected persons are expected to seroconvert: use sexual abstinence or condoms to prevent sexual transmission and to avoid pregnancy; and refrain from donating blood, plasma, organs, tissue, or semen.If the exposed HCW is breastfeeding, she should be counseled about the risk for HIV transmission through breast milk, and discontinuation of breastfeeding should be considered, especially following high-risk exposures.If the HCW chooses to receive PEP, temporary discontinuation of breastfeeding while she is taking PEP should be considered to avoid exposing the infant to these agents.NRTIs are known to pass into breast milk; it is not known whether this also is true for PIs. There is no need to modify an HCW's patient-care responsibilities to prevent transmission to patients based solely on an HIV exposure.If HIV seroconversion is detected, the HCW should be evaluated according to published recommendations for HIV-infected HCWs (104 ). Exposed HCWs should be advised to seek medical evaluation for any acute illness that occurs during the follow-up period.Such an illness, particularly if characterized by fever, rash, myalgia, fatigue, malaise, or lymphadenopathy, may be indicative of acute HIV infection but also may be due to a drug reaction or another medical condition. Exposed HCWs who choose to take PEP should be advised of the importance of completing the prescribed regimen.Information should be provided about potential drug interactions and the drugs that should not be taken with PEP, the side effects of the drugs that have been prescribed (See Appendix), measures to minimize these effects, and the methods of clinical monitoring for toxicity during the follow-up period.They should be advised that the evaluation of certain symptoms should not be delayed (e.g., back or abdominal pain, pain on urination or blood in the urine, or symptoms of hyperglycemia ). # RECOMMENDATIONS FOR THE SELECTION OF DRUGS FOR PEP The selection of a drug regimen for HIV PEP must strive to balance the risk for infection against the potential toxicity of the agent(s) used.Because PEP is potentially toxic, its use is not justified for exposures that pose a negligible risk for transmission (Figure 1).Also, there is insufficient evidence to recommend a highly active regimen for all HIV exposures.Therefore, two regimens for PEP are provided (Table 1): a "basic" two-drug regimen that should be appropriate for most HIV exposures and an "expanded" three-drug regimen that should be used for exposures that pose an increased risk for transmission (Figure 1) or where resistance to one or more antiretroviral agents is known or suspected.When possible, the regimens should be implemented in consultation with persons having expertise in antiretroviral treatment and HIV transmission. # Situations That Require Special Consideration # Resistance of the Source Virus to Antiretroviral Drugs It is unknown whether drug resistance influences transmission risk; however, transmission of drug-resistant HIV has been reported (81,82 ) and is therefore a theoretical concern when choosing PEP regimens.If the source-person's virus is known or suspected to be resistant to one or more of the drugs included in the PEP regimen, the selection of drugs to which the source person's virus is unlikely to be resistant is recommended (69 ).If the resistance is to one class of antiretroviral drugs, the addition to the basic PEP regimen of a drug from another class might be considered (e.g., addition of a PI when a source patient has not been treated with a PI but has virus resistant to one or more NRTIs).It is strongly recommended that PEP be started regardless of the resistance status in the source virus; if resistance is known or suspected, a third or fourth drug may be added to the regimen until consultation with a clinical expert in the treatment of HIV infection or disease can be obtained. # Known or Suspected Pregnancy in the HCW Pregnancy should not preclude the use of optimal PEP regimens, and PEP should not be denied to an HCW solely on the basis of pregnancy.However, as discussed previously, an occupationally exposed pregnant HCW must be provided with full information about what is known and not known regarding the potential benefits and risks associated with use of the antiretroviral drugs to her and her fetus for her to make an informed decision regarding the use of PEP.The choice of antiretroviral drugs to use for PEP in pregnant HCWs is complicated by the potential need to alter dosing because of physiologic changes associated with pregnancy and the potential for short-or longterm effects on the fetus and newborn.Thus, considerations that should be discussed with a pregnant HCW include the potential risk for HIV transmission based on the type of exposure; the stage of pregnancy (the first trimester being the period of maximal organogenesis and risk for teratogenesis); and what is known about the pharmacokinetics, safety, and tolerability of the drug or combination of drugs in pregnancy. # Basic Occupational HIV exposures for which there is a recognized transmission risk (Figure 1). 4 weeks (28 days) of both zidovudine 600 mg every day in divided doses (i.e., 300 mg twice a day, 200 mg three times a day, or 100 mg every 4 hours) and lamivudine 150 mg twice a day. # Expanded Occupational HIV exposures that pose an increased risk for transmission (e.g., larger volume of blood and/or higher virus titer in blood) (Figure 1). Basic regimen plus either indinavir 800 mg every 8 hours or nelfinavir 750 mg three times a day.- *Indinavir should be taken on an empty stomach (i.e., without food or with a light meal) and with increased fluid consumption (i.e., drinking six 8 oz glasses of water throughout the day); nelfinavir should be taken with meals.

Despite substantial progress in prevention of perinatal group B streptococcal (GBS) disease since the 1990s, GBS remains the leading cause of early-onset neonatal sepsis in the United States.In 1996, CDC, in collaboration with relevant professional societies, published guidelines for the prevention of perinatal group B streptococcal disease (CDC.#Introduction In the 1970s, the bacterium group B Streptococcus (GBS) emerged as the leading infectious cause of early neonatal morbidity and mortality in the United States (1)(2)(3)(4).Initial case series reported case-fatality ratios as high as 50% (5).Maternal as experts in GBS epidemiology, clinical microbiology, and pharmacology.The group held regular telephone conference calls to identify potential areas of change in the recommendations to prevent GBS disease, and to define sources of newly available data (published and unpublished) to inform the revision of the guidelines. The working group identified a subset of topics for in-depth review, including areas in which new technologies and/or evidence had become available since the publication of the 2002 guidelines, areas in which implementation of the 2002 guidelines was found to be suboptimal on the basis of published and unpublished data, and areas in which interpretation of the 2002 guidelines was found to be variable on the basis of inquiries received at CDC and the experience of experts in the field.For these topics, a thorough review was conducted of published literature through PubMed searches, other sources (including abstracts and conference proceedings), and unpublished data from ongoing surveillance and research activities of which the working group was aware.For topics on which several sources of data were available, evidence was summarized in tables.For topics on which relatively little new evidence was available, summaries of pertinent data were provided to working group members.Expert opinion was sought from working group members regarding topics on which no new evidence was available. In June 2009, an in-person meeting of the technical working group was held to review available data and develop updated recommendations using an evidence-based approach when possible and relying on expert scientific opinion when sufficient data were lacking (Table 1).These updated guidelines replace CDC's 2002 guidelines.They are intended for providers of prenatal, obstetric, and neonatal care; supporting microbiol-- A list of the members appears on page 32 of this report.Evidence from at least one well-executed randomized, controlled trial or one rigorously designed laboratory-based experimental study that has been replicated by an independent investigator II Evidence from at least one well-designed clinical trial without randomization, cohort or case-controlled analytic studies (preferably from more than one center), multiple time-series studies, dramatic results from uncontrolled studies, or some evidence from laboratory experiments III Evidence from opinions of respected authorities based on clinical or laboratory experience, descriptive studies, or reports of expert committees Source: Adapted from LaForce FM.Immunizations, immunoprophylaxis, and chemoprophylaxis to prevent selected infections.US Preventive Services Task Force.JAMA 1987;257:2464-70. -gy laboratories, hospital administrators, and managed-care organizations; childbirth educators; public health authorities; and expectant parents and their advocates. # Invasive Group B Streptococcal Disease Group B Streptococcus, or Streptococcus agalactiae, is a grampositive bacterium that causes invasive disease primarily in infants, pregnant or postpartum women (19,(21)(22)(23)(24)(25)(26)(27), and older adults, with the highest incidence among young infants (19).Infections in newborns occurring within the first week of life are designated early-onset disease.Late-onset infections occur in infants aged >1 week, with most infections evident during the first 3 months of life.Because of the burden of disease among infants and the availability of effective interventions to prevent early-onset GBS disease, these guidelines concern only early-onset disease.The measures used to prevent earlyonset GBS disease also might prevent some perinatal maternal infections (17,28); however, they do not prevent late-onset infant disease (29). # Early-onset GBS Disease GBS is the leading infectious cause of morbidity and mortality among infants in the United States.As a result of prevention efforts, incidence of GBS has declined dramatically over the past 15 years, from 1.7 cases per 1,000 live births in the early 1990s to 0.34-0.37 cases per 1,000 live births in recent years (Figure 1).On the basis of data from CDC's Active Bacterial Core surveillance (ABCs) system, a network of 10 sites across the United States that conduct active, population-based surveillance, CDC estimates that in recent years, GBS has caused approximately 1,200 cases of early-onset invasive disease per year (30); approximately 70% of cases are among babies born at term (≥37 weeks' gestation) (19). Infants with early-onset GBS disease generally present with respiratory distress, apnea, or other signs of sepsis within the first 24-48 hours of life (3,31).The most common clinical syndromes of early-onset disease are sepsis and pneumonia; less frequently, earlyonset infections can lead to meningitis.The case-fatality ratio of early-onset disease has declined from as high as 50% in the 1970s (5) to 4%-6% in recent years, primarily because of advances in neonatal care (17,19).Mortality is higher among preterm infants, with case-fatality rates of approximately 20% and as high as 30% among those ≤33 weeks' gestation, compared with 2%-3% among full-term infants (17,19). Early-onset infections are acquired vertically through exposure to GBS from the vagina of a colonized woman.Neonatal infection occurs primarily when GBS ascends from the vagina to the amniotic fluid after onset of labor or rupture of membranes, although GBS also can invade through intact membranes (32,33).GBS can be aspirated into the fetal lungs, which in turn can lead to bacteremia.Infants also can become infected with GBS during passage through the birth canal; infants who are exposed to the organism through this route can become colonized at mucus membrane sites in the gastrointestinal or respiratory tracts, but these colonized infants most commonly remain healthy. # Risk Factors for Early-onset GBS Disease Maternal intrapartum GBS colonization is the primary risk factor for early-onset disease in infants.A classic prospective cohort study conducted during the 1980s revealed that pregnant women with GBS colonization were >25 times more likely than pregnant women with negative prenatal cultures to deliver infants with early-onset GBS disease (34).In the absence of any intervention, an estimated 1%-2% of infants born to colonized mothers develop early-onset GBS infections (13,34,35).Approximately 10%-30% of pregnant women are colonized with GBS in the vagina or rectum (36)(37)(38).GBS colonization during pregnancy can be transient, intermittent, or persistent (39)(40)(41).Although some women with GBS colonization during a pregnancy will be colonized during subsequent pregnancies, a substantial proportion will not (42,43).The gastrointestinal tract serves as the primary reservoir for GBS and is the likely source of vaginal colonization.Heavy colonization, defined as culture of GBS from direct plating rather than from selective broth only, is associated with higher risk for early-onset disease (44,45).GBS identified in clean-catch urine specimens during any trimester is considered a surrogate for heavy maternal colonization and also is associated with a higher risk for earlyonset GBS disease (46)(47)(48)(49)(50). In addition to maternal colonization with GBS, other factors that increase the risk for early-onset disease include gestational age 12 hours, or intrapartum temperature >99.5 º F (>37.5 º C) had 6.5 times the risk for having an infant with early-onset GBS disease compared with women who had none of these risk factors (34).Of note, women who had one of these risk factors but who had negative prenatal screening cultures were at relatively low risk for early-onset GBS disease (incidence: 0.9 cases per 1,000 births) compared with women who were colonized prenatally but had none of the risk factors (incidence: 5.1 cases per 1,000 births) (34). Some observational studies have reported an association between early-onset GBS disease and certain obstetric procedures, such as the use of internal fetal monitoring devices (58,63) and more than five or six digital vaginal examinations after onset of labor or rupture of membranes (55,63).However, lack of randomization in observational studies can result in confounding, because certain procedures might be used more frequently in high-risk settings (64).Although concern has been raised about performing other obstetric procedures (e.g., membrane stripping and mechanical and/or pharmacologic cervical ripening) on GBS-colonized women, available data are not sufficient to determine whether these procedures are associated with an increased risk for early-onset disease (65,66). # Prevention of Early-onset Group B Streptococcal Disease Intravenous Intrapartum Antibiotic Prophylaxis The use of intravenous intrapartum antibiotic prophylaxis to prevent early-onset GBS disease in the infant was first studied in the 1980s.Clinical trials and well-designed observational studies found that intrapartum antibiotic prophylaxis reduced vertical transmission of GBS, as measured by infant colonization (6,8,11,67) or by protection against early-onset disease (6)(7)(8)(9)(10)(11).Early trials suggested an efficacy of 100% for intrapartum antibiotic prophylaxis to prevent early-onset disease among infants born to women with GBS colonization (7,8,10,11).Subsequent observational studies have found the effectiveness to be 86%-89% among infants born to women who received intrapartum GBS prophylaxis (62,68). Other strategies to reduce maternal colonization and vertical transmission have been studied, including intramuscular intrapartum antibiotic prophylaxis (67), antenatal (oral or intramuscular) antibiotics (69)(70)(71), and chlorhexidine vaginal wipes or douches (72)(73)(74)(75)(76); however, none has proven to be effective at preventing early-onset disease.Although some nonrandomized studies on chlorhexidine have yielded promising results (72,75), randomized clinical trials have found no protection against early-onset GBS disease or neonatal sepsis (76,77). # Intrapartum Antibiotic Prophylaxis Agents The efficacy of both penicillin (10) and ampicillin (7) as intravenously administered intrapartum agents for the prevention of early-onset neonatal GBS disease was demonstrated in clinical trials.Penicillin has a narrower spectrum of antimicrobial activity and therefore might be less likely to select for resistant organisms, although one clinical trial found that penicillin and ampicillin administered intravenously intrapartum were associated equally with the presence of ampicillin-resistant gram-negative organisms on postpartum vaginal-perineal culture (78).The dosages of penicillin and ampicillin used for intrapartum GBS prophylaxis are aimed at achieving adequate levels in the fetal circulation and amniotic fluid rapidly while avoiding potentially neurotoxic serum levels in the mother or fetus (79)(80)(81)(82)(83).Although the exact duration of antibiotics needed to prevent vertical transmission of GBS has been debated (84,85), beta-lactam antibiotics for GBS prophylaxis administered for ≥4 hours before delivery have been found to be highly effective at preventing vertical transmission of GBS (86) and early-onset GBS disease (68).Shorter durations of appropriate antibiotics might provide some protection; in particular, colonization data suggest durations of ≥2 hours before delivery might confer some protection (86). The efficacy of alternatives to penicillin or ampicillin that have been used to prevent early-onset GBS disease among infants born to penicillin-allergic mothers (including cefazolin, clindamycin, erythromycin, and vancomycin) has not been measured in controlled trials.Cefazolin has a relatively narrow spectrum of activity, similar pharmacokinetics and dynamics to penicillin and ampicillin, and achieves high intra-amniotic concentrations (87)(88)(89).However, an estimated 10% of persons with penicillin allergy also have immediate hypersensitivity reactions to cephalosporins (90).In contrast, data on the ability of clindamycin, erythromycin and vancomycin to reach bactericidal levels in the fetal circulation and amniotic fluid are very limited; available data suggest that erythromycin and clindamycin provided to pregnant women do not reach fetal tissues reliably (91)(92)(93)(94)(95). # Safety Maternal anaphylaxis associated with GBS intrapartum chemoprophylaxis occurs but is sufficiently rare that any morbidity associated with anaphylaxis is offset greatly by reductions in the incidence of maternal and neonatal invasive GBS disease.Anaphylaxis-related mortality is likely to be a rare event because the majority of women receiving intrapartum antibiotics will be in hospital settings where rapid intervention is readily available.Allergic reactions occur in an estimated 0.7%-4.0% of all treatment courses with penicillin, the most common of which is a maculopapular rash (96).Estimates of the rate of anaphylaxis caused by penicillin range from four per 10,000 to four per 100,000 recipients (96).Maternal anaphylaxis associated with GBS prophylaxis was reported in the early 1990s (97); since the release of the 1996 guidelines, four reports of nonfatal cases of anaphylaxis associated with GBS chemoprophylaxis in the United States have been published (98)(99)(100)(101).In a CDC multistate sample of approximately 5,000 live births occurring during 1998-1999, a single, nonfatal anaphylactic reaction was noted among the 27% of deliveries in which intrapartum antibiotics were administered (62).In that case, a single dose of penicillin was administered approximately 4 hours before a preterm cesarean delivery, and an anaphylactic reaction occurred shortly after the mother received a single dose of a cephalosporin following umbilical cord clamping.A similar sample of approximately 7,600 live births occurring during 2003-2004 revealed no cases of anaphylaxis among the 32% of deliveries in which mothers received intrapartum antibiotic prophylaxis for GBS (102). Because a fetus or newborn is unlikely to have had a previous exposure to the antibiotic, and because specific maternal IgE antibodies are not transmitted across the placenta (103), there is no risk for anaphylaxis in the fetus or newborn resulting from intrapartum antibiotic prophylaxis.Although limited data are available on the impact of intrapartum antibiotics on neonatal gastrointestinal flora, one study comparing stool from infants born to women who received intrapartum GBS prophylaxis with stool from infants whose mothers received no intrapartum antibiotics found no significant difference in colonization with antibiotic-resistant enterobacteria between the two groups (104). # Antibiotic Resistance of GBS The widespread use of intrapartum antibiotic prophylaxis to prevent early-onset GBS disease has raised concern about the development of antibiotic resistance among GBS isolates.GBS continues to be susceptible to penicillin, ampicillin, and firstgeneration cephalosporins (19,(105)(106)(107)(108)(109).However, isolates with increasing minimum inhibitory concentrations (MICs) to penicillin or ampicillin have been reported, including 14 noninvasive isolates during 1995-2005 among adults in Japan (110), and 11 (0.2%) of 5,631 invasive isolates recovered during 1999-2005 from patients of varying ages in the United States (111).Alterations in a penicillin-binding protein (PBP 2X) were found in all of the isolates from Japan and four of those from the United States.The measured MICs from the 11 invasive isolates from the United States are just at the threshold of susceptibility (≤0.12 µg/ml for penicillin and ≤0.25 µg/ml for ampicillin) (112), but the clinical significance of these MIC values is as yet unclear. Relatively elevated MICs to cefazolin (1 µg/ml) also were reported among three (0.05%) of 5,631 invasive GBS isolates collected through CDC's active surveillance during 1999-2005; two of the three isolates also had elevated MICs to penicillin (0.12 µg/ml) (111).Although Clinical and Laboratory Standards Institute guidelines do not specify susceptibility breakpoints for cefazolin, they recommend that all isolates susceptible to penicillin be considered susceptible to cefazolin (112).As with the elevated MICs to penicillin and ampicillin, the clinical significance of higher MICs to cefazolin among GBS isolates remains unclear. The proportions of GBS isolates with in vitro resistance to clindamycin or erythromycin have increased over the past 20 years.The prevalence of resistance among invasive GBS isolates in the United States ranged from 25% to 32% for erythromycin and from 13% to 20% for clindamycin in reports published during 2006-2009 (19,106,108).Resistance to erythromycin is associated frequently but not always with resistance to clindamycin.One longitudinal study of GBS early-onset sepsis found that although the overall rate of GBS early-onset disease declined over time, erythromycin-resistant GBS caused an increasing proportion of disease during this interval; however, the incidence of antibiotic-resistant GBS early-onset sepsis remained stable (105). # Vaccines to Prevent GBS Disease GBS vaccines have been investigated as a tool for reducing maternal colonization and preventing transmission to neonates (113,114); however, no licensed vaccine is available currently.Sufficient amounts of GBS capsular polysaccharide type-specific serum IgG in mothers have been shown to protect against invasive disease in their infants (51,(115)(116)(117)(118).Phase I and II clinical trials among healthy, nonpregnant adults of monovalent polysaccharide-protein conjugate vaccines of GBS disease-associated types have shown these vaccines to be well tolerated and immunogenic (116)(117)(118)(119)(120)(121).A recent, double-blind randomized trial of a conjugate vaccine against GBS serotype III among nonpregnant women of reproductive age found a significant delay in acquisition of colonization with the vaccineserotype among vaccine recipients (122).Although an effective GBS vaccine would be a powerful tool against GBS disease, no licensed vaccine is yet available. # Identification of Candidates for Intrapartum Antibiotic Prophylaxis # Culture-Versus Risk-Based Screening Early guidelines recommended the use of one of two approaches to identifying women who should receive intrapartum antibiotic prophylaxis: a risk-based approach or a culture-based screening approach (13).Providers using the risk-based method identified candidates for intrapartum chemoprophylaxis according to the presence of any of the following intrapartum risk factors: delivery at <37 weeks' gestation, intrapartum temperature ≥100.4 º F (≥38.0 º C), or rupture of membranes for ≥18 hours.Providers using the culture-based screening method screened all pregnant women for vaginal and rectal GBS colonization between 35 and 37 week's gestation.Colonized women were offered intrapartum antibiotics at the time of labor onset or rupture of membranes if before labor.Under both strategies, intrapartum antibiotic prophylaxis was recommended for women with GBS bacteriuria at any time during their current pregnancy or for women who had given birth previously to an infant with invasive early-onset GBS disease. A large population-based study conducted during 1998-1999 demonstrated the superiority of culture-based screening over the risk-based approach to prevention of early-onset GBS disease (62).The study found that culture-based screening resulted in the identification of a greater proportion of women at risk for transmitting GBS to their newborns.Furthermore, women with a positive antenatal GBS culture were more likely to receive intrapartum antibiotic prophylaxis than those women with a risk-based indication for chemoprophylaxis.In 2002, CDC's guidelines for GBS prevention were updated to recommend universal culture-based screening to determine which women should receive intrapartum GBS chemoprophylaxis (15).CDC recommended that women with unknown GBS colonization status at the time of delivery be managed according to the presence of intrapartum risk factors. # Preterm Delivery Because preterm (at <37 weeks and 0 days' gestation) delivery is an important risk factor for early-onset GBS disease, and because assessing whether preterm labor or rupture of membranes will result in preterm delivery can be difficult, management of intrapartum antibiotic prophylaxis for women with threatened preterm delivery is challenging.

Assessing the need for intrapartum prophylaxis for these women also can be difficult because GBS colonization status often is unknown when labor or rupture of membranes occur before 35-37 weeks' gestation.In addition, appropriate use of antibiotic prophylaxis for women with threatened preterm delivery is critical.For women remote from term with premature rupture of membranes, clinical trials have demonstrated that certain antibiotic regimens prolong latency (123,124).However, data from clinical trials also have suggested that certain antibiotics administered for preterm premature rupture of membranes can be associated with necrotizing enterocolitis in the neonate (125,126) and that antibiotics administered in the setting of spontaneous preterm labor can be associated with adverse neonatal outcomes, such as increased need for supplementary oxygen (127) or cerebral palsy (128). The 2002 guidelines recommended that if GBS colonization status from the current pregnancy is not known, and if onset of labor or rupture of membranes occurred before 37 weeks' gestation with a substantial risk for preterm delivery, then GBS screening should be performed and intrapartum antibiotic prophylaxis for GBS should be provided pending culture results.The implementation of those recommendations has been suboptimal, with limited GBS screening on hospital admission and limited administration of intrapartum antibiotic prophylaxis (102).However, when penicillin, ampicillin, or cefazolin prophylaxis was administered for ≥4 hours before delivery to women delivering at <37 weeks' gestation, antibiotic prophylaxis was 78% (95% confidence interval: 44%-91%) effective in preventing early-onset GBS disease (CDC, unpublished data, 2009).No data are available on the effectiveness of antibiotics given before the intrapartum period in GBS-colonized women with preterm premature rupture of membranes for preventing early-onset GBS disease in the infant. # Bacteriuria GBS is found in the urine of 2%-7% of pregnant women (46)(47)(48)129,130).GBS bacteriuria in a pregnant woman is a marker for heavy genital tract colonization, and maternal GBS bacteriuria (including pure and predominant growth of GBS in the urine) has been associated with GBS colonization and an increased risk for early-onset disease in the newborn (46)(47)(48)(49)(50)129).Although some women receive antibiotics to treat GBS bacteriuria during pregnancy, antibiotics do not eliminate GBS from the genitourinary and gastrointestinal tracts, and recolonization after a course of antibiotics is typical (71,131,132).Studies have found that some women with GBS bacteriuria during the first trimester might not have vaginalrectal colonization detected at 35-37 weeks' gestation (130) or at the time of delivery (133).However, maternal GBS bacteriuria at any point during pregnancy is a recognized risk factor for early-onset GBS disease and therefore has been included as an indication for intrapartum antibiotic prophylaxis since 1996 (13,15). The 1996 guidelines did not specify a colony-count threshold for defining GBS bacteriuria.In 2002, the guidelines recommended that laboratory personnel report GBS present in any concentration in the urine.Most data on the risk for early-onset GBS disease among infants born to women with GBS bacteriuria are derived from studies of significant GBS bacteriuria (generally >10 5 colony-forming units per millimeter of urine) (47)(48)(49).Although lower concentrations (<10 4 cfu/ ml) of GBS in the urine can be associated with vaginal-rectal colonization (134), relatively few data are available on the risk for early-onset GBS disease among infants born to women with low colony-count GBS bacteriuria (48).One study from a vertically integrated health system in Utah found an elevated risk for early-onset GBS disease among infants born to women with low colony-count GBS bacteriuria compared with those whose mothers did not have GBS bacteriuria (135).However, because the majority of pregnant women in the study population had no urine culture performed, those with urine culture results might have been a biased subset.Therefore, the findings on women with low colony-count bacteriuria in this study might not be generalizable to all pregnant women with low colony-count bacteriuria.The recommendation to report any colony count of GBS in the urine represents increased workload for clinical microbiology laboratories, which generally do not report bacterial growth in urine of other pathogens at concentrations <10 4 cfu/ml (136) and rarely know whether urine samples are from pregnant women; as a result, some laboratories search for any GBS colonies in urine cultures from all women of reproductive age.Routine screening for asymptomatic bacteriuria is recommended in pregnant women (137); the identification of GBS through this screening represents an opportunity to detect women at high risk for transmitting GBS to their infant.However, in the context of universal late antenatal GBS screening, it is unclear how much additional disease is prevented by screening for low colony-count GBS bacteriuria and whether identification of low colony-count bacteriuria is cost-effective. # Cesarean Delivery Performed Before Labor onset on a Woman With Intact Amniotic Membranes Cesarean delivery does not prevent mother-to-child transmission of GBS because GBS can cross intact amniotic membranes (32,33).A risk does exist for transmission of GBS from a colonized mother to her infant during a cesarean delivery.However, a retrospective study at a single hospital (138), a national population-based study from Sweden (139), and a review of CDC active, population-based surveillance data (CDC, unpublished data, 1998(CDC, unpublished data, -1999(CDC, unpublished data, and 2003(CDC, unpublished data, -2004 indicated that when a cesarean delivery is performed before onset of labor on a woman with intact amniotic membranes, the risk for early-onset GBS disease among full-term infants is extremely low.Data on risk for transmission to preterm infants born via cesarean delivery performed before onset of labor on a woman with intact amniotic membranes are limited; however, the risk for transmission is likely much lower than in the setting of vaginal delivery or cesarean delivery following rupture of membranes or onset of labor. # Specimen Collection and Processing for GBS Screening timing of Screening Because GBS colonization status can change over the course of a pregnancy, the timing of specimen collection for determination of colonization status is important.Because colonization can be transient, colonization early in pregnancy is not predictive of early-onset GBS disease (44).Late third trimester colonization status has been used as a proxy for intrapartum colonization (140).The negative predictive value of GBS cultures performed ≤5 weeks before delivery is 95%-98%; however, the clinical utility decreases when a prenatal culture is performed more than 5 weeks before delivery because the negative predictive value declines (37). # MMWR November 19, 2010 # Specimen Collection Swabbing both the lower vagina and rectum (through the anal sphincter) increases the culture yield substantially compared with sampling the cervix or the vagina without also swabbing the rectum (40,(141)(142)(143)(144)(145)(146).Although a small number of studies have examined the ability of perianal or vaginal-perianal cultures to detect GBS colonization (147,148), the available data on their performance compared with vaginal-rectal cultures are limited.Studies have indicated that when women in the outpatient clinic setting collect their own vaginal-rectal screening specimens, with appropriate instruction, GBS yield is similar to when specimens are collected by a health-care provider (149)(150)(151)(152). The use of appropriate transport media can help sustain the viability of GBS in settings where immediate laboratory processing is not possible (153,154).GBS isolates can remain viable in transport media for several days at room temperature; however, the recovery of isolates declines during 1-4 days, particularly at high temperatures.Even when appropriate transport media are used, the sensitivity of culture is greatest when the specimen is stored at 4°C before culture and processed within 24 hours of collection (139,(155)(156)(157). # Specimen Processing Regardless of the test selected to identify GBS, use of an enrichment broth improves detection substantially.When direct agar plating is used instead of selective enrichment broth, as many as 50% of women who are GBS carriers have false-negative culture results (143,144,158,159).Examples of selective enrichment broths include Todd-Hewitt broth supplemented either with gentamicin (8 µg/ml) and nalidixic acid (15 µg/ml) or with colistin (10 µg/ml) and nalidixic acid (15 µg/ml) (160).Although TransVag and Lim broth media are often available without blood, the addition of 5% sheep blood can increase the recovery of GBS (161).Selective enrichment broth also can contain chromogenic substrates that provide for a change in color in the setting of beta-hemolytic GBS.Such broths can facilitate the identification of beta-hemolytic GBS; however, nonhemolytic isolates will not be detected by these broths alone (162)(163)(164)(165)(166)(167)(168).Among 265 GBS isolates from invasive early-onset cases that occurred in the 10 ABCs system areas during 2006-2008, a total of 4% were nonhemolytic (CDC, unpublished data, 2006(CDC, unpublished data, -2008. Following enrichment, the conventional means for identifying GBS is through isolation on subculture to blood agar plates and presumptive identification by the CAMP test (169) or serologic identification using latex agglutination with group B streptococcal antisera (170).More recently, chromogenic agars that undergo color change in the presence of beta-hemolytic colonies of GBS have become available (171,172).As with pigmented enrichment broths, these chromogenic agars can facilitate detection of beta-hemolytic GBS, but the majority will not detect nonhemolytic strains.In addition more rapid techniques for identifying GBS directly from enrichment broth, or after subculture have been developed, including DNA probes (173)(174)(175)(176) and nucleic acid amplification tests (NAAT) such as polymerase chain reaction (177,178). Published studies on the performance of commercially available NAAT on nonenriched samples have demonstrated varying sensitivities (range: 62.5%-98.5%) and specificities (range: 64.5%-99.6%) compared with the gold standard of enrichment followed by subculture (179-188) (Table 2).Three studies have compared both intrapartum NAAT on nonenriched samples and late antepartum enriched culture results to intrapartum enriched culture (179,182,185).When comparing swabs collected at the two different time points, two of the studies found intrapartum NAAT to be slightly more sensitive (95.8% and 90.7%, respectively) than antepartum culture (83.3% and 84.3%, respectively) (182,185), although with widely overlapping confidence intervals.One study reported a statistically significant difference between the sensitivity of swabs collected intrapartum and tested with NAAT (94.0%) compared with enriched culture performed on swabs collected prenatally (54.3%) (179).The sensitivity of NAAT for GBS increases to 92.5%-100.0% with use of an enrichment step before testing the sample (177,178,188).Use of an enrichment step lengthens the time to obtain a final result; however, for antenatal testing, the accuracy of results is much more important than timeliness. Despite the availability of NAAT for GBS, utility of such assays in the intrapartum setting remains limited.Although a highly sensitive and specific test with rapid turnaround time could be used to assess intrapartum GBS colonization and therefore obviate the need for antenatal screening, data on currently available assays do not support their use in replacement of antenatal culture or risk-based assessment of women with unknown GBS status on admission for labor.The additional time required for enrichment of samples makes it not feasible for intrapartum testing, and the sensitivity of assays in the absence of enrichment is not adequate in comparison to culture.In addition, concerns remain regarding real-world turnaround time, test complexity, availability of testing at all times, staffing requirements, and costs.In settings that can perform NAAT, such tests might prove useful for the limited circumstance of a woman at term with unknown colonization status and no other risk factors.Even optimal NAAT would have drawbacks in the intrapartum setting, including a delay in administration of antibiotics while waiting for the result, and no antimicrobial susceptibility testing for penicillin-allergic women.Other rapid tests in addition to NAAT have been developed to detect GBS rapidly from nonenriched samples, including optical immunoassays and enzyme immunoassays; however, none is sufficiently sensitive when used on a direct specimen to detect GBS colonization reliably in the intrapartum setting (180,(189)(190)(191)(192). # Antimicrobial Susceptibility testing Antimicrobial susceptibility testing of GBS isolates is crucial for appropriate antibiotic prophylaxis selection for penicillin-allergic women who are at high risk for anaphylaxis because resistance to clindamycin, the most common agent used in this population, is increasing among GBS isolates.In addition, appropriate methodologies for susceptibility testing are important because inducible clindamycin resistance can occur in some strains that appear susceptible in broth susceptibility tests (193,194).D-zone testing using the double-disk diffusion method has been used to identify isolates that are erythromycin-resistant and clindamycin-susceptible, yet have inducible resistance to clindamycin (195).Isolates that are D-zone positive are considered to have inducible clindamycin resistance and are presumed to be resistant although the clinical significance of this resistance is not clear (196). # Secondary Prevention of Early-onset GBS Among Infants Currently available GBS prevention strategies will not prevent all cases of early-onset disease.Rapid detection of neonatal infections and initiation of appropriate treatment is needed to minimize morbidity and mortality among the cases that continue to occur.The detection of early-onset GBS disease poses certain clinical challenges, because neonatal providers must take into account the clinical appearance of the infant, the presence of maternal risk factors for GBS disease, and infant exposure to intrapartum antibiotics. # Infants with Signs of Sepsis As use of intrapartum antibiotics to prevent early-onset GBS disease increased, concern was expressed that signs of sepsis in the newborn could be delayed or masked, impairing the ability of clinicians to detect early-onset GBS disease (197)(198)(199).However, several studies conducted since 1996 have found no significant difference in the clinical presentation of early-onset GBS disease between infants exposed to intrapartum antibiotics and those not exposed (200)(201)(202)(203)(204).Approximately 90% of cases of early-onset disease continue to manifest within the first 24 hours of life. Although maternal GBS colonization might increase clinical suspicion for early-onset GBS disease in an infant, in the era of universal screening, >60% of early-onset GBS cases have occurred among infants born to women who had a negative prenatal GBS culture screen (102,203,204).False-negative cases are not unexpected because culture at 35-37 weeks' gestation will fail to detect some women with intrapartum GBS colonization.As effective prevention strategies are increasingly implemented, a growing proportion of the remaining relatively low burden of disease will reflect inherent limitations in the strategies.Signs of sepsis in any newborn can be an indication of early-onset GBS disease, regardless of maternal colonization status. Among infants with signs of early-onset disease, the detection of GBS can be increased by performing culture of both blood and cerebrospinal fluid (CSF).Blood cultures can be sterile in as many as 15%-33% of newborns with meningitis (205)(206)(207)(208)(209), and the clinical management of an infant with abnormal CSF findings differs from that of an infant with normal CSF. # Infants Born to Women with Chorioamnionitis Chorioamnionitis is an important risk factor for earlyonset GBS disease in women with GBS colonization and can reflect an intrauterine onset of infection in the neonate (45,63,(210)(211)(212).Intrapartum fever, one sign of chorioamnionitis in parturient women, has been associated with failure of intrapartum antibiotics to prevent GBS disease in the newborn (68,213).Intrapartum treatment of chorioamnionitis can prevent neonatal sepsis (214,215).The diagnosis of chorioamnionitis usually is made clinically on the basis of signs and symptoms such as fever (which might be low-grade), uterine tenderness, fetal tachycardia, maternal tachycardia, and foulsmelling or purulent amniotic fluid.In an effort to avert neonatal infections, maternal fever alone in labor may be used as a sign of chorioamnionitis and hence indication for antibiotic treatment, particularly among women with a significant risk factor for chorioamnionitis (e.g., prolonged labor or prolonged rupture of membranes). Because an association has been observed between epidural labor analgesia and fever, chorioamnionitis might be overdiagnosed in women with epidurals, which could lead to unnecessary diagnostic evaluations and unnecessary exposure to empirical antibiotics in neonates (216).However, multistate surveillance data suggest that although epidural use is common (in 67% of births), intrapartum temperature of ≥100.4 º F (3.3% of births) and physician diagnoses of chorioamnionitis (3.1% of births) remain relatively rare (102) (CDC, unpublished data, 2009).Consultation with obstetric providers to determine whether chorioamnionitis is suspected is important for guiding neonatal management. # Well-Appearing Infants Exposed to Inadequate Intrapartum Antibiotics The management of well-appearing infants whose mothers received inadequate intrapartum antibiotic prophylaxis (because of either a short duration of exposure before delivery or use of an agent with limited efficacy data) can be challenging.Previous GBS prevention guidelines have recommended that infants whose mothers received inadequate intrapartum antibiotic prophylaxis and those <35 weeks' gestational age exposed to intrapartum antibiotics be evaluated with a blood culture and complete blood count (CBC) with differential (13,15).There are limitations to this diagnostic approach.The sensitivity of blood culture can be low among newborns exposed to intrapartum antibiotics (217,218).Available data on the performance of the CBC as a screening test for neonatal sepsis suggest that although the negative predictive value is high, the positive predictive value is low, particularly among healthy-appearing term infants (219)(220)(221).The sensitivity of the CBC is lowest immediately after birth, and its performance as a screen for sepsis can be improved by obtaining the blood specimen between 6-12 hours of life (220,222,223).Clinical signs of sepsis have been found to be a more sensitive indicator of neonatal sepsis than hematologic tests (201). Certain centers provide intramuscular penicillin to asymptomatic infants within 1 hour of birth; this practice is based on results of observational studies demonstrating declines in early-onset GBS disease coincident with a policy of universal administration of intramuscular penicillin to newborns (224)(225)(226).However, because the studies used historic control groups and were conducted at a single center that does not screen pregnant women routinely for antenatal GBS colonization, the findings are not generalizable to other settings. # Implementation and Impact of GBS Prevention Efforts # Implementation of the 2002 Guidelines After the issuance of the 2002 recommendation for universal culture screening, implementation was rapid and widespread.The most robust evaluation comes from a multistate, population-based analysis of 819,000 live births during 2003-2004 (102) and a similarly designed study of births during 1998-1999 (62).The proportion of infants whose mothers were screened for GBS colonization before delivery increased from 48.1% during 1998-1999 to 85.0% during 2003-2004 (Figure 2); among women screened during 2003-2004, a total of 98.4% had a result available at labor.Among screened women, 24.2% were documented as GBS-positive, within the range of expected colonization rates.

The proportion of mothers with an indication for intrapartum antibiotic prophylaxis who received them also increased substantially, from 73.8% during 1998-1999 to 85.1% during 2003-2004 (Figure 3). Despite widespread uptake of universal screening, implementation fell short in several key areas.Infants born preterm have an elevated risk for earlyonset disease, and because antenatal screening is recommended at 35-37 weeks of gestation, only 50.3% of women delivering preterm had a known colonization status at the time of hospital admission.Although it is recommended that women with unknown GBS status who deliver preterm receive intrapartum antibiotic prophylaxis, only 63.4% received prophylaxis.In addition, intrapartum antibiotic prophylaxis administration for the indications of GBS bacteriuria or having delivered a previous infant with GBS disease was also low (73.5%) among preterm deliveries.Intrapartum antibiotic prophylaxis was provided to a greater proportion (84.5%) of women delivering preterm who had a positive GBS screening result.Screening for GBS on admission among women with threatened preterm delivery and unknown colonization status was suboptimal; only 18% of women who progressed to delivery and 31% of women who did not progress to delivery were screened despite a recommendation to perform cultures for GBS at hospital admission for this population (15,102). As anticipated, the proportion of laboring women who received intrapartum antibiotics increased only slightly, from 26.8% to 31.7%, under universal screening.Penicillin and ampicillin, the recommended agents for intrapartum GBS prophylaxis for women with no allergy to penicillin, remained the most common agents administered (76.7% of women receiving intrapartum antibiotic prophylaxis received these agents).However, among penicillin-allergic women, the agents most often administered did not reflect the 2002 recommendations.In particular, only 13.8% of penicillin-allergic women who were not at high risk for anaphylaxis received cefazolin, despite a recommendation that this more effective agent be used.Clindamycin remained the leading agent among penicillinallergic women (69.9% of those at low risk for anaphylaxis and 83.5% of those at high risk).Among women receiving clindamycin for prophylaxis, clindamycin and erythromycin susceptibility testing were performed rarely despite recommendations that susceptibility testing be conducted on all vaginalrectal specimens from women who are allergic to penicillin and at high risk for anaphylaxis (15,102).A single-hospital study in Rhode Island reported similar findings (227). The multistate population-based study conducted during 2003-2004 also identified a greater-than-expected number of cases of early-onset GBS occurring among infants born to women with negative prenatal screening results (61% observed compared with 23%-46% expected cases of early-onset GBS disease among full-term infants) (102).Some false-negative results are expected because culture is not perfectly sensitive and GBS can be acquired by the mother during the period between screening and delivery.However, the high proportion of cases born to women with negative screening results suggests possible problems in the steps required to identify GBS colonization.Suboptimal specimen collection timing, methods, transport, and/or laboratory processing might be contributing factors.Among screened women, the date of the antenatal screening test was missing from 36% of labor and delivery charts.Documentation of the date allows for an assessment of whether screening was performed during the recommended gestation time window. # trends in neonatal GBS Disease Incidence of invasive early-onset GBS disease has declined approximately 80% (Figure 1) since the early 1990s, when implementation of intrapartum antibiotic prophylaxis to prevent GBS disease began.Nationally representative hospital discharge diagnostic code data also demonstrated a steady decrease in clinical sepsis rates during 1990-2002, with a marked decline in clinical sepsis among term infants during the 2 years following the issuance of the 1996 GBS prevention guidelines (228); these data suggest that the observed decline in early-onset GBS disease is a result of prevented cases of illness and not simply of sterilization of neonatal blood cultures as a result of exposure to maternal antibiotics.During 1999-2001, incidence of early-onset GBS disease achieved a plateau of approximately 0.5 cases per 1,000 live births.After the 2002 guidelines were issued, incidence declined further and in recent years has ranged from 0.3 to 0.4 cases per 1,000 live births.This additional decline of 20%-40% is consistent with that predicted for the transition from the 1996 prevention strategy to the universal screening approach recommended in 2002 (62).Similar trends have been reported among infants delivered in all U.S. military hospitals (229).However, the disparity in early-onset GBS disease incidence between black and white infants has persisted (Figure 4) and is evident among both term and preterm infants (18,20).Preliminary surveillance data from 2008 suggest that the racial disparity was reduced somewhat in 2008 (30).Incidence among all black infants declined to 0.49 cases per 1,000 live births, showing progress towards the Healthy People 2010 objective of 0.5 cases per 1,000 live births for all racial and ethnic groups (230).However final data from 2008, including enhanced race/ethnicity reporting on cases and the 2008 live birth denominators, and more years of data are needed to determine whether this trend is sustained. # trends in non-GBS Pathogens Decreases in the incidence of early-onset GBS sepsis have not been accompanied by increases in incidence of early-onset sepsis caused by other pathogens, including those that are antimicrobial-resistant.Most studies, including population-based multicenter studies, have found stable (231)(232)(233)(234)(235)(236)(237)(238)(239) or decreasing (240,241) rates of non-GBS early-onset sepsis during a period of increasing use of intrapartum antibiotic prophylaxis for GBS.Increases in invasive Escherichia coli infections have been reported among preterm and lowbirth-weight or very low-birth-weight infants (242)(243)(244)(245)(246), and some studies have found an increasing proportion of ampicillin-resistant isolates among preterm or very low birth-weight infants with E. coli sepsis (235,245,247).However, the trends have not been consistent over time or across studies.A multicenter study of sepsis in preterm infants that reported an increase in E. coli incidence from 1991-1993 to 1998-2000 (246) found stable rates of E. coli sepsis from 1998-2000 to 2002-2003 and reported no significant change in the proportion of E. coli isolates that were resistant to ampicillin (248).Whether any observed increase in ampicillin-resistant E. coli is attributable to the use of intrapartum antibiotics for GBS prophylaxis is unclear because ampicillin resistance among E. coli isolates has increased communitywide (249).Currently available evidence does not suggest any increase in non-GBS early-onset sepsis among term infants. An association between intrapartum antibiotic exposure and ampicillin resistance in newborns with E. coli or other non-GBS early-onset sepsis has been observed in several studies among all newborns (55,239,242,(250)(251)(252) and among preterm or very low birth-weight infants (245,246).However, studies using infants infected with nonresistant pathogens as a control group do not account for ampicillin-susceptible infections prevented by intrapartum antibiotic prophylaxis and therefore might overestimate an association between antibiotic exposure and antibiotic resistance (253).A multicenter case-control study of early-onset E. coli cases that enrolled uninfected infants born at the same hospitals found no association between intrapartum antibiotic prophylaxis exposure and infection with ampicillinresistant E. coli (254). The reported increases in E. coli early-onset sepsis among preterm infants and antibiotic-resistant early-onset infections are not of sufficient magnitude to outweigh the benefits of intrapartum antibiotic prophylaxis to prevent early-onset GBS disease.Among all neonates, rates of E. coli early-onset sepsis have remained stable and lower than those of GBS early-onset disease, despite declines in GBS (CDC, unpublished data, 2009).However, to ensure early detection of increases in the rate of disease or deaths caused by organisms other than GBS, continued surveillance of neonatal sepsis caused by organisms other than GBS is needed. # Impact of GBS Prevention Efforts on Infant Management Provider surveys conducted in the early to mid 1990s indicated that pediatricians and neonatologists were more likely to conduct diagnostic evaluations and initiate empiric antibiotics for an infant whose mother received intrapartum antibiotic prophylaxis than they were for an infant whose mother who did not receive prophylaxis (197)(198)(199).Results of studies conducted during 1996-2002 were inconsistent, reporting increased (255), stable (256), or decreased (257) use of health services (including diagnostic tests, antibiotics, and/or length of hospital stay) for neonates born to women receiving intrapartum antibiotics.No studies have reported on the impact of the 2002 guidelines on health-care services for neonates.Continued monitoring of the influence of GBS prevention recommendations on the management of newborns is needed. # Recommendations The following updated recommendations for the prevention of early-onset GBS disease are based on critical appraisal of data that have become available since publication of previous CDC (13,15) and ACOG (258) recommendations and replace previous recommendations from CDC.These recommendations have been endorsed by ACOG, AAP, ACNM, AAFP, and ASM.After each recommendation, its strength (indicated by a letter) and the quality of supporting evidence (indicated by a Roman numeral) are shown in parentheses according to the evidence-based rating system used (Table 1). Obstetric and neonatal health-care providers, in conjunction with supporting laboratories and labor and delivery facilities, should adopt the following recommendations for the prevention of early-onset GBS disease. # Identification of Candidates for Intrapartum Antibiotic Prophylaxis Universal Screening for GBS Candidates to receive intrapartum antibiotic prophylaxis to prevent early-onset GBS disease should be identified according to the indications and nonindications provided (Table 3). The following are key components of the screening strategy: - Women with GBS isolated from the urine at any time during the current pregnancy or who had a previous infant with invasive GBS disease should receive intrapartum antibiotic prophylaxis and do not need third trimester screening for GBS colonization (AII).Women with symptomatic or asymptomatic GBS urinary tract infection detected during pregnancy should be treated according to current standards of care for urinary tract infection during pregnancy and should receive intrapartum antibiotic prophylaxis to prevent early-onset GBS disease (AIII). - All other pregnant women should be screened at weeks' gestation for vaginal and rectal GBS colonization (AII). -At the time of labor or rupture of membranes, intrapartum antibiotic prophylaxis should be given to all pregnant women who tested positive for GBS colonization (AII), except in the instance of cesarean delivery performed before onset of labor on a woman with intact amniotic membranes. -For circumstances in which screening results are not available at the time of labor and delivery, intrapartum antibiotic prophylaxis should be given to women who are <37 weeks and 0 days' gestation, have a duration of membrane rupture ≥18 hours, or have a temperature of ≥100.4 º F (≥38.0 º C) (AII). -In the absence of GBS urinary tract infection, antimicrobial agents should not be used before the intrapartum period to eradicate GBS genitorectal colonization, because such treat- # TABLE 3.Indications and nonindications for intrapartum antibiotic prophylaxis to prevent early-onset group B streptococcal (GBS) disease # Intrapartum GBS prophylaxis indicated Intrapartum GBS prophylaxis not indicated - Previous infant with invasive GBS disease - Colonization with GBS during a previous pregnancy (unless an indication for GBS prophylaxis is present for current pregnancy) - GBS bacteriuria during any trimester of the current pregnancy- - GBS bacteriuria during previous pregnancy (unless an indication for GBS prophylaxis is present for current pregnancy) - Positive GBS vaginal-rectal screening culture in late gestation † during current pregnancy* - Negative vaginal and rectal GBS screening culture in late gestation † during the current pregnancy, regardless of intrapartum risk factors - Unknown GBS status at the onset of labor (culture not done, incomplete, or results unknown) and any of the following: -Delivery at <37 weeks' gestation § -Amniotic membrane rupture ≥18 hours -Intrapartum temperature ≥100.4°F (≥38.0°C) ¶ -Intrapartum NAAT positive for GBS - Cesarean delivery performed before onset of labor on a woman with intact amniotic membranes, regardless of GBS colonization status or gestational age Abbreviation: NAAT = Nucleic acid amplification tests - Intrapartum antibiotic prophylaxis is not indicated in this circumstance if a cesarean delivery is performed before onset of labor on a woman with intact amniotic membranes. †Optimal timing for prenatal GBS screening is at 35-37 weeks' gestation. §Recommendations for the use of intrapartum antibiotics for prevention of early-onset GBS disease in the setting of threatened preterm delivery are presented in Figures 5 and 6. ¶If amnionitis is suspected, broad-spectrum antibiotic therapy that includes an agent known to be active against GBS should replace GBS prophylaxis. NAAT testing for GBS is optional and might not be available in all settings.If intrapartum NAAT is negative for GBS but any other intrapartum risk factor (delivery at <37 weeks' gestation, amniotic membrane rupture at ≥18 hours, or temperature ≥100.4°F ) is present, then intrapartum antibiotic prophylaxis is indicated. ment is not effective in eliminating carriage or preventing neonatal disease and can cause adverse consequences (DI). -Intrapartum antibiotic prophylaxis to prevent early-onset GBS disease is not recommended as a routine practice for cesarean deliveries performed before labor onset on women with intact amniotic membranes, regardless of the GBS colonization status of the woman or the gestational age of the pregnancy (CIII).The use of perioperative prophylactic antibiotics to prevent infectious complications of cesarean delivery should not be altered or affected by GBS status. Women expected to undergo cesarean deliveries should undergo routine vaginal and rectal screening for GBS at 35-37 weeks' gestation because onset of labor or rupture of membranes can occur before the planned cesarean delivery, and under those circumstances GBS-colonized women should receive intrapartum antibiotic prophylaxis (AII). -Health-care providers should inform women of their GBS screening test result and the recommended interventions (BIII). The following key changes were made from the 2002 guidelines: - Guidance regarding cesarean deliveries performed before onset of labor on a woman with intact amniotic membranes is clarified as applying to cesarean deliveries performed at any gestational age (CIII). -In settings in which NAAT for GBS is available, obstetric providers can choose to perform intrapartum testing of vaginal-rectal samples from women with unknown GBS colonization status and no intrapartum risk factors (temperature of ≥100.4 º F or rupture of amniotic membranes ≥18 hours) at the time of testing and who are delivering at term (CII).If an intrapartum risk factor subsequently develops, antibiotic prophylaxis should be administered regardless of the intrapartum testing results (AIII). -Women with positive intrapartum NAAT results for GBS should receive antibiotic prophylaxis (AII).NAAT testing is optional and might not be available in all settings. # threatened Preterm Delivery Women admitted with signs and symptoms of preterm labor (before 37 weeks and 0 days' gestation) should be managed according to the algorithm provided (Figure 5).Women with rupture of membranes at <37 weeks and 0 days' gestation should be managed according to the algorithm provided (Figure 6). The following are key components of threatened preterm delivery GBS management: - Women admitted with signs and symptoms of labor or with rupture of membranes at <37 weeks and 0 days' gestation should be screened for GBS colonization at hospital admis-sion unless a vaginal-rectal GBS screen was performed within the preceding 5 weeks (AII). -Women admitted with signs and symptoms of preterm labor who have unknown GBS colonization status at admission or a positive GBS screen within the preceding 5 weeks should receive GBS prophylaxis at hospital admission (AII). -Antibiotics given for GBS prophylaxis to a woman with preterm labor should be discontinued immediately if at any # FIGURE 5.Algorithm for screening for group B streptococcal (GBS) colonization and use of intrapartum prophylaxis for women with preterm- labor (PTL) - At <37 weeks and 0 days' gestation. † If patient has undergone vaginal-rectal GBS culture within the preceding 5 weeks, the results of that culture should guide management.GBS-colonized women should receive intrapartum antibiotic prophylaxis.No antibiotics are indicated for GBS prophylaxis if a vaginal-rectal screen within 5 weeks was negative. §See Figure 8 for recommended antibiotic regimens. ¶Patient should be regularly assessed for progression to true labor; if the patient is considered not to be in true labor, discontinue GBS prophylaxis. If GBS culture results become available prior to delivery and are negative, then discontinue GBS prophylaxis. † †Unless subsequent GBS culture prior to delivery is positive. § §A negative GBS screen is considered valid for 5 weeks.If a patient with a history of PTL is re-admitted with signs and symptoms of PTL and had a negative GBS screen >5 weeks prior, she should be rescreened and managed according to this algorithm at that time. -At <37 weeks and 0 days' gestation. † If patient has undergone vaginal-rectal GBS culture within the preceding 5 weeks, the results of that culture should guide management.GBS-colonized women should receive intrapartum antibiotic prophylaxis.No antibiotics are indicated for GBS prophylaxis if a vaginal-rectal screen within 5 weeks was negative. §Antibiotics given for latency in the setting of pPROM that include ampicillin 2 g intravenously (IV) once, followed by 1 g IV every 6 hours for at least 48 hours are adequate for GBS prophylaxis.If other regimens are used, GBS prophylaxis should be initiated in addition. ¶See Figure 8 for recommended antibiotic regimens. GBS prophylaxis should be discontinued at 48 hours for women with pPROM who are not in labor.If results from a GBS screen performed on admission become available during the 48-hour period and are negative, GBS prophylaxis should be discontinued at that time. † †Unless subsequent GBS culture prior to delivery is positive. § §A negative GBS screen is considered valid for 5 weeks.If a patient with pPROM is entering labor and had a negative GBS screen >5 weeks prior, she should be rescreened and managed according to this algorithm at that time.point it is determined that she is not in true labor or if the GBS culture at admission is negative (AII). - Negative GBS colonization status should not affect the administration of antibiotics for other indications (AIII). -Women with threatened preterm delivery who have a GBS screen performed that is positive and do not deliver at that time should receive GBS prophylaxis when true labor begins (AII). -Women with threatened preterm delivery who have a GBS screen performed that is negative but do not deliver at that time should undergo repeat screening at 35-37 weeks' gestation.

If such women are re-admitted at a later date with threatened preterm delivery, they should undergo repeat screening if the previous culture was performed >5 weeks prior (AIII). The following key changes were made from the 2002 guidelines: - Separate algorithms are presented for GBS prophylaxis in the setting of threatened preterm delivery, one for spontaneous preterm labor (Figure 5) and one for preterm premature rupture of membranes (Figure 6). -GBS prophylaxis provided to women with signs and symptoms of preterm labor should be discontinued if it is determined that the patient is not in true labor (AI). -Antibiotics given to prolong latency for preterm premature rupture of membranes with adequate GBS coverage (specifically 2 g ampicillin administered intravenously followed by 1 g administered intravenously every 6 hours for 48 hours) are sufficient for GBS prophylaxis if delivery occurs while the patient is receiving that antibiotic regime (CIII).Oral antibiotics alone are not adequate for GBS prophylaxis (DII). -Women with preterm premature rupture of membranes who are not in labor and are receiving antibiotics to prolong latency with adequate GBS coverage should be managed according to standard of care for preterm premature rupture of membranes; GBS testing results should not affect the duration of antibiotics (BIII). -Women with preterm premature rupture of membranes who are not in labor and are not receiving antibiotics to prolong latency (or are receiving antibiotics that do not have adequate GBS coverage) should receive GBS prophylaxis for 48 hours, unless a GBS screen performed within the preceding 5 weeks was negative (CIII).If the results from a GBS screen performed on admission become available during that 48-hour period and are negative, then GBS prophylaxis should be discontinued at that time. # GBS Specimen Collection and Processing GBS specimen collection and processing should be conducted according to the recommendations provided (Boxes 1-3 and Figure 7). The following are key components of specimen collection and processing: - GBS colonization status should be determined by collecting both vaginal and rectal specimens at 35-37 weeks' gestation. A single combined vaginal-rectal specimen can be collected (AII). -Specimens should undergo 18-24 hour incubation at 35°-37°C in an appropriate enrichment broth medium to enhance the recovery of GBS (AI). -Accurate results are more important than rapid turnaround time for antenatal screening (AIII). -To ensure proper testing of specimens, clinicians must inform laboratories when submitted urine specimens are from pregnant women (AIII). -Antimicrobial susceptibility testing should be performed on antenatal GBS isolates from penicillin-allergic women at high risk for anaphylaxis because of a history of anaphylaxis, angioedema, respiratory distress, or urticaria following administration of a penicillin or a cephalosporin. (AII) (Box 3). The following key changes were made from the 2002 guidelines: - Specimen transport options and timing until processing are clarified. -GBS identification options are expanded to include a positive identification from chromogenic media and identification directly from enriched broth.NAAT, such as commercially available PCR assays, can also be used after enrichment, if laboratories have validated NAAT performance and instituted appropriate quality controls (CII). -A direct plating option can be included in addition to enriched culture (CII).Direct plating has a lower sensitivity than enriched culture and should not be used as sole means to identify GBS. -Testing for inducible clindamycin resistance should be performed on antenatal GBS isolates that are susceptible to clindamycin, resistant to erythromycin, and are from penicillinallergic women at high risk for anaphylaxis (CIII). -Laboratories should report GBS in urine culture specimens when present at concentrations of ≥10 4 colony-forming units/ml in pure culture or mixed with a second microorganism (AII) (Box 4). # Intrapartum Antibiotic Prophylaxis Intrapartum antibiotic prophylaxis agents and dosing should be administered according to the recommendations provided (Figure 8). The following are key components of intrapartum antibiotic prophylaxis agents and dosing: - Penicillin remains the agent of choice for intrapartum antibiotic prophylaxis, with ampicillin as an acceptable alternative (AI). -Penicillin-allergic women who do not have a history of anaphylaxis, angioedema, respiratory distress or urticaria following administration of a penicillin or a cephalosporin should receive cefazolin (BII). -Antimicrobial susceptibility testing should be ordered for antenatal GBS cultures performed on penicillin-allergic women at high risk for anaphylaxis because of a history of anaphylaxis, angioedema, respiratory distress or urticaria .This approach should be taken only in addition to, and not instead of, inoculation into selective broth.The directly inoculated blood agar plate should be streaked for isolation, incubated at 35°-37°C in ambient air or 5% CO 2 for 18-24 hours and inspected for organisms suggestive of GBS as described above.If suspected colonies are confirmed as GBS, the selective broth can be discarded, thus shortening the time to obtaining culture results.The directly inoculated chromogenic agar should be streaked for isolation and incubated at 35°-37°C for 18-24 hours.Hemolytic GBS isolates are identified by colored colonies as directed by specific manufacturers' instructions, and selective broth can be discarded if GBS positive. †Source: Fenton LJ, Harper MH.Evaluation of colistin and nalidixic acid in Todd-Hewitt broth for selective isolation of groupB streptococci.J Clin Microbiol 1979;9:167-9.Although Trans-Vag medium often is available without sheep blood, direct comparison of medium with and without sheep blood has shown higher yield when blood is added.Lim broth also might benefit from the addition of sheep blood, although the improvement in yield is smaller, and sufficient data are not yet available to support a recommendation.If a rapid test performed on enriched broth yields positive results and antimicrobial susceptibility testing is recommended (for penicillan-allergic women at high risk for anaphylaxis), the enriched broth should be subcultured to obtain an isolate. following administration of a penicillin or a cephalosporin (AII).To ensure proper testing, clinicians must inform laboratories of the need for antimicrobial susceptibility testing in such cases (AIII). -Penicillin-allergic women at high risk for anaphylaxis should receive clindamycin if their GBS isolate is susceptible to clindamycin and erythromycin, as determined by antimicrobial susceptibility testing; if the isolate is sensitive to clindamycin but resistant to erythromycin, clindamycin may be used if testing for inducible clindamycin resistance is negative (CIII).Penicillin-allergic women at high risk for anaphylaxis should receive vancomycin if their isolate is intrinsically resistant to clindamycin as determined by antimicrobial susceptibility testing, if the isolate demonstrates inducible resistance to clindamycin, or if susceptibility to both agents is unknown (CIII) (Box 3). The following key changes were made from the 2002 guidelines: - The definition of high risk for anaphylaxis is clarified as a history of anaphylaxis, angioedema, respiratory distress or urticaria following administration of a penicillin or a cephalosporin. -The recommended dosing regimen of penicillin G is 5 million units intravenously, followed by 2.5-3.0 million units intravenously every 4 hours (AII).The range of 2.5-3.0 million units is recommended to achieve adequate drug levels in the fetal circulation and amniotic fluid while avoiding neurotoxicity.The choice of dose within that range should be guided by which formulations of penicillin G are readily available in order to reduce the need for pharmacies to specially prepare doses. -Erythromycin is no longer an acceptable alternative for intrapartum GBS prophylaxis for penicillin-allergic women at high risk for anaphylaxis. # other obstetric Management Issues - Available data are not sufficient to suggest that GBS colonization should differentially affect the use of obstetric proce-dures for monitoring, cervical ripening or labor induction.These procedures should be reserved for appropriate indications and not altered for GBS-colonized women (CIII). -Data are not sufficient to make recommendations regarding the timing of procedures intended to facilitate progression of labor, such as amniotomy, in GBS-colonized women.Intrapartum antibiotic prophylaxis is optimal if administered # Secondary Prevention Among Infants To detect potential sepsis cases in newborns as early as possible, newborns should be managed according to the algorithm provided (Figure 9).The following are key components of the neonatal management algorithm: - Routine screening for asymptomatic bacteriuria is recommended in pregnant women, and laboratories should screen urine culture specimens for the presence of GBS in concentrations of 10 4 colony-forming units (cfu)/ml or greater. -Laboratories should identify GBS when present at ≥10 4 cfu/ml in pure culture or mixed with a second microorganism. # FIGURE 8.Recommended regimens for intrapartum antibiotic prophylaxis for prevention of early-onset group B streptococcal (GBS) disease* Abbreviation: IV = intravenously. -Broader spectrum agents, including an agent active against GBS, might be necessary for treatment of chorioamnionitis. †Doses ranging from 2.5 to 3.0 million units are acceptable for the doses administered every 4 hours following the initial dose.The choice of dose within that range should be guided by which formulations of penicillin G are readily available to reduce the need for pharmacies to specially prepare doses. §Penicillin-allergic patients with a history of anaphylaxis, angioedema, respiratory distress, or urticaria following administration of penicillin or a cephalosporin are considered to be at high risk for anaphylaxis and should not receive penicillin, ampicillin, or cefazolin for GBS intrapartum prophylaxis.For penicillinallergic patients who do not have a history of those reactions, cefazolin is the preferred agent because pharmacologic data suggest it achieves effective intraamniotic concentrations.Vancomycin and clindamycin should be reserved for penicillin-allergic women at high risk for anaphylaxis. ¶If laboratory facilities are adequate, clindamycin and erythromycin susceptibility testing (Box 3) should be performed on prenatal GBS isolates from penicillin-allergic women at high risk for anaphylaxis.If no susceptibility testing is performed, or the results are not available at the time of labor, vancomycin is the preferred agent for GBS intrapartum prophylaxis for penicillin-allergic women at high risk for anaphylaxis. Resistance to erythromycin is often but not always associated with clindamycin resistance.If an isolate is resistant to erythromycin, it might have inducible resistance to clindamycin, even if it appears susceptible to clindamycin.If a GBS isolate is susceptible to clindamycin, resistant to erythromycin, and testing for inducible clindamycin resistance has been performed and is negative (no inducible resistance) , then clindamycin can be used for GBS intrapartum prophylaxis instead of vancomycin. Patient allergic to penicillin? Penicillin G, 5 million units IV initial dose, then 2.5-3.0 million units † every 4 hrs until delivery or Ampicillin, 2 g IV initial dose, then 1 g IV every 4 hrs until delivery . †Antibiotic therapy should be directed toward the most common causes of neonatal sepsis, including intravenous ampicillin for GBS and coverage for other organisms (including Escherichia coli and other gram-negative pathogens) and should take into account local antibiotic resistance patterns. §Consultation with obstetric providers is important to determine the level of clinical suspicion for chorioamnionitis.Chorioamnionitis is diagnosed clinically and some of the signs are nonspecific. ¶Limited evaluation includes blood culture (at birth) and CBC with differential and platelets (at birth and/or at 6-12 hours of life). See table 3 for indications for intrapartum GBS prophylaxis. † † If signs of sepsis develop, a full diagnostic evaluation should be conducted and antibiotic therapy initiated. § §If ≥37 weeks' gestation, observation may occur at home after 24 hours if other discharge criteria have been met, access to medical care is readily available, and a person who is able to comply fully with instructions for home observation will be present.If any of these conditions is not met, the infant should be observed in the hospital for at least 48 hours and until discharge criteria are achieved. ¶ ¶Some experts recommend a CBC with differential and platelets at age 6-12 hours. -Well-appearing infants of any gestational age whose mother received adequate intrapartum GBS prophylaxis (≥4 hours of penicillin, ampicillin, or cefazolin before delivery) should be observed for ≥48 hours, and no routine diagnostic testing is recommended (BIII).Such infants can be discharged home as early as 24 hours after delivery, assuming that other discharge criteria have been met, ready access to medical care exists, and that a person able to comply fully with instructions for home observation will be present (CIII). -For well-appearing infants born to mothers who had an indication for GBS prophylaxis but received no or inadequate prophylaxis, if the infant is well-appearing and ≥37 weeks and 0 days' gestational age and the duration of membrane rupture before delivery was <18 hours, then the infant should be observed for ≥48 hours, and no routine diagnostic testing is recommended (BIII).If the infant is well-appearing and either <37 weeks and 0 days' gestational age or the duration of membrane rupture before delivery was ≥18 hours, then the infant should undergo a limited evaluation and observation for ≥48 hours (BIII). The following key changes were made from the 2002 guidelines: - The algorithm now applies to all newborns. - The definition of adequate intrapartum antibiotic prophylaxis is clarified as ≥4 hours of IV penicillin, ampicillin, or cefazolin before delivery (AII).All other agents or durations are considered inadequate for purposes of neonatal management. -Well-appearing infants whose mother had an indication for GBS prophylaxis but received no or inadequate intrapartum antibiotics can be managed with observation for ≥48 hours, unless the infant is <37 weeks and 0 days' gestational age or membranes were ruptured ≥18 hours before delivery, in which case a limited evaluation and observation for ≥48 hours is recommended (BIII). -Well-appearing infants with a gestational age of 35-36 weeks whose mothers received adequate intrapartum antibiotic prophylaxis do not routinely require diagnostic evaluations (CIII). # Monitoring Implementation and Impact of Guidelines - Local and state public health agencies, in conjunction with appropriate groups of hospitals, are encouraged to establish surveillance for early-onset GBS disease and to take other steps to promote perinatal GBS disease prevention and education to reduce the incidence of early-onset GBS disease in their states (CIII). burden of prenatal-onset GBS disease has not been assessed adequately (32,33,(259)(260)(261)(262), and no effective prevention tools have been identified before the intrapartum period.GBS disease among nonpregnant adults has increased in recent years. Although GBS vaccines might be expected to aid in reduction of racial disparities and prevention of invasive GBS disease among adults and infants (both early-and late-onset), continued exploration of other means to improve and strengthen GBS prevention efforts is warranted.Until a safe and efficacious vaccine achieves licensure, continued monitoring for potential unintended consequences of intrapartum antibiotic chemoprophylaxis is needed, with an emphasis on tracking key sentinel events signaling a need for revision of the guidelines.Such sentinel events include the emergence of penicillin resistance among GBS isolates and an increase in the incidence of disease or deaths due to neonatal pathogens other than GBS that offsets the burden of earlyonset disease prevented by intrapartum antibiotic prophylaxis.Monitoring for the latter will require long-term surveillance of a large population of term and preterm births (246,248). States are encouraged to monitor incidence of GBS disease, to promote activities that enhance perinatal GBS disease prevention and education, and to assess progress toward national objectives for disease reduction, such as objectives for Healthy People 2010 (230) and the forthcoming Healthy People 2020 (263).Practical tools to assist with monitoring for missed opportunities for perinatal GBS prevention within hospitals have been published (264); additional prevention information and tools for providers, patients and clinical microbiologists are available at , .acog.org, , , http:// www.midwife.org, and . - Efforts to monitor the emergence of perinatal infections caused by other organisms are also encouraged (CIII). # Future of GBS Prevention Although much progress has been made in the prevention of early-onset GBS disease, important challenges remain.Earlyonset disease has declined among all racial and ethnic groups, yet significant disparities persist.Research aimed at better understanding racial or ethnic differences in GBS disease might lead to opportunities for more effective prevention efforts.In addition, the evidence is incomplete for several key areas related to GBS prevention, including: strategies to prevent early-onset GBS disease among preterm infants, the role of bacteriuria as a risk factor in the era of universal screening, effectiveness of recommended intrapartum antibiotic prophylaxis agents for penicillin-allergic women at high risk for anaphylaxis, the impact and effectiveness of recommendations for secondary prevention of early-onset GBS disease among neonates, and factors contributing to the higher-than-anticipated proportion of early-onset GBS disease cases occurring among infants born to women with negative prenatal GBS screens. The development of relatively rapid laboratory tests to identify GBS moves us closer to the possibility of an intrapartum test for GBS colonization screening.A highly sensitive, lowcomplexity test with a rapid turnaround time could be used to determine intrapartum GBS colonization, thereby overcoming some of the inherent limitations in late antenatal screening.Although available NAATs have demonstrated high sensitivity when performed on enriched samples, enrichment is not feasible in the intrapartum setting when results are needed quickly.Manufacturers and some researchers (180,185) have reported turn-around-times of <2 hours; however, the complexity of available NAAT for GBS is still moderate to high.To be clinically useful in the intrapartum period, a screening test for GBS should consist of a simple bedside kit that enables labor and delivery staff to perform a test, have a turn-around time of <30 minutes, and have a sensitivity and specificity of ≥90%.Ideally, a rapid test for intrapartum use also would be able to detect mutations likely to confer resistance to clindamycin and/or erythromycin in order to guide antibiotic choice for penicillin-allergic women. Universal screening and intrapartum antibiotic prophylaxis have had no measurable impact on late-onset GBS disease, prenatal-onset disease (including stillbirths and miscarriages), or GBS disease among nonpregnant adults.Because of declines in early-onset GBS disease, the burden of late-onset disease is now similar to that of early-onset disease.More research on preventive measures against late-onset disease is needed.The

Each year, CDC's Advisory Committee on Immunization Practices (ACIP) reviews the recommended childhood and adolescent immunization schedule to ensure that it is current with changes in manufacturers' vaccine formulations and reflects revised recommendations for the use of licensed vaccines, including those newly licensed.The recommended childhood and adolescent immunization schedule for January-June 2004 (Figure ), recommendations, and format have been approved by ACIP, the American Academy of Family Physicians, and the American Academy of Pediatrics.A catch-up immunization schedule for children and adolescents who start late or who are >1 month behind was introduced in 2003 (1) and remains the same (Table ).Minimum ages and minimum intervals between doses are provided for each of the routinely recommended childhood and adolescent vaccines.The schedule is divided into two age groups: children aged 4 months-6 years and children/adolescents aged 7-18 years.#Hepatitis B Vaccine The schedule indicates a change in the recommendation for the minimum age for the last dose in the hepatitis B vaccination schedule.The last dose in the vaccination series should not be administered before age 24 weeks (updating the previous recommendation not to administer the last dose before age 6 months). # Adolescent Tetanus and Diphtheria Toxoids (Td) Vaccine The range of recommended ages for the adolescent Td vaccine dose has been updated to emphasize a preference for vaccinating at ages 11-12 years with ages 13-18 years to serve as a catch-up interval. # Clarification Regarding Certain Final Doses Clarification was added to the footnotes regarding the timing of the final vaccine doses in the series for diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine, Haemophilus influenzae type b (Hib) conjugate vaccine, and pneumococcal conjugate vaccine (PCV).The final dose in the DTaP series should be given at age >4 years.The final doses in the Hib and PCV series should be given at age >12 months. # Influenza Vaccine Healthy children aged 6-23 months are encouraged to receive influenza vaccine when feasible during the 2003-2004 influenza season.Children in this age group are at substantially increased risk for influenza-related hospitalizations (2).ACIP has indicated further that beginning in fall 2004, children aged 6-23 months will be recommended to receive annual influenza vaccine.An updated childhood and adolescent immunization schedule for July-December 2004 will be released to reflect this change. An intranasally administered, live, attenuated influenza vaccine (LAIV) was approved for use in the United States in June 2003.For healthy persons aged 5-49 years, LAIV is an acceptable alternative to the intramuscular trivalent inactivated influenza vaccine (TIV) (3). # Vaccine Information Statements The National Childhood Vaccine Injury Act requires that all health-care providers give parents or patients copies of Vaccine Information Statements before administering each dose of the vaccines listed in the schedule.Additional information is available from state health departments and at http:// www.cdc.gov/nip/publications/vis.Detailed recommendations for using vaccines are available from the manufacturers' package inserts, ACIP statements on specific vaccines, and the 2003 Red Book (4).ACIP statements for each recommended childhood vaccine can be viewed, downloaded, and printed from The Recommended Childhood and Adolescent Immunization Schedule and the Catchup Childhood and Adolescent Immunization Schedule have been adopted by the Advisory Committee on Immunization Practices, the Academy of Pediatrics, and the Academy of Family Physicians.The standard MMWR footnote format has been modified for joint publication of this harmonized schedule. Indicates age groups that warrant special effort to administer those vaccines not given previously.Additional vaccines may be licensed and recommended during the year.Licensed combination vaccines may be used whenever any components of the combination are indicated and the vaccine's other components are not contraindicated.Providers should consult the manufacturers' package inserts for detailed recommendations.Clinically significant adverse events that follow vaccination should be reported to the Vaccine Adverse Event Reporting System (VAERS).Guidance on how to obtain and complete a VAERS form is available at or by telephone, 800-822-7967. # Hepatitis B vaccine (HepB). All infants should receive the first dose of HepB vaccine soon after birth and before hospital discharge; the first dose also may be given by age 2 months if the infant's mother is HBsAg-negative.Only monovalent HepB vaccine can be used for the birth dose.Monovalent or combination vaccine containing HepB may be used to complete the series; 4 doses of vaccine may be administered when a birth dose is given.The second dose should be given at least 4 weeks after the first dose except for combination vaccines, which cannot be administered before age 6 weeks.The third dose should be given at least 16 weeks after the first dose and at least 8 weeks after the second dose.The last dose in the vaccination series (third or fourth dose) should not be administered before age 24 weeks.Infants born to HBsAg-positive mothers should receive HepB vaccine and 0.5 mL hepatitis B immune globulin (HBIG) within 12 hours of birth at separate sites.The second dose is recommended at age 1-2 months.The last dose in the vaccination series should not be administered before age 24 weeks.These infants should be tested for HBsAg and anti-HBs at age 9-15 months.Infants born to mothers whose HBsAg status is unknown should receive the first dose of the HepB vaccine series within 12 hours of birth.Maternal blood should be drawn as soon as possible to determine the mother's HBsAg status; if the HBsAg test is positive, the infant should receive HBIG as soon as possible (no later than age 1 week).The second dose is recommended at age 1-2 months.The last dose in the vaccination series should not be administered before age 24 weeks. # Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP). The fourth dose of DTaP may be administered at age 12 months provided that 6 months have elapsed since the third dose and the child is unlikely to return at age 15-18 months.The final dose in the series should be given at age >4 years.Tetanus and diphtheria toxoids (Td) is recommended at age 11-12 years if at least 5 years have elapsed since the last dose of tetanus and diphtheria toxoid-containing vaccine.Subsequent routine Td boosters are recommended every 10 years. Additional information about vaccines, including precautions and contraindications for vaccination and vaccine shortages, is available at or from the National Immunization information hotline, telephone 800-232-2522 (English) or 800-232-0233 (Spanish).Approved by the Advisory Committee on Immunization Practices (), the American Academy of Pediatrics (), and the American Academy of Family Physicians (). # Haemophilus influenzae type b (Hib # TABLE.Catch-up immunization schedule for children and adolescents who start late or who are >1 month behind # Catch-up schedule for children aged 4 months-6 years # Catch-up schedule for children aged 7-18 years Note: A vaccine series does not require restarting, regardless of the time that has elapsed between doses. 1.Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP): The fifth dose is not necessary if the fourth dose was given after the fourth birthday. # Inactivated polio vaccine (IPV): For children who received an all-IPV or all-oral poliovirus (OPV) series, a fourth dose is not necessary if third dose was given at age >4 years.If both OPV and IPV were given as part of a series, a total of 4 doses should be given, regardless of the child's current age.3.Hepatitis B vaccine (HepB): All children and adolescents who have not been vaccinated against hepatitis B should begin the hepatitis B vaccination series during any visit. Providers should make special efforts to immunize children who were born in, or whose parents were born in, areas of the world where hepatitis B virus infection is moderately or highly endemic. # Measles, mumps, and rubella vaccine (MMR): The second dose of MMR is recommended routinely at age 4-6 years, but may be given earlier if desired.5.Haemophilus influenzae type b (Hib) conjugate vaccine: Vaccine generally is not recommended for children aged >5 years.6.Hib: If current age is 5 years.8.Tetanus and diphtheria toxoids (Td): For children aged 7-10 years, the interval between the third and booster dose is determined by the age when the first dose was given. For adolescents aged 11-18 years, the interval is determined by the age when the third dose was given.9.IPV: Vaccine generally is not recommended for persons aged >18 years.10.Varicella vaccine (VAR): Give 2-dose series to all susceptible adolescents aged >13 years.Reporting adverse reactions.Clinically significant adverse events that follow vaccination should be reported to the Vaccine Adverse Event Reporting System (VAERS).Guidance on completing a VAERS form is available at or at telephone, 800-822-7967.Disease reporting.Suspected cases of vaccine-preventable diseases should be reported to state or local health departments.Additional information about vaccines, including precautions and contraindications for vaccination and vaccine shortages, is available at or at the National Immunization information hotline, telephone 800-232-2522 (English) or 800-232-0233 (Spanish).

At its February 2008 meeting, the Advisory Committee on Immunization Practices (ACIP) decided not to recommend routine vaccination of children aged 2--10 years against meningococcal disease unless the child is at increased risk for the disease.This report summarizes the deliberations of ACIP and the rationale for its decision and restates existing recommendations for meningococcal vaccination among children aged 2--10 years at increased risk for meningococcal disease.ACIP continues to recommend routine vaccination against meningococcal disease for all persons aged 11--18 years and those persons aged 2--55 years who are at increased risk for meningococcal disease (1--3).Users should not rely on this HTML document, but are referred to the electronic PDF version and/or the original MMWR paper copy for the official text, figures, and tables.An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800.Contact GPO for current prices.# On October 17, 2007, the Food and Drug Administration added approval for use of quadrivalent meningococcal conjugate vaccine (MCV4) (Menactra ® , Sanofi Pasteur, Swiftwater, Pennsylvania) in children aged 2--10 years to existing approval for use in persons aged 11--55 years (4).Before licensure of MCV4, quadrivalent meningococcal polysaccharide vaccine (MPSV4) (Menomune ® , Sanofi Pasteur) was the only meningococcal vaccine available in the United States.MPSV4 was recommended for routine use only among persons at increased risk for meningococcal disease (1).Because clinical efficacy trials were not feasible in the United States, MCV4 licensure was based on clinical trials in which the safety and immunogenicity of MCV4 was compared with MPSV4.Immunogenicity was measured by serum bactericidal activity (SBA), a correlate of protection.Rates of most solicited local and systemic adverse events after MCV4 vaccination were comparable to rates observed after administration of MPSV4 (5).The proportion of children aged 2--10 years who did not have detectable SBA (titer 1:32) by day 28 after MCV4 vaccination was 98.6% for serogroup A, 87.9% for serogroup C, 86.2% for serogroup Y, and 96.0% for serogroup W-135, similar to MPSV4 for all serogroups (Table) (5).Hence, MCV4 was found to be safe and noninferior to MPSV4 for all serogroups. During June 2007--February 2008, the ACIP Meningococcal Vaccine Workgroup considered use of MCV4 among children aged 2--10 years by reviewing data on MCV4 immunogenicity and safety in this age group, the epidemiology and burden of meningococcal disease, cost-effectiveness of various vaccination strategies, and programmatic implications.These data, expert opinion of workgroup members, and feedback from partner organizations were presented by the workgroup to the full ACIP at the October 2007 and February 2008 ACIP meetings for its deliberation regarding a potential recommendation to vaccinate only those children at increased risk for meningococcal disease, among children aged 2--10 years. # Summary of ACIP Deliberations and Rationale ACIP evaluated data to determine the anticipated duration of protection from a single dose of MCV4 in children aged 2--10 years.The duration of protection of MPSV4 is considered to be short (3--5 years), especially in young children, based on substantial declines in measurable levels of antibodies against group A and C polysaccharides by 3 years after vaccination (6,7).Although SBA titers at 28 days and 6 months after vaccination were significantly higher in children aged 2--10 years who received MCV4 compared with children who received MPSV4 for all four serogroups (p<0.001) ( 5), the difference in magnitude of SBA titers between children in the two groups was not substantial (Table ).Further, SBA activity among children aged 2--3 years who received MCV4 was lower than in children aged 4--10 years.Based on these data, ACIP concluded that evidence was insufficient to determine that 1 dose of MCV4 administered at age 2 years would provide protection against meningococcal disease through late adolescence and college entry. ACIP also reviewed the burden of meningococcal disease among children aged 2--10 years.In the United States, during 1998--2007, overall rates of meningococcal disease were lower in children aged 2--10 years (0.68 per 100,000 population) than in infants aged <2 years and adolescents aged 11--19 years (3.9 and 0.81 per 100,000, respectively).A cost-effectiveness analysis of vaccinating a cohort of U.S. children aged 2 years also was presented at the February 2008 ACIP meeting.A Monte Carlo simulation analysis was used in which multiple parameters were varied simultaneously over specified probability distributions.Data on age-and serogroup-specific meningococcal incidence rates during 1991--2005 and case-fatality ratios from ABCs were used, in addition to published estimates of meningococcal disease complications (e.g., hearing loss and limb amputations) and vaccine efficacy (8).Duration of protection of 10 years from vaccination was assumed.Using standard costeffectiveness methods, the analysis estimated that 205 meningococcal cases and 14 premature deaths could be prevented by vaccinating a cohort of 4 million children aged 2 years at a cost of $160,000 per quality-adjusted life year (QALY) saved.For a program conducting routine vaccination of children aged 11 years, the analysis estimated a cost of $90,000 per QALY saved.Hence, vaccinating children aged 2 years was determined to be less cost-effective than vaccinating children aged 11 years (8). Because approximately 75% of cases of disease in children aged 2 years occur at age 24--29 months, the effectiveness of routine MCV4 vaccination of children aged 2 years in reducing the burden of disease is dependent on achieving high coverage at age 24 months (ABCs, unpublished data, 2008).However, achieving high coverage with MCV4 at age 24 months might be challenging.For example, during 1999--2006, before licensure of hepatitis A vaccine for use in children aged 12--23 months, ACIP recommended administration of hepatitis A vaccine to children at age 2 years in states with historically high rates of hepatitis A. After that recommendation was in effect for 5 years in the 11 states where vaccination was recommended, 1-dose coverage was 54.4% (range by state: 8.6%--74.4%) among children aged 24--35 months (9). # ACIP Decision and Continuing Recommendations Based on reviews of safety and immunogenicity data, the epidemiology of meningococcal disease, a costeffectiveness analysis, and programmatic considerations, ACIP decided not to recommend routine vaccination against meningococcal disease for all children aged 2--10 years at its February 2008 meeting.ACIP continues to recommend vaccination for children aged 2--10 years at increased risk for meningococcal disease.These children include travelers to or residents of countries in which meningococcal disease is hyperendemic or epidemic, children who have terminal complement deficiencies, and children who have anatomic or functional asplenia.Health-care providers also may elect to vaccinate children aged 2--10 years who are infected with human immunodeficiency virus (HIV).- MCV4 is preferred to MPSV4 for children aged 2--10 years in these groups at increased risk and for control of meningococcal disease outbreaks.In addition, if health-care providers or parents elect to provide meningococcal vaccination to other children in this age group, MCV4 is preferred to MPSV4.Recommendations for use of MCV4 in persons aged 11--55 years, including a recommendation for routine vaccination with MCV4 of persons aged 11--18 years, have been published previously and remain unchanged (1,3). For children aged 2--10 years who have received MPSV4 and remain at increased risk for meningococcal disease, ACIP recommends vaccination with MCV4 at 3 years after receipt of MPSV4.Children who last received MPSV4 more than 3 years before and remain at increased risk for meningococcal disease should be vaccinated with MCV4 as soon as possible.For children at lifelong increased risk for meningococcal disease, subsequent doses of MCV4 likely will be needed.ACIP will monitor available data on duration of protection to determine whether recommendations for revaccination with MCV4 are indicated.Persons with a history of Guillain-Barré syndrome (GBS) might be at increased risk for GBS after MCV4 vaccination (3); therefore, a history of GBS is a precaution to administration of MCV4. Effective meningococcal conjugate vaccines for infants might be available in the near future.Phase III clinical trials for meningococcal conjugate vaccine in infants are ongoing, and published data suggest these vaccines are safe and immunogenic (10).Vaccines that provide protection against meningococcal disease early in life have the potential to greatly reduce the burden of meningococcal disease, especially if they provide protection against serogroup B meningococcal disease.

Criteria documents provide the scientific basis for new occupational safety and health standards.These documents generally contain a critical review of the scientific and technical information available on the prevalence of hazards, the existence of safety and health risks, and the adequacy of control methods.In addition to transmitting these documents to the Department of Labor, NIOSH also distributes them to health professionals in academic institutions, industry, organized labor, public interest groups, and other government agencies.This criteria document reviews available information about the adverse health effects associated with exposure to ethylene glycol monobutyl ether (EGBE) and ethylene glycol monobutyl ether acetate (EGBEA).The results of studies in animals have clearly demonstrated dose-related adverse effects on the central nervous system, the hematopoietic tissues, the blood, the kidneys, and the liver in several species by different routes of administration.Limited data from humans also indicate the risk of adverse effects on the central nervous and hematopoietic tissues, the blood, and the kidneys.Because limited data are available from studies in humans, NIOSH bases its recommended exposure limits (RELs) for EGBE and EGBEA on data from studies in animals.The data were adjusted to allow for uncertainties in the extrapolation from animals to humans.NIOSH takes sole responsibility for the conclusions and recommendations presented in this document.All reviewers' comments are being sent with this document to OSHA and MSHA for consideration in standard setting.^A# The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to ethylene glycol monobutyl ether (EGBE) and ethylene glycol monobutyl ether acetate (EGBEA) be controlled in the workplace by complying with the provisions presented in Chapter 1 of this document.These recommendations are designed to protect the health and provide for the safety of workers for up to a 10-hr workshift and a 40-hr workweek over a working lifetime.Adherence to these recommendations should prevent or greatly reduce the risk of adverse effects on exposed workers. Because environmental concentrations of contaminants vary from day to day, a timeweighted average (TWA) exposure that is below the NIOSH recommended exposure limit (REL) on a given day does not necessarily indicate that exposure on other days will also be below the REL.If a worker's TWA exposure during a workshift is one-half or more of the REL, it is probable that exposures will exceed the REL on other days.Therefore an "action level" of one-half the REL should be adopted to ensure adequate protection of workers. # SECTION 1.1 RECOMMENDED EXPOSURE LIMITS FOR EGBE AND EGBEA # Exposure Exposure to EGBE and EGBEA in the workplace shall be controlled so that workers are not exposed to concentrations greater than 5 parts per million parts of air (5 ppm) (24 mg EGBE/m3 or 33 mg EGBEA/m3).Dermal contact shall be prohibited because EGBE and EGBEA are readily absorbed through the skin. # Sampling and Analysis Workplace air samples shall be collected and analyzed for EGBE as described in the NIOSH Manual of Analytical Methods, Method No.1403 (see Appendix A); this method may be adapted for EGBEA as well.OSHA Method No.83 is also recommended for sampling and analysis of EGBE and EGBEA. *In this recommended standard for EGBE and EGBEA, the "action level" is the concentration at which exposure monitoring and medical monitoring should be initiated. # SECTION 1.2 EXPOSURE MONITORING Exposure monitoring shall be conducted as specified in Sections 1.2.1, 1.2.2, and 1.2.3.Results of all exposure monitoring shall be recorded and maintained as specified in Section 1.9. # Industrial Hygiene Surveys In work areas where airborne exposures to EGBE or EGBEA may occur, the employer shall conduct initial industrial hygiene surveys to determine their magnitude by using personal sampling techniques for an entire workshift.The employer shall keep records of these surveys.If the employer concludes that exposures to EGBE and EGBEA are below the REL, the records must show the basis for this conclusion.Surveys shall be repeated at least annually and whenever any process change is likely to increase concentrations of airborne EGBE and EGBEA.The employer shall also look for, evaluate, and record the potential for skin exposure. # Personal Monitoring If workers are exposed to EGBE or EGBEA at or above the action level (one-half the REL), a program of personal monitoring shall be instituted to identify and measure or calculate the exposure of each worker occupationally exposed to airborne EGBE and EGBEA (see Section 8.8).Source and area monitoring may be a useful supplement to personal monitor ing.In all personal monitoring, samples representative of the TWA exposures to airborne EGBE and EGBEA shall be collected in the breathing zone of the worker.Procedures for sampling and analysis shall be in accordance with Section 1.1.2.For each determination of an occupational exposure concentration, a sufficient number of samples shall be collected to characterize each worker's exposure during each workshift (see Section 8.8).Although not all workers must be monitored, sufficient samples must be collected to characterize the exposure of all workers.Variations in work and production schedules as well as worker locations and job functions shall be considered when deciding about sampling locations, times, and frequencies. If a worker is found to be exposed to EGBE or EGBEA below the REL but at or above the action level, the exposure of that worker shall be monitored at least once every 6 months or as otherwise indicated by a professional industrial hygienist.If a worker is found to be exposed to EGBE or EGBEA above the REL, the worker must wear a respirator for protection until adequate engineering controls or work practices are instituted.Controls shall then be initiated, the worker shall be notified of the exposure and of the control measures being implemented, and the worker's exposure shall be evaluated at least once a week.Such monitoring shall continue until two consecutive determinations at least 1 week apart indicate that the worker's exposure no longer exceeds the REL.At that time, semiannual monitoring shall be instituted; if concentrations of EGBE and EGBEA below the action level are noted after two semiannual consecutive surveys, sampling can be conducted annually. Measurement of urinary butoxyacetic acid (BAA), the metabolite of EGBE and EGBEA, may help characterize occupational EGBE and EGBEA exposures when the potential exists for airborne concentrations at the REL, or for skin contact from accidental exposure or breakdown of chemical protective clothing (see Section 8.6.1).Guidelines for biological monitoring are presented in Appendix D. # SECTION 1.3 MEDICAL MONITORING The employer shall provide the following information to the physician who performs or is responsible for the medical monitoring program: - The requirements of the applicable standard - An estimate of the worker's potential exposure to EGBE or EGBEA, including any available workplace sampling results - A description of the worker's duties as they relate to exposure - A description of any protective equipment the worker may be required to use # General - The employer shall institute a medical monitoring program for all workers who are exposed to airborne concentrations of EGBE or EGBEA at or above the action level, or who have the potential for skin exposure. -The employer shall ensure that all medical examinations and procedures are performed by or under the direction of a licensed physician. -The employer shall provide the required medical monitoring without loss of pay or other cost to the workers, and at a reasonable time and place. # Preplacement Medical Examinations Pteplacement medical examinations shall include at least the following: - A comprehensive medical and work history that emphasizes identification of existing medical conditions (e.g., those affecting the blood, hematopoietic and central nervous systems, skin, liver, and kidneys) and previous occupational exposure to chemical or physical agents - A medical examination giving special attention to the blood, hematopoietic and central nervous systems, skin, liver, and kidneys - A judgment about the worker's ability to use positive-and negative-pressure respirators # Periodic Medical Examinations Periodic medical examinations shall be provided at least annually to all workers occupation ally exposed to airborne concentrations of EGBE or EGBEA at or above the action level, and to workers with the potential for skin exposure.These examinations shall include at least the following: - An update of medical and work histories - A medical examination and tests giving special attention to the hematopoietic and central nervous systems, blood, skin, liver, and kidneys - Urinary monitoring, which may serve as a useful adjunct to environmental monitor ing because it indicates both airborne and dermal exposures (see Section 1.2.3) # SECTION 1.4 LABELING AND POSTING All labels and warning signs shall be printed both in English and the predominant language of workers who do not read English.Workers unable to read the labels and warning signs shall be informed verbally regarding the instructions printed on labels and signs in the hazardous work areas of the plant. # Labeling Containers of EGBE or EGBEA used or stored in the workplace shall carry a permanently attached label that is readily visible.The label shall identify the glycol ether and give information regarding its effects on human health and emergency procedures (see Figure 1-1). # Posting Signs bearing information about the health effects of EGBE and EGBEA shall be posted in readily visible positions in work areas and at entrances to work areas or building enclosures where exposures may exceed the REL and where skin exposures may occur (see . If respirators and personal protective clothing are needed when there is the possibility of skin exposure and airborne exposure at or above the REL during the manufacturing or handling of these glycol ethers or during the installation or implementation of required engineering controls, the following statement shall be added in large letters to the signs required in this section: In any area where emergency situations may arise, the required signs shall be supplemented with emergency first-aid procedures and the locations of emergency showers and eyewash fountains. # SECTION 1.5 PROTECTIVE CLOTHING AND EQUIPMENT Engineering controls and good work practices shall be used to keep the airborne concentra tions of EGBE and EGBEA below the REL and to prevent skin and eye contact When protective clothing and equipment are needed, they shall be provided by the employer. # Eye and Face Protection The employer shall provide chemical splash-proof safety goggles or face shields (20-cm minimum) with goggles and shall ensure that workers wear the protective equipment during any operation in which splashes of EGBE or EGBEA are likely to occur.Devices for eye and face protection shall be selected, used, and maintained in accordance with 29 CFR- 1910.133 and 30 CFR 56.150004 and 57.150004. # Skin Protection - Workers at risk of skin exposure to EGBE or EGBEA shall be provided with appropriate protective clothing such as gloves and disposable clothing.Informa tion presented in Section 8.6.1 provides guidance in the selection of appropriate materials for gloves and clothing. -Clothing contaminated with EGBE or EGBEA shall be cleaned before reuse. Anyone who handles contaminated clothing or is responsible for its cleaning shall be informed about the hazards of these glycol ethers and the proper precautions for their safe handling and use. -The employer shall ensure that all personal protective clothing and equipment is inspected regularly and maintained in a clean and satisfactory working condition. # Respiratory Protection - Engineering controls and good work practices shall be used to control respiratory exposure to airborne contaminants.The use of respirators is the least desirable method of controlling worker exposures and should not be used as the primary control method during routine operations.However, NIOSH recognizes that respirators may be required to provide protection in certain situations such as implementation of engineering controls, short-duration maintenance procedures, and emergencies.Respirator selection guides for protection against EGBE and EGBEA are presented in Tables 1-1 and 1-2, respectively. Code of Federal Regulations.See CFR in references.Any self-contained breathing apparatus with a full facepiece, or Any powered, air-purifying respirator equipped with a tight-fitting facepiece and organic vapor cartridges or canister 700 ppm or less Any supplied-air respirator equipped with a full facepiece and operated in a pressure-demand or other positive-pressure mode Greater than 700 ppm Any self-contained breathing apparatus equipped with a full facepiece and operated in a pressure-demand or other positivepressure mode Fire fighting Any self-contained breathing apparatus equipped with a full facepiece and operated in a pressure-demand or other positivepressure mode Escape Any air-purifying, full-facepiece respirator (gas mask) with a chinstyle or front-or back-mounted organic vapor canister, or Any appropriate escape-type, self-contained breathing apparatus Only NIOSH-or MSHA-approved equipment shall be used. *If eye irritation occurs, a respirator equipped with full facepiece, helmet, or hood shall be used.Any self-contained breathing apparatus with a full facepiece, or Any powered, air-purifying respirator equipped with a tight-fitting facepiece and organic vapor cartridges or canister 700 ppm or less Any supplied-air respirator equipped with a full facepiece and operated in a pressure-demand or other positive-pressure mode Greater than 700 ppm Any self-contained breathing apparatus operated in a pressuredemand or other positive-pressure mode Fire fighting Any self-contained breathing apparatus equipped with a full facepiece and operated in a pressure-demand or other positivepressure mode Escape Any air-purifying, full-facepiece respirator (gas mask) with a chinstyle or front-or back-mounted organic vapor canister, or Any appropriate escape-type, self-contained breathing apparatus Only NIOSH-or MSHA-approved equipment shall be used *If eye irritation occurs, a respirator equipped with full facepiece, helmet, or hood shall be used. - Respirators shall be provided by the employer when such equipment is necessary to protect the health of the worker.The worker shall use the provided respiratory protection in accordance with instructions and training received. -The employer shall ensure that respirators are properly fitted and that workers are instructed at least annually in the proper use and testing for leakage of respirators assigned to them. -Workers should not be assigned to tasks requiring the use of respirators unless it has been determined that they are physically able to perform the work and use the equipment.The medical status of the respirator user should be reviewed at least annually or as recommended by the physician responsible for the physical examina tion.See Appendix E for additional information on the medical aspects of wearing respirators. -The employer shall be responsible for establishing and maintaining a respiratory protection program as summarized below: 1.Written standard operating procedures governing selection and use of respirators shall be established. 2.The worker shall be instructed and trained in the proper use of respirators and their limitations. Where practicable, the respirators should be assigned to individual workers for their exclusive use. Respirators shall be regularly cleaned and disinfected. 5.Respirators shall be stored in a convenient, clean, and sanitary location. 6.Respirators used routinely shall be inspected during cleaning.Worn or deteriorated parts shall be replaced.Respirators for emergency use (e.g., self-contained devices) shall be thoroughly inspected at least once a month and after each use. 7.The respiratory protection program shall be regularly evaluated by the employer to determine its continued effectiveness. 8.Additional information on the selection, maintenance, and use of respirators can be found in the NIOSH Respirator Decision Logic and the NIOSH Guide to Industrial Respiratory Protection .All workers who are assigned to areas where airborne exposures to EGBE or EGBEA ate at or above the action level or who have the potential for skin exposure shall be kept informed of the hazards, relevant signs and symptoms of toxicity, and proper conditions and precautions for the safe use and handling of EGBE and EGBEA.Workers shall be made aware of possible central nervous system (CNS) and hematologic effects of exposure to EGBE and EGBEA. # Training The employer shall institute a continuing education program conducted by persons qualified by experience or training in occupational safety and health.The program shall ensure that all workers exposed to EGBE or EGBEA have current knowledge of glycol ether hazards, proper maintenance, cleanup methods, and proper use of protective clothing and equipment, including respirators.The instructional program shall include oral and written descriptions of the environmental and medical monitoring programs and of the advantages of worker participation in these surveillance programs.The employer shall maintain a written plan of these training and surveillance programs.In addition, employers shall follow the OSHA regulations in 29 CFR 1910.1200 Workers shall also be instructed about their responsibilities for following proper work practices and sanitation procedures to help protect their health and provide for their safety and that of their fellow workers. All workers in areas where EGBE or EGBEA exposures may occur during spills or emergencies shall be trained in proper emergency and evacuation procedures. # File of Written Hazard Information Required information shall be recorded on the material safety data sheet (MSDS) shown in Appendix B, or on a similar OSHA form that describes the relevant toxic, physical, and chemical properties of the glycol ethers and mixtures of glycol ethers that are used or otherwise handled in the workplace.This information shall be kept on file and shall be readily available to workers for examination and copying. # SECTION 1.7 ENGINEERING CONTROLS AND WORK PRACTICES # Engineering Controls Engineering controls shall be used when needed to maintain exposure to airborne EGBE or EGBEA within the limits prescribed in Section 1.1. # Local Exhauat Ventilation Local exhaust ventilation may be effective when used alone or in combination with process enclosure.When a local exhaust ventilation system is used, it shall be designed and operated to prevent accumulation or recirculation of airborne EGBE or EGBEA in the workplace.Exhaust ventilation systems discharging to outside air shall conform with applicable local, State, and Federal air pollution regulations and shall not constitute a hazard to workers or to the general population.Before maintenance work on control equipment begins, the generation of airborne EGBE or EGBEA shall be eliminated to the greatest extent feasible.

# Maintaining Design Airflow Enclosures, exhaust hoods, and ductwork shall be kept in good repair to maintain designed airflows.Measurements such as capture velocity, duct velocity, or static pressure shall be made at least semiannually, and preferably monthly, to demonstrate the effectiveness (quantitatively, the ability of the control system to maintain exposures below the REL) of the mechanical ventilation system.NIOSH recommends the use of continuous airflow indicators such as water or oil manometers marked to indicate acceptable airflow.A record shall be kept showing design airflow and the results of all airflow measurements.Measure ments of the effectiveness of the system in controlling exposures shall also be made as soon as possible after any change in production, process, or control devices that may increase airborne concentrations of EGBE or EGBEA. # Forced-Draft Ventilation Forced-draft ventilation systems shall be equipped with remote manual controls and should be designed to shut off automatically in the event of a fire. # General Work Practices - Operating instructions for all equipment shall be developed and posted where EGBE and EGBEA are handled or used. -Transportation and use of EGBE and EGBEA shall comply with all applicable local, State, and Federal regulations. -EGBE and EGBEA shall be stored in tightly closed containers and in well ventilated areas. -Containers shall be moved only with the proper equipment and shall be secured to prevent loss of control or dropping during transport. -Storage facilities shall be designed to prevent contamination of workroom air and to contain spills completely within surrounding dikes. -Ventilation switches and emergency respiratory equipment shall be located outside storage areas in readily accessible locations. - Process valves and pumps shall be readily accessible and shall not be located in pits or congested areas. -EGBE and EGBEA containers and systems shall be handled and opened with care. Approved protective clothing and equipment as specified in Section 1.5 shall be worn by workers who open, connect, and disconnect EGBE and EGBEA containers and systems.Adequate ventilation shall be provided to minimize exposures of such workers to airborne EGBE or EGBEA. -EGBE and EGBEA storage equipment and systems shall be inspected daily for signs of leakage.All equipment, including valves, fittings, and connections, shall be checked for leaks immediately after EGBE and EGBEA are introduced therein. -When a leak is found, it shall be repaired promptly.Work shall resume normally only after necessary repair or replacement has been completed and the area has been well ventilated. # Confined or Enclosed Spaces - A permit system shall be used to control entry into confined or enclosed spaces such as tanks, pits, tank cars, and process vessels where egress is limited.Permits shall be signed by an authorized representative of the employer and shall certify that preparation of the confined space, precautionary measures, and personal protective equipment are adequate and that precautions have been taken to ensure that prescribed procedures will be followed. -Confined spaces that hold containers of EGBE or EGBEA shall be thoroughly ventilated, inspected, and tested for oxygen deficiency and for airborne concentra tions of these compounds.Every effort shall be made to prevent the inadvertent release of hazardous amounts of EGBE or EGBEA into confined spaces where work is in progress.EGBE or EGBEA supply lines shall be disconnected or blocked off before such work begins. -No worker shall enter a confined space without an entry large enough to admit a worker wearing safety harness, lifeline, and appropriate personal protective equip ment as specified in Section 1.5. -Confined spaces shall be ventilated while work is in progress to keep the concentra tion of EGBE and EGBEA below the REL, to keep the concentration of other contaminants below toxic or dangerous levels, and to prevent oxygen deficiency. -If the concentration of EGBE or EGBEA in the confined space exceeds the REL, respiratory protective equipment is required for entry. -Anyone entering a confined space shall be observed from the outside by another properly trained and protected worker.An additional supplied-air or self-contained breathing apparatus with safety harness and lifeline shall be located outside the confined space for emergency use.The person entering the confined space shall maintain continuous communication with the standby worker. # Emergency Procedures Emergency plans and procedures shall be developed for all work areas where there is a potential for exposure to EGBE or EGBEA.These plans and procedures shall include those specified below and any others considered appropriate for a specific operation or process. Workers shall be instructed in the effective implementation of these plans and procedures. - The following steps shall be taken in the event of a leak or spill of EGBE or EGBEA: -All nonessential personnel shall be evacuated from the leak or spill area. -Persons not wearing the appropriate protective equipment and clothing shall be restricted from the leak or spill area until cleanup has been completed. -All ignition sources shall be removed. -The area where the leak or spill occurs shall be adequately ventilated to prevent the accumulation of vapor. -The EGBE and EGBEA shall be contained and absorbed with vermiculite, sand, or paper towels. -Small quantities of absorbed material shall be placed under a fume hood and sufficient time shall be allowed for the liquid to evaporate and for the vapors to clear the ductwork in the hood. -Large quantities of absorbed material shall be pyrolyzed in a suitable combus tion chamber. -Contaminated absorbent materials shall be disposed of as hazardous waste. -The spill area shall be cleaned with water. - Only personnel trained in the emergency procedures and protected against the attendant glycol ether hazards shall clean up spills and control and repair leaks. -Personnel entering the spill or leak area shall be furnished with appropriate personal protective clothing and equipment.Other personnel shall be prohibited from entering the area. -Safety showers, eyewash fountains, and washroom facilities shall be provided, maintained in working condition, and made readily accessible to workers in all areas where skin or eye contact with EGBE or EGBEA is likely.If EGBE or EGBEA is splashed or spilled on a worker, contaminated clothing shall be removed promptly, and the skin shall be washed thoroughly with soap and water.Eyes splashed by EGBE or EGBEA shall be irrigated immediately with a copious flow of water for 15 min.If irritation persists, the worker should seek medical attention. # Storage EGBE and EGBEA shall be stored in cool, well-ventilated areas and kept away from acids, bases, and oxidizing agents. # Waste Disposal All waste material shall be securely packaged in double bags, labeled, and incinerated.The following shall be prohibited in areas where EGBE or EGBEA is produced or used: the storage, preparation, dispensing, or consumption of food or beverages; the storage or application of cosmetics; and the storage or use of all tobacco products. # Handwashing The employer shall provide handwashing facilities and encourage workers to use them before eating, smoking, using the toilet, or leaving the worksite. # Laundering - Protective clothing, equipment, and tools shall be cleaned periodically. - The employer shall provide for the cleaning, laundering, or disposal of con taminated work clothing and equipment. -Any person who cleans or launders this work clothing or equipment must be informed by the employer that it may be contaminated with EGBE or EGBEA-chemicals that may cause adverse hematologic (blood) and CNS effects. # Cleanup of Work Area The work area shall be cleaned at the end of each shift (or more frequently if needed) using vacuum pickup.Collected wastes shall be placed in sealed containers with labels that indicate the contents.Cleanup and disposal shall be conducted in a manner that prevents worker contact with wastes and complies with all applicable local, State, and Federal regulations. # Showering and Changing Facilities Workers shall be provided with facilities for showering and changing clothes at the end of each workshift. SECTION 1.9 RECORDKEEPING # Exposure Monitoring The employer shall establish and maintain an accurate record of all exposure measurements required in Section 1.8 of this document.These records shall include the name of the worker being monitored, social security number, duties performed and job locations, dates and times of measurements, sampling and analytical methods used, type of personal protection used (if any), and number, duration, and results of samples taken. # Medical Monitoring The employer shall establish and maintain an accurate record for each worker subject to the medical monitoring specified in Section 1.3 of this document.Pertinent medical records (i.e., the physician's written statement, the results of medical examinations and tests, medical complaints, etc.)shall be retained in the medical files of all workers subject to airborne concentrations of EGBE or EGBEA in the workplace at or above the action level.Copies of applicable environmental monitoring data shall also be included in the worker's medical file. # Record Retention In accordance with the requirements of 29 CFR 1910.20(d), Preservation of Records, the employer shall retain the records described in Sections 1.2 and 1.3 of this document for at least the following periods: - 30 years for exposure monitoring records, and - Duration of employment plus 30 years for medical surveillance records # Availability of Records In accordance with 29 CFR 1910.20, Access to Employee Exposure and Medical Records, the employer shall, upon request, allow examination and copying of exposure monitoring records by the subject worker, the former worker, or anyone having the specific written consent of the subject or former worker. Any medical records required by this recommended standard shall be provided upon request, for examination and copying, to the subject worker, the former worker, or anyone having the specific written consent of the subject or former worker. # Transfer of Records The employer shall comply with the requirements for the transfer of records as set forth in 29 CFR 1910.20(h), Transfer of Records. # INTRODUCTION # PURPOSE This document presents the criteria and recommended standards necessary to prevent health impairment from exposure to EGBE and EGBEA-two solvents used primarily in surface coatings.The principal signs and symptoms of acute overexposure to these compounds are irritation of the eyes, nose, and throat; drowsiness; nausea; shaking; and weakness.Repeated exposure may damage the bone marrow, blood cells, kidneys, and liver.The document was developed in response to Section 20(a)( 3) of the Occupational Safety and Health (OSH) Act of 1970 .In this act, NIOSH is charged with developing criteria for toxic materials and harmful physical agents to describe exposure concentrations at which no worker will suffer impaired health or functional capacities or diminished life expectancy as a result of work experience.This document also responds to Section 2.2(c)( 1) of the OSH Act, which authorizes the National Institute for Occupational Safety and Health (NIOSH) to develop and establish recommended occupational safety and health standards. NIOSH has formalized a system for developing criteria on which to base standards for ensuring the health and safety of workers exposed to hazardous chemical and physical agents.Simple compliance with these standards is not the only goal.The criteria and recommended standards are intended to help management and labor develop better engineer ing controls and more healthful work practices. Recommended standards for EGBE and EGBEA apply only to workplace exposures arising from the processing, manufacturing, handling, and use of EGBE and EGBEA.The recommendations are not designed for the population at large, and any extrapolation beyond the occupational environment may not be warranted.The recommended standards are intended to protect workers from the acute and chronic effects of EGBE and EGBEA.Exposure concentrations are measurable by techniques that are valid, reproducible, and available to industry and government agencies. # SCOPE The information in this document assesses the hazards associated with occupational ex posure to EGBE and EGBEA.Chapter 1 presents the recommended standard and describes its requirements.Chapter 3 gives information about the chemical and physical properties of EGBE and EGBEA, production methods, uses, and the extent of worker exposure.Chapter 4 discusses and summarizes the effects of exposure to these glycol ethers on humans and animals.Subsequent chapters describe environmental sampling and analytical methods, medical monitoring, existing occupational health standards, and a correlation of exposure and effect.In addition, methods for worker protection are discussed, including suggested work practices, engineering controls, personal protective clothing and equipment, and exposure monitoring and recordkeeping. .This compound is miscible in water and is soluble in most organic solvents. EGBEA, the acetate ester of EGBE, is also known as butyl Cellosolve acetate, 2-butoxyethyl acetate (2-BEA), Ektasolve EB® acetate, or butyl glycol acetate.This organic compound has the chemical formula ^HgOCF^CI^OCOCHg.EGBEA is a colorless liquid with a fruity odor .The compound is only slightly soluble in water, but it is soluble in hydrocarbons and organic solvents.Other chemical and physical properties are listed in Table 3-1. # PRODUCTION METHODS AND USES EGBE is usually produced by a reaction of ethylene oxide with butyl alcohol, but it may also be made by the direct alkylation of ethylene glycol with an agent such as dibutyl sulfate .Temperature, pressure, reactant molar ratios, and catalysts are selected to give the product mix desired.Ethylene glycol monoalkyl ethers are not formed as pure compounds but must be separated from the diethers of diethylene glycol, triethylene glycol, and the higher glycols.EGBEA is prepared by esterifying EGBE with acetic acid, acetic acid anhydride, or acetic acid chloride. EGBE is widely used as a solvent in surface coatings such as spray lacquers, quick-dry lacquers, enamels, varnishes, varnish removers, and latex paint .In surface coatings, it imparts blush resistance, gloss, and good flow-out .EGBE is also used as a coupling agent in metal cleaning formulas and household cleaners, as an intermediate in EGBEA production, and as a component in herbicides and automotive brake fluids . EGBEA is primarily used as a retarder solvent for nitrocellulose lacquer and epoxy and acrylic enamels; it is also a film-coalescing aid for polyvinyl acetate latex, and it may be used in some ink and spot remover formulations . # NUMBER OF WORKERS POTENTIALLY EXPOSED The National Occupational Exposure Survey (NOES) .In contrast to these data, EGBE exposures in a Belgian study of various industrial operations ranged from 0.04 to 367.2 ppm, and exposures to EGBEA ranged from 0.70 to 4.04 ppm (see Table 3 -5). Veulemans et al. .^Concentration recorded in a mirror-manufacturing plant # EFFECTS OF EXPOSURE # EFFECTS ON HUMANS # Case Studies A case of severe poisoning from massive ingestion of EGBE has been described by Rambourg-Schepens et al. .In a suicide attempt, a 50-year-old woman ingested 250 to 500 ml of a window cleaner containing 12% EGBE.When admitted to the hospital 12 hr later, the woman was comatose with no response to painful stimuli; she ventilated poorly and was placed under mechanical ventilation.Metabolic acidosis, hypokalemia (an abnor mally small amount of potassium in the blood), a rise in serum creatinine level, hemoglobinuria, and oxaluria were observed.The hemoglobinuria was paralleled by a progressive erythropenia (a deficiency in the number of red blood cells).The clinical status of the woman improved gradually, and she was discharged on the 10th day. Gijsenbergh et al. described a suicide attempt by a 23-year-old woman who ingested about 500 ml of a window-cleaning agent that contained EGBE and a small quantity of alcohol (the percentage of each compound was not presented).When admitted to the hospital 1 hr after ingesting the substance, the woman was comatose and suffering from hypotension.She subsequently developed severe metabolic acidosis.Routine laboratory blood examination revealed no abnormalities.The woman recovered after forced diuresis and hemodialysis. NIOSH conducted a health hazard evaluation in 1983 to evaluate worker exposure to two solvent cleaners-an image remover and a paint remover used in a silk screening process .A silk screener using the image remover was monitored for exposure to ethylene glycol monoethyl ether acetate (EGEEA) and cyclohexanone, and a worker using the paint remover was monitored for a variety of organic solvents, one of which was EGBEA.Although the workers were primarily exposed by inhalation, they also may have been exposed by skin absorption because personal protective equipment was not always worn.The workers complained of headaches, lethargy, sinus problems, nausea, and heartburn.When the workers were away from work, their symptoms improved.Measurement of the silk screener's airborne exposures to EGBEA indicated that the TWA exposures ranged from 0.8 to 3.9 ppm, with a short-term excursion to 5.3 ppm; however, absorption through the skin may have contributed to the workers' overall exposure.Boiano concluded that a health hazard from exposures to airborne solvent mixtures did not exist at this facility. # Experimental Exposure Two men and six rats were exposed simultaneously in a 1,250-cubic-ft room to 113 ppm EGBE for 4 hr .Symptoms of the men included nasal and eye irritation, disagreeable metallic taste, occasional belching, and a slight increase in nasal mucous discharge.Although erythrocyte osmotic fragility did not change for the men, it rose appreciably for the rats. In a second experiment about a year later, the same two men and one woman were exposed to 195 ppm EGBE for two 4-hr periods, separated by a 30-min recess for lunch .Exposure took place in a 6 i/2-ft cube (7,900 liters).The responses of all three subjects included immediate irritation of the nose and throat, followed by eye irritation and disturbed taste.The woman also developed a headache that lasted about 24 hr.Erythrocyte osmotic fragility did not change.However, increased osmotic fragility was found in vitro with the human erythrocytes.Therefore, increased osmotic fragility would be expected after inhalation of EGBE at concentrations higher than 200 ppm (approximate).Erythrocyte osmotic fragility increased steadily in three female rats concurrently exposed.Concentra tions of butoxyacetic acid (BAA), demonstrated as a metabolite of EGBE (see Section 4.2), were determined in urine samples collected during the 24-hr period following exposure.

The woman and one of the men excreted considerable amounts of BAA (300 mg and 175 mg, respectively) in the 24-hr period following exposure, but the other man excreted only trace amounts of the metabolite.The three subjects agreed that 195 ppm EGBE caused discomfort when breathed continually. In a third study, four subjects-two men and two women (including the man who had participated in the second study and had excreted only trace amounts of BAA)-were exposed to 100 ppm EGBE for 8 hr.Following this exposure, all four subjects excreted significant amounts of BAA in their urine (75 to 250 mg).Other effects of exposure included vomiting and headaches; there was no effect on the osmotic fragility of erythrocytes .Carpenter et al. postulated that EGBE is oxidized to BAA in mammals.The authors verified this postulate with the identification of BAA in the urine of various animal species (dog, rabbit, rat, and guinea pig) exposed to EGBE vapor.The data (excluding that on the dogs) suggested that a correlation existed between the EGBE vapor concentration and urinary BAA .Although BAA was not identified in the blood of the dogs, rats, or guinea pigs, it was found in the blood of the rabbits 4 hr after i. v. administration of EGBE, and in the urine collected during the 24 hr after injection.The authors suggested that EGBE was present in the blood at a concentration too low for detection by the analytical method used.Jonsson and Steen exposed male albino rats to 414 ppm EGBE for 1 hr, and then collected urine for 20 hr.Gas chromatographic analysis of organic acids in urine after EGBE exposure was conducted.Gas chromatography retention time and mass spectrum of the EGBE metabolite were the same as that of synthetic BAA.Johanson et al. exposed seven male volunteers to 20 ppm EGBE for 2 hr during light physical exercise on a bicycle ergometer.Expired air was collected at regular time intervals to estimate respiratory uptake of EGBE.Blood and urine samples were collected and analyzed for EGBE and BAA.The respiratory uptake of EGBE averaged 57% of the inspired amount.The concentration of EGBE in the blood reached a plateau of 7.4 micromoles (fimol)/liter (1 ppm volume/volume) within 1 to 2 hr and could no longer be detected in the blood 2 to 4 hr after exposure.The elimination half-time was 40 min, mean residence time was 42 min, total blood clearance time was 1.2 liters/min, and steady-state volume of distribution was 54 liters.Less than 0.03% of the total uptake of EGBE was excreted in the urine, whereas urinary excretion as BAA tanged from 17% to 55%. studied the percutaneous uptake of EGBE in five healthy males (see Section 5.4.5.1).The subjects kept two or four fingers immersed in undiluted EGBE for 2 hr.Blood samples were collected from the unexposed hand before, during, and up to 4 hr after the EGBE-exposure and analyzed for EGBE by gas chromatography.Urine samples were collected for 24 hr and analyzed for BAA by gas chromatography.The authors concluded that detection of EGBE in the blood of all subjects was indicative of systemic uptake of EGBE through the skin in vivo.The percutaneous uptake varied from 127 to 1,891 ^mol/subject.The acid metabolite BAA was found in the urine.Urinary excretion peaked 3 hr after exposure and then declined with an average half-life of 3.1 hr.The accumulated excretion ofBAA ranged from 8.7 to 313 nmol, corresponding to 2.5% to 39% of the uptake.The authors concluded that their study clearly showed that EGBE is absorbed through human skin in vivo and enters the systemic circulation.A comparison of dermal uptake rate with inhalatory uptake suggested that both skin and respiratory uptake should be considered when workers are exposed to EGBE.Both studies by Johanson et al. [1986 are assessed and discussed under biological monitoring in Section 5.4. # METABOLISM, UPTAKE, AND ELIMINATION # Research Studies A lack of data exists concerning the metabolism of EGBEA.However, reports in the literature have identified ethoxyacetic acid (EAA) as the metabolite of both ethylene glycol monoethyl ether (EGEE) and its acetate (EGEEA) .The findings confirmed that EGEEA is first converted to EGEE by hydrolysis of the ester moiety and then passes through the same pathway as EGEE to EAA.By analogy to EGEE and EGEEA, it is reasonable to assume that EGBEA is first hydrolyzed to EGBE and then oxidized to BAA .Carpenter et al. identified BAA in the urine of various animal species exposed to EGBE vapor.Analysis of organic acids in urine after EGBE exposure of rats revealed the presence of BAA . # Summary of Studies on Metabolism, Uptake, and Elimination Exposure of male volunteers to EGBE vapors during light physical exercise resulted in 57 % respiratory uptake of inspired EGBE .Less than 0.03% of the total uptake of EGBE was excreted unchanged in urine, and urinary BAA excretion ranged from 17% to 55% of the EGBE absorbed.Percutaneous exposure of male volunteers to EGBE resulted in systemic uptake of EGBE through the skin in vivo, and BAA was found in the urine .A comparison of dermal and respiratory uptake suggested that both routes of exposure should be considered when workers are exposed to EGBE . The metabolite of EGBEA has not been identified.However, by analogy to EGEEA, which is converted to EGEE and then to EAA , it is logical to assume that EGBEA is metabolized to EGBE and then to BAA. # EFFECTS ON ANIMALS Kidney, hematologic, and central nervous system (CNS) effects have been observed in experimental animals exposed to EGBE and EGBEA. # Acute Toxicity Many experiments have been performed to investigate the acute toxicity of glycol ethers in animals.These investigations have led to the establishment of a lethal concentration or lethal dose for 50% of the exposed animals (LC50 or LDjq) in a variety of species by a variety of routes (inhalation, oral, dermal, and injection).A summary of the available data by animal species is presented in Table 4-1, and more detailed information is given in Table 4-2. # Oral Administration When rabbits were dosed by a single gavage with 890 or 1,780 mg EGBE/kg, death occurred within 30 or 22 hr .Sluggishness, ruffling of coats, prostration, and narcosis occurred after oral administration of lethal concentrations of EGBE to male and female rats (2,400 and 2,500 mg/kg, respectively) .Necropsies revealed con gested or hemorrhaged lungs, mottled livers, congested kidneys, and hemoglobinuria.When EGBEA was administered by gastric intubation to male and female Wistar rats (3,000 and 2,400 mg/kg, respectively), hypertrophic and bloody kidneys were observed at necropsy .Werner et al. demonstrated an adverse effect of EGBE on the hematopoietic system.Single 7-hr exposures of White-Swiss mice to EGBE (390 to 1,210 ppm) caused marked follicular phagocytosis in the spleen, congestion of the cavernous veins of the spleen, and hemoglobinuria.The usual sign of toxic action was dyspnea. ----------1,100 ----------700 (7 hr) ___ 'Abbreviations: LD^-mean lethal dose; LCjqmean lethal concentration. Truhaut et al.1979 Single 4-hr exposures of male and female Fischer 344 rats to EGBE (486 ppm and 450 ppm, respectively) caused hematuria; enlarged and discolored kidneys were observed at autopsy . # Inhalation Exposure # Dermal Exposure The percutaneous toxicity of EGBE and EGBEA has been investigated in the rabbit .Toxic effects on the kidneys were seen consistently.Male albino New Zealand rabbits were immobilized during 24 hr of skin contact with undiluted EGBE (0.48 to 0.64 ml/kg); they were observed for 14 days thereafter .Autopsy of the rabbits revealed congestion of the kidneys, hemoglobinuria, pale livers, and engorged spleens.Truhaut et al. exposed rabbits to 7.5 to 23.5 g EGBEA/kg for 24 hr using an occluded bandage technique.Bloody kidneys were found at necropsy; histologic examination revealed necrotizing, hemorrhagic, atrophic, acute, tubular nephrosis with occasional glomerular lesions.Gross administered single subcutaneous (s.c.)injections of varying doses of EGBE to 13 rabbits.At 180 mg/kg, a slight, temporary, kidney inflammation was noted.Doses of 360 to 1,800 mg/kg caused death within 20 to 72 hr from kidney inflammation, and a dose of 2,700 mg/kg caused death within 2 hr from respiratory paralysis.A cat injected s.c.with 900 mg EGBE/kg did not show signs of illness; a second cat received 1,800 mg EGBE/kg s.c.and died 3 days later with signs of kidney injury. # Subcutaneous Administration # Summary of Acute Toxicity The acute toxicity of EGBE and EGBEA has been investigated in a number of experiments with a variety of species and routes of exposure.Animals exhibited inactivity, weakness, and dyspnea.Autopsies revealed congested lungs and kidneys .The principal effect exerted by these compounds was damage to the kidneys , which included extreme tubular necrosis and degeneration.Additional adverse effects included increased osmotic fragility of erythrocytes and damaged spleens .The acute toxic effects of EGBE and EGBEA are summarized in Table 4-2. # Hematologic Effects EGBE and EGBEA have been shown to have adverse hematologic effects.These effects include increased osmotic fragility and decreased levels of hemoglobin (Hb), hematocrit (Hct), platelets, red blood cells (RBCs), white blood cells (WBCs), and mean cell volume (MCV). Inhalation exposures of groups of female rats to 62 ppm EGBE for 4 hr resulted in increased osmotic fragility of rat erythrocytes , In an early investigation , the hemolytic action of EGBE was studied by adding 1 cc of EGBE to 5-cc suspensions of dog or beef blood corpuscles in Ringer solution.The investigators reported that hemolysis occurred in the presence of EGBE. # Oral Administration In a study by Nagano et al. ,male JCL-ICR mice were treated orally with 500 or 1,000 mg EGBE/kg per day, 5 days/wk for 5 wk.Although EGBE exerted no effect on WBC counts, MC V, or Hb levels, it significantly reduced RBC counts at doses of both 500 mg EGBE/kg per day (P<0.05) and 1,000 mg EGBE/kg per day (P<0.01). EGBE-induced hematotoxicity in rats is age-dependent, with older rats more susceptible to EGBE treatment than young rats .EGBE (0, 125, or 500 mg/kg) was administered orally to young (4-to 5-week-old) and adult (9-to 13-week-old) male F344 rats (>5 rats/group).No significant hematologic effects were observed in the younger rats at any time intervals (2,4,8,24, and 48 hr) investigated in the group receiving 125 mg EGBE/kg.However, a significant decrease (P<0.05) in RBCs, Hct, and Hb was detected in the adult rats 8 and 24 hr after oral administration of 125 mg EGBE/kg.Free Hb concentrations in plasma were significantly increased (P£0.05) in adult rats 8 hr after oral administration of 125 mg EGBE/kg; there was no effect on free Hb concentrations in plasma of young rats.Twenty-four hours after dosing, free Hb concentrations in plasma of older rats were comparable with those in untreated control rats . Decreases in RBCs, Hb, and Hct were accompanied by a significant (P<0.05) dose-dependent increase in the free Hb concentrations of both age groups treated with 500 mg EGBE/kg .The authors state that a gradual recovery from hematotoxicity was observed after 48 hr in both of these groups. Hemoglobinuria secondary to the hemolytic effect of EGBE was also observed.Table 4-3 demonstrates the incidence of hemoglobinuria in rats of various ages treated orally with various doses of EGBE. # ND ND A 100% incidence of hemoglobinuria was detected in 16-month-old rats treated with 32 mg EGBE/kg, but no effect was observed in rats younger than 16 months treated with the same dosage.A dose of 125 mg EGBE/kg caused 100% incidence of hemoglobinuria in all rats older than 4 to 5 weeks and a 9% incidence in 4-to 5-wk-old rats. Histopathologic evaluation of tissues from rats of various ages examined 24 hr after EGBE administration demonstrated that EGBE caused dose-and age-dependent liver and kidney changes.These histopathologic changes exhibited signs of regression when examined 48 hr after EGBE-dosing. The results presented in this report clearly demonstrate that a direct relationship exists between toxicity of EGBE and the age of the rats .Older rats are more susceptible than younger rats to hematotoxicity and liver/kidney damage caused by EGBE.Severe acute hemolytic anemia was evidenced by a decrease in circulating RBCs, an increase in the concentration of free Hb in plasma, and the development of hemoglobinuria. state that the greater susceptibility of older rats to EGBE-induced toxicity may be caused by ( 1) a longer half-life of its metabolite butoxyacetic acid (BAA) in older rats compared with younger rats and ( 2) an enhanced ability of younger rats to degrade BAA to C02 and/or excrete BAA in the urine.Grant et al. exposed male F344 rats (24 per group) orally to 500 or 1,000 mg EGBE/kg per day for 4 consecutive days.Six animals from each group were bled from a lateral caudal vein and then sacrificed and necropsied 1, 4, 8, and 22 days after the last EGBE treatment.EGBE caused pronounced dose-dependent effects on circulating RBCs and WBCs.Reduced erythrocyte counts, reduced Hct and Hb levels, and elevated MCV, reticulocyte counts, and mean cell hemoglobin concentration (MCHC) (P< 0.001) were noted at the end of treatment in animals dosed with 1,000 mg EGBE/kg per day. Most of these alterations in the RBCs disappeared over the 22-day recovery period, although the MCV and MCHC values were slightly elevated at day 22.In the high-dose EGBE group (1,000 mg/kg per day), leukocyte counts were also depressed on day 1 CP<0.001); this was principally because of reduced numbers of circulating lymphocytes.Although the leukocyte numbers gradually increased, they did not reach control levels by the end of the recovery period.These effects on RBCs and WBCs were also observed in the group receiving 500 mg EGBE/kg per day, although the severity of the changes was less marked. EGBE was administered by gavage to groups of 10 male rats at doses of 0, 222, 443, or 885 mg/kg per day, 5 days/wk for 6 wk .At termination, the animals were sacrificed and blood was collected for hematologic and serum chemistry determinations.During the treatment period, two rats in the high-dose group and one rat in the intermediate dose group died.All the other animals survived to termination.The principal effect of EGBE was on the RBC.Hb and RBC levels were significantly reduced at all doses (P<0.05), and MCHC was statistically lower (P<0.05) than the control at the high and intermediate doses.Statistically significant increases were noted for mean cell hemoglobin (MCHb) at all doses and for MCV at the high and intermediate doses.Hct and WBC counts were unaffected. In two separate inhalation studies, Wistar-derived rats and dogs of an unspecified strain were exposed to EGBE, and the effects on hematologic parameters were examined.In the rat study, 23 animals per group were exposed to 0, 135, or 320 ppm EGBE for 7 hr/day, 5 days per wk over a 5-wk period; the animals were sacrificed 3 wk after termination of exposure.Hematologic examinations were made before, during, and after the 5 wk of exposure; they consisted of RBC and WBC counts, differential counts, reticulocyte counts, and Hb estimations.No statistical analysis was presented.The authors concluded that exposure of rats to 320 ppm EGBE resulted in an increased percentage of circulating immature granulocytes, a decrease in Hb concentration and RBC count, and an increase in the reticulocyte count.These hematologic changes were not severe and were reversed 3 wk after discontinuing exposure. There was no effect on the WBC population. In the second inhalation study , groups of 2 dogs were exposed to 0 or 415 ppm EGBE for 7 hr/day, 5 days/wk during a 12-wk period.Animals were sacrificed 5 wk after discontinuing exposure.Hematologic determinations were again made before, during, and after the exposure period.No statistical analysis was presented.The authors concluded that exposure of dogs to EGBE vapors resulted in ( 1) decreased Hb concentration and RBC count, and ( 2) increased hypochromia, polychromatophilia, and microcystosis, as shown by the RBC.These hematologic changes were not severe and were reversed 5 wk after exposure ceased .Carpenter et al. also studied the hemolytic effects exerted by the inhalation of EGBE vapors on various animal species.No statistical evaluations were presented.Exposure to 62 ppm EGBE for 4 hr caused significant osmotic fragility of erythrocytes in six female Carworth-Wistar rats.Groups of 15 rats of both sexes and 10 male guinea pigs (strains not specified) inhaled various concentrations of EGBE, 7 hr/day, 5 days/wk for 30 days.Erythrocyte osmotic fragility was found in rats immediately after a single 7-hr exposure to 107 ppm or higher (203, 314, or 432 ppm EGBE) and after 30 daily 7-hr exposures to 54 ppm EGBE.Osmotic fragility values for females usually exceeded those for the males. In almost all cases, these high fragility values returned to normal after the rats rested overnight.No effect was exerted on the osmotic fragility of guinea pig erythrocytes at the concentrations tested (54,107,203,376,or 494 ppm EGBE).The authors also exposed groups of 10 male C3H mice to 100,200, or 400 ppm EGBE for 7 hr/day over 30-, 60-, or 90-day periods.Increased erythrocyte osmotic fragility occurred at all concentrations.The increase was as great after the first exposure as it was after the 89th exposure.In all instances, erythrocyte osmotic fragility was normal after a 17-hr rest. Repeated exposure of one male and one female basenji dog to 385 ppm EGBE caused increased RBC osmotic fragility in both dogs, but a significant reduction in RBC count and Hb level occurred only in the male .The female dog died after eight exposures.When one male and one female basenji from the same litter were exposed to 200 ppm EGBE for 7 hr/day over a 31-day period, RBC osmotic fragility increased slightly in both dogs.

WBC counts doubled in the male, and the RBC count and Hb level fell slightly # Inhalation in the female.When one male and one female wire-haired terrier from the same litter were exposed to 100 ppm EGBE for 7 hr/day over a 90-day period, a transitory doubling of WBC counts occurred in both dogs midway in the 90-day period.At the end of the exposure period, the female's WBC count returned to the preexposure level, but the male's remained 50% higher.The Hct level of the male also dropped by 8.5%. In another part of the study by Carpenter et al. ,two monkeys were exposed to 100 ppm EGBE for 7 hr/day, 5 days/wk over a 90-day period.RBC osmotic fragility rose on several occasions, higher in the female than in the male, but returned to normal at the end of the exposure period.RBC counts also fell briefly but returned to normal.In addition, a rhesus monkey inhaled 210 ppm EGBE for 7 hr/day, 5 days/wk over a 30-day period.RBC osmotic fragility rose after the fourth exposure but returned to normal overnight.At the end of the exposure period, the RBC count and Hb level had been reduced to one-half the initial values.Dodd et al. conducted inhalation studies with Fischer 344 rats of both sexes.In these studies, 8 animals per group were exposed to 0,20, 8 6 , or 245 ppm EGBE during a 9-day period, or 16 animals per group were exposed to 0,5,25, or 77 ppm EGBE during a 90-day period.For the 9-day study, the rats were exposed for 6 hr/day during 5 consecutive days, followed by 2 days of nonexposure and 4 consecutive days of exposure.For the 90-day study, rats were exposed for 6 hr/day, 5 days/wk over a 13-wk period.All blood samples for hematologic measurements were obtained on the day before sacrifice. In the 9-day study, both sexes of the group exposed to 245 ppm EGBE had significantly depressed RBC counts (P<0.001), Hb levels (P<0.001), and MCHC (P<0.01).These rats also had a significant increase (P<0.001 in all cases) in MC V, nucleated RBC, reticulocytes, and (in males only) lymphocytes (P<0.001).Following a 14-day postexposure period, a substantial recovery of the affected erythroid parameters was observed; however, statisti cally significant differences from controls were still present for the males (i.e., RBC count , MCV , and MCHb ).During the 14-day postexposure recovery period, the WBC count, which had been elevated (P<0.001) in males, returned to control values.There was a significant but less profound effect on erythroid parameters in both sexes of the group exposed to 8 6 ppm EGBE.In male rats, Hb concentration was reduced relative to that of the controls (P<0.01); in female rats, Hb concentration (P<0.001) and MCHC (P<0.01) were reduced, and Hct (P<0.01) and MCV (P<0.05) were increased. In the 90-day study, after 6 wk of the exposure regimen, the authors concluded that the female rats exposed to 77 ppm EGBE had slight but statistically significant decreases in RBC counts (P<0.01) and Hb levels (statistics not reported) accompanied by an increase in MCHb 11 % above the values for controls (P<0.001).At the end of the study, these effects had either decreased or returned to the ranges of the control values.The only significant hematologic finding for male rats in the group exposed to 77 ppm EGBE was a 5% decrease in RBC count after 6 6 EGBE exposures (statistics not given). In a later study by Tyl et al. ,Fischer 344 rats and New Zealand white rabbits were exposed to EGBE vapors (25 to 200 ppm) on g.d.6 through 15 (rats) or 6 through 18 (rabbits). Blood samples were collected before sacrifice.Hematologic determinations in rats exposed to EGBE indicated no alterations in RBC osmotic fragility, but there were significant reductions in RBC count, and significant increases in Hb and Hct at 200 ppm (P<0.001).RBC count was also reduced at 100 ppm (P<0.001).In rats exposed to 100 and 200 ppm EGBE, MCV and MCHb were significantly increased relative to those of the controls (P<0.001).In addition, the MCHC was reduced significantly at 100 ppm EGBE (P<0.01) and 200 ppm EGBE (P<0.001) relative to that of the controls.Hematologic determinations in rabbits exposed to EGBE revealed no apparent exposure-related effects.Statistically significant increases in Hb concentration and Hct were observed at 100 ppm (P<0.01) but not at 200 ppm EGBE.Truhaut et al. carried out inhalation studies of EGBEA using groups of 10 Wistar rats of both sexes and 4 New Zealand rabbits, two of each sex.Exposure of rats and rabbits to 400 ppm EGBEA for 4 hr resulted in slight and transient hemoglobinuria and/or hematuria only in rabbits, but this effect did not last more than 24 to 48 hr.Exposure of rats (10 male and 10 female) and rabbits (2 male and 2 female) to 400 ppm EGBEA for 4 hr/day, 5 days/wk over a 1-month period resulted in hemoglobinuria and/or hematuria (slight in rats, more pronounced in rabbits) from the second week of exposure onward.RBC counts and Hb concentrations were normal during the first 3 weeks, then decreased slightly in two of four rabbits, and severely in the two others.These latter two rabbits died during the fourth week.Administration of 100 ppm EGBEA for 4 hr/day, 5 days/wk over a 1 0 -month period to rats and rabbits of both sexes had no effect on hematologic parameters. # Dermal Exposure Percutaneous treatment by Truhaut et al. of New Zealand rabbits of both sexes with a single application of 1,500 mg/kg EGBEA resulted in RBC counts and Hb levels that were 20% to 25% of the control value (statistics not given).These values returned to normal after 8 to 14 days.Bartnik et al. applied a single dose of 260, 320, 375, or 500 mg EGBE/kg to the shaved dorsal skin of groups of three female rats; they also applied 200 mg/kg EGBE to the shaved dorsal skin of six female rats.Blood was collected retroorbitally six hr after dosing.Test animals were then sacrificed by carbon dioxide asphyxiation, and blood samples were taken immediately by cardiac puncture.Preliminary test results indicated that 500 mg EGBE/kg caused adverse effects such as an increase in mean cell volume, a lowered erythrocyte count and Hb level, and hemoglobinuria within 6 hr of dosing.No adverse effects were caused by 200 mg EGBE/kg.EGBE at doses of 260,320,375, and 500 mg/kg produced the effects described above in at least some animals in each group, but there was no discernible dose-response relationship.Bartnik et al. attributed this result to inherent biologic variation in percutaneous absorption and hemolytic susceptibility of erythrocytes, and to the small number of animals per group.Bartnik et al. also examined the effects of EGBE and BAA on human and rat erythrocytes.Human erythrocytes were isolated from the blood of healthy adult male donors (number unspecified) and rat erythrocytes were collected from four adult male Wistar rats.Under in vitro conditions, 175,200, 225, and 250 millimoles (mmol) EGBE/liter induced complete lysis of rat eiythrocytes, and200,225, and250 mmol EGBE/liter induced complete lysis of human erythrocytes.At a concentration of 3.75 to 7.5 mmol/liter, BAA caused complete lysis of rat erythrocytes but failed to cause lysis of human erythrocytes.These results indicate that the rat may be more susceptible than humans to the effects of EGBE (see Tables 4-4 and 4-5). # In Vitro Exposure Ghanayem examined the effect of EGBE and its metabolite BAA on whole blood collected by cardiac puncture from male F344 rats.The addition of 5 or 10 mM EGBE to whole blood exerted no effect on Hct levels and rat erythrocytes, whereas 20 mM EGBE caused a significant reduction in Hct along with significant hemolysis (P<0.05). The addition of 0.5 or 1 mM BAA to rat erythrocytes caused a time-and concentrationdependent increase in Hct followed by hemolysis, while adding 2 mM BAA caused a faster time-dependent increase in Hct.The Hct level reached its maximum after 2 hr followed by nearly complete hemolysis after 4 hr.Ghanayem also examined the effect of BAA (0.5, 1, 2,4, 8 mM) on human blood obtained from healthy young male and female volúnteos.No significant changes in Hct or hemolysis occurred at BAA concentrations of 4 mM and below.However, at 8 mM BAA there was a slight but significant increase in Hct (P0.05), followed by slight but significant hemolysis (P<0.05) of human eiythrocytes. # 4.3.2.S Summary of Hematologic Effects Early investigators demonstrated the hemolytic activity of EGBE in vitro.In later studies, adverse hematologic effects of EGBE were shown in a variety of species by various exposure routes (i.e., oral, inhalation, dermal).These effects included decreased RBC, Hb, and Hct levels [Werner et al.1943a,b;Carpenter et al.1956;Nagano et al.1979;Dodd et al.1983;Grant et al.1985;Tyl et al.1984;Bartnik et al.1987;; the responses were transitory and their severity was dose-dependent. In addition demonstrated that EGBE-induced hematotoxicity in rats is age-dependent, with older rats more susceptible than younger rats.In the study by Carpenter et al. ,exposure to EGBE vapors induced a transitory increase in RBC osmotic fragility in mice, rats, and monkeys.Although inhalation of EGBE vapors caused an increase in WBC levels , oral EGBE exposure reduced WBC levels in a dose-dependent manner .Exposure of rats and rabbits to EGBEA vapors caused slight hematuria and hemoglobinuria .Under in vitro conditions, 200,225, and 250 mmol EGBE/liter induced complete lysis of human erythrocytes .At a concentration of 3.75 to 7.5 mmol/liter, BAA caused complete lysis of rat eiythrocytes ; 8 mM BAA caused a slight but statistically significant lysis of human erythrocytes .Studies of the hematologic effects of EGBE and EGBEA are summarized in Table 4-6. # Reproductive Effects in Males A number of experimental animal studies have demonstrated that EGBE does not exert adverse effects on the male reproductive system. # Oral Administration In a study by Nagano et al. ,groups of five JCL-ICR male mice were treated orally with various doses of EGBE (500,1,000, or 2,000 mg/kg per day, 5 days/wk for 5 wk).The mice treated with 2,000 mg EGBE/kg died.The day after the final administration of EGBE, the remaining mice were sacrificed and dissected.Weight of the testes was not significantly affected by treatment with EGBE.Krasavage administered EGBE by gavage to groups of 10 male rats at doses of 0, 222,443, or 885 mg/kg per day, 5 days/wk for 6 wk.The animals were sacrificed at the end of the exposure period.Organs were removed, weighed, and examined histopathologically. No adverse effects on the testes were observed.Foster et al. exposed groups of six male Alpk/AP (Wistar-derived) rats to single oral doses (174, 434, or 8 6 8 mg/kg) of BAA, the metabolite of EGBE (see Section 4.2), to determine the initial target for testicular toxicity.Rats were sacrificed on days 1, 2, 4, and 14 after treatment.No testicular damage was induced by BAA at any dose for any length of exposure, but rats receiving the high dose of BAA did show evidence of hematuria throughout the study.The addition of 5 mM BAA to Sertoli male germ cell culture systems did not produce any specific changes in testicular cell populations. # Inhalation In an inhalation study by Doe , male Alpk/Ap Wistar-derived rats were exposed to 800 ppm EGBE for 3 hr; the rats were then observed throughout the next 14 days.The animals were sacrificed on day 15 and subjected to gross macroscopic postmortem examina tion, which included the weighing of the testes.EGBE had no effect on testicular weights. # Summary of Reproductive Effects in Males Studies using EGBE and BAA , the metabolite of EGBE (see Section 4.2), have demonstrated no adverse effects on the male reproductive system.No studies exist for EGBEA.However, because EGBEA would be metabolized to EGBE (see Section 4.2), it would also be expected to cause no reproductive effects. # Effects on the Female Reproductive System and the Embryo The following studies in animals have been conducted to investigate the effects of EGBE on the female reproductive system and the embryo. # Oral Administration Schuler et al. exposed CD-1 mice orally to 4,000 mg EGBE/kg once per day on g.d.7 through 14.This treatment resulted in 20% maternal mortality and in 77% viable litters, which differed significantly from 100% viability in the control group (P<0.05). # Inhalation In an inhalation study, Nelson et al. exposed Sprague-Dawley rats on g.d.7 through 15 to 150 or 200 ppm EGBE for 7 hr/day.The investigators had reduced the doses from 250 and 500 ppm EGBE because of maternal toxicity.Three of four nonpregnant rats exposed to 500 ppm EGBE for 6.5 hr died within 36 hr after termination of EGBE exposure; of three nonpregnant rats exposed to 250 ppm EGBE for 7 hr, one died within 18 hr after exposure ended, and a second died 2 days after exposure.Some hematuria was observed on the first day of exposure in the group exposed to 200 ppm EGBE.No other adverse effects were observed in the dams or the pups in either treatment group.The number of resorptions, fetal weights, and incidence of malformations did not differ from the controls. Tyl et al. When rats were exposed to 200 ppm EGBE, the number of viable implants (P<0.001) and the percentage of live fetuses (P<0.01) per litter were reduced relative to controls .However, treatment with EGBE resulted in no statistically significant increases in the incidence of external, visceral, skeletal, or total malformations.Evidence of retarded skeletal ossification was seen at 100 and 200 ppm EGBE.At 100 and 200 ppm EGBE, a significant increase (P<0.05) occurred in the number of litters containing one or more fetuses with unossified or poorly ossified skeletal elements. Significant reductions in maternal body weight, gravid uterine weight, and numbers of total implants and viable implants were noted at 200 ppm EGBE relative to controls (P<0.05). No statistically significant increases in the number of fetuses or litters with malformations were observed in any treatment group.Two significant variations were seen in rabbit fetuses.At 200 ppm EGBE, there was a significant reduction in unossified stemebrae and in rudimentary rib (P<0.05).The occurrence of unossified skeletal elements in both rats and rabbits was considered an indication of delayed development None of the observations indicated abnormal development in rats or rabbits exposed to EGBE in this study . # Dermal Exposure Hardin et al. applied EGBE to the skin of pregnant Sprague-Dawley rats to investigate its potential for developmental toxicity.Four daily doses of 106 mg EGBE (total daily dose of 424 mg) were applied to shaved interscapular skin of rats on g.d.7 through 16.No maternal, embryotoxic, fetotoxic, or teratogenic effects were detected in litters of the EGBE-exposed dams. # In Vitro The in vitro culture system of Yonemoto et al. was used by Rawlings et al. to study the mechanism of teratogenicity of EGBE.Conceptuses were explanted from pregnant Wistar-Porton rats at the embryonic age of 9.5 days and cultured for 48 hr with 2 or 5 mmol BAA/liter.At the end of the culture period, crown-rump length, head length, and yolk sac diameter were measured, and the degree of differentiation and development was evaluated by a morphological scoring system.BAA at the 5mM concentration had an adverse effect on all parameters except crown-rump length.BAA produced statistically significant reductions in somite number (P<0.01), head length (P<0.01), yolk sac diameter (P<0.05), and protein content of the embryo (P<0.05).No statistically significant reductions in growth parameters were seen at the 2-mM level.Irregularity of the neural suture line was seen in 29% of the embryos exposed to 5 mM BAA.BAA-exposed embryos also showed abnormal otic and somite development.None of the observations indicated abnormal development. # Summary of Reproductive Effects in Females The preceding studies demonstrated that EGBE administered by a variety of routes in a variety of species did not have teratogenic effects on litters of EGBE-exposed dams .At the maternal LD20 (lethal dose for 20% of the test animals), EGBE induced fetal death .BAA, the metabolite of EGBE (see Section 4.2), did not adversely affect fetal development in vitro . No studies are reported for EGBEA.However, because it would be metabolized to EGBE (see Section 4.2), it would also be expected to cause no effects on the female reproductive system and the embryo.Table 4-7 summarizes the studies of reproductive and develop mental effects of EGBE. # Carcinogenicity Prechronic carcinogenicity studies of EGBE are currently in progress . # Mutagenicity A limited number of studies concerning the potential mutagenicity of EGBE have been performed.Most of these involved tests with microorganisms or mammalian cell cultures in vitro.EGBE does not appear to be mutagenic.No data are available concerning the mutagenicity of EGBEA. EGBE was tested for mutagenic activity by using an assay of unscheduled DNA synthesis (UDS) in rat primary hepatocytes; total radioactivity was measured by scintillation counting .In this study, EGBE was tested at concentrations up to 0.1% of the culture medium for 2 hr.The results suggested that EGBE might be inhibiting UDS, but further testing is needed to confirm this possibility.McGregor also examined the ability of EGBE to induce point mutations in vitro.EGBE was not mutagenic at the HGPRT locus of Chinese hamster ovary (CHO) cells in either the presence or absence of rat S9 mix at concentrations up to 1 % of the culture medium for 5 hr, followed by a 7-day expression period.Data from the McGregor study are presented in Table 4-8. # Cytotoxicity The in vitro cytotoxicity of EGBE and BAA was studied using CHO cells .CHO cells were seeded into culture flasks, and after 4 to 5 hr, test material was added to the medium.

After 16 hr, the medium was renewed and the cells were allowed to grow in colonies for 6 to 7 days before counting.Cloning efficiency was used as an indication of cytotoxicity.Concentrations that allowed approximately 50% of the seeded cells to form colonies (EC50) were calculated.EGBE was cytotoxic (EC5 0 -0.05 mmol/ml or 6.9 mg/ml).The ECjq for BAA was 0.04 mmol/ml (5.3 mg/ml). Chinese hamster V79 cells display a specific form of cell-to-cell communication called metabolic cooperation, which is characterized by the exchange of molecules between cells through permeable junctions formed at sites of cell contact .The effects of EGBE on cell-to-cell communication in Chinese hamster V79 cells were demonstrated in two separate studies Loch-Caruso et al.1984].In both studies, EGBE was able to block metabolic cooperation in vitro.Each employer who manufactures, transports, packages, stores, or uses EGBE and EGBEA in any capacity should determine the potential for occupational exposure of any worker at or above the action level (one-half the REL). # ENVIRONMENTAL SAMPLING Environmental sampling for EGBE and EGBEA can be conducted by using NIOSH Method No.1403 and collecting a total air volume of 10 liters with a charcoal tube at a flow rate of 0.01 to 0.05 liter/min.Sampling can also be conducted by using OSHA Method No.83 and collecting a total air volume of 48 liters with a coconut charcoal shell tube at a flow rate of 0.1 liter/min . # ANALYTICAL METHODS Laboratory analysis for EGBE can be performed by NIOSH Method No.1403, which is described in detail in Appendix A; the quantitation limit of the analytical procedure is 2 ppm in 10 liters of air.NIOSH Method No.1403 may be adapted for EGBEA .The following steps should be taken to adapt Method No.1403 for EGBEA: (1) analytical conditions should be developed for capillary column gas chromatographic analysis, and (2 ) the limits of detection and quantitation should be evaluated at concentra tions below the proposed NIOSH REL.The recovery of EGBEA from charcoal should be studied to determine whether the analyte is adequately recovered (>75%).The capacity of the charcoal tube sampler should be checked to ensure that an adequate amount of analyte can be collected to allow quantitation at or below the proposed REL.Finally, the stability of the analyte on the charcoal tube sampler should be verified . Laboratory analysis for EGBE and EGBEA can also be performed by using OSHA Method No.83, which is described in detail in Appendix A. The quantitation limits of the analytical procedure are 0.031 ppm for EGBE and 0.024 ppm for EGBEA .Although the method states that the presence of a glycol ether should be confirmed by gas chromatog raphy/mass spectrometry (GC/MS), NIOSH recommends that all samples be analyzed by GC/MS because of the number of potential interferences present in the sample .To better define the potential interferences, NIOSH also recommends that bulk samples of the solutions containing EGBE/EGBEA be returned to the laboratory for analysis. To prevent potential contamination, these samples should be shipped separately.A material safety data sheet should also accompany each bulk sample returned to the laboratory. # MEDICAL MONITORING EGBE and EGBEA have been shown to have adverse effects on the central nervous, hematopoietic, and renal systems in humans and animals; furthermore, exposure to these glycol ethers may impair liver function.Preplacement and periodic medical examinations should therefore be instituted for workers who may be exposed to EGBE and EGBEA.Medical monitoring should include the following: - An initial medical examination.A complete medical history and examination will establish a baseline for further monitoring and detect any preexisting conditions that may place the exposed worker at increased risk.Special attention should be given to tests of the following systems and organs. -Blood and hematopoietic system.A complete blood count should be done. Because of adverse effects of EGBE and EGBEA on the blood and hematopoietic system, workers with blood diseases may be at increased risk from exposure to EGBE or EGBEA. -Skin.Because EGBE and EGBEA are readily absorbed through the skin, workers with chronic skin disease characterized by eczema or fissures may be at increased risk of absorption of these substances. -Liver.Although glycol ethers are not known as liver toxins in humans, the detoxification properties of this organ should place workers with impaired liver function under special consideration. -Kidneys.A urinalysis should be done to ascertain whether impaired renal function exists.Because of the importance of the kidneys in eliminating toxic substances, special consideration should be given to workers with impaired renal function who may be exposed to EGBE or EGBEA. -Central nervous system.The need for examinations of the central nervous system should be stressed. - Periodic medical examinations.The aforementioned medical examinations should be performed annually for all workers occupationally exposed to EGBE and EGBEA at or above the action levels, especially those who have the potential for significant skin exposure. # BIOLOGICAL MONITORING Biological monitoring may be a useful adjunct to environmental monitoring in assessing worker exposure to EGBE and EGBEA.Biological monitoring takes into account the influence of workload and percutaneous absorption. # Justification for Biological Monitoring Johanson et al. and Van Vlem described the uptake of EGBE by humans in experimental inhalation studies.The study that included different workloads in the ex perimental design demonstrated a linear relationship between workload and uptake of EGBE.A linear relationship was also found for exposure concentration and uptake. In vitro dermal absorption of EGBE has been shown in human abdominal skin , The rate of absorption for EGBE was 0.198 mg/cm2 ± 0.7.Bartnik et al. demonstrated in vitro dermal absorption of EGBE through forearm skin.In vivo studies in humans have also demonstrated uptake of EGBE through the skin.Johanson et al. compared the inhalation and dermal uptake rates of EGBE.Humans exposed by inhalation to 4 ppm (20 mg/m3) EGBE for 2 hr at 50 W of exercise had uptake similar to subjects with four fingers immersed in pure EGBE for 2 hr (see Section 4.2). Metabolism studies in animals (described in Section 4.2) demonstrated that EGBE is metabolized to its corresponding alkoxyacetic acid, BAA, which is excreted in the urine.This urinary metabolite has been shown to produce hematologic toxicity in rats .Thus measurement of this metabolite can be viewed as an indicator of potential health effects as well as an assessment of total uptake through inhalation and dermal absorption. Assessment of worker exposure to EGBE and EGBEA should include biological monitoring.Industrial hygiene measurements are used to assess the workroom concentrations, and the inhalation exposures may be measured with personal breathing zone samples.However, dermal absorption may be a principal route of exposure, and workload can dramatically affect the actual inhalation uptake of EGBE and EGBEA.Therefore, biological monitoring should be considered an additional technique to assess the total exposure of the worker. # Selection of Monitoring Medium Johanson et al. studied blood and expired air concentrations in subjects exposed to EGBE under controlled experimental conditions.Johanson concluded that the small concentrations of EGBE found in blood and expired air, and the rapid elimination of EGBE precluded the use of blood and expired air for biological monitoring. According to Johanson , the concentration of the alkoxyacetic acid BAA in the urine is the best indicator of exposure by all routes.The advantages of using the urinary alkoxyacetic acid for biological monitoring of EGBE and its acetate are as follows: - The acid metabolite BAA is not normally present in human urine. - The expected concentration for this metabolite at the proposed REL can be measured by the recommended analytical method (see Appendix C). - BAA exerts hematologic toxicity and may reflect the concentration of the "active agent" at the target sites. -The elimination half-life of EGBE (4 to 7 hr) reflects the integrated exposure over a workday . -Collection of urine samples is a noninvasive procedure. # Limitations of Biological Monitoring Limitations and possible sources of error exist in the biological monitoring of the acid metabolite of EGBE and EGBEA.Biological monitoring primarily assesses uptake and not exposure concentration.In addition to the lack of well designed field evaluations of workers exposed to EGBE and EGBEA, the following factors limit the use of biological monitoring to assess exposure : - Variability in uptake through inhalation caused by workload-dependent uptake - Intraindividual variations in excretion rates of metabolites, possibly caused by fluid intake or the effects of alcohol consumption - Interindividual variations in excretion rates of metabolites, possibly caused by differences in body fat, sex, personal habits (e.g., smoking, dietary factors, ethanol consumption), and coexposure to other chemicals Johanson concluded that monitoring the acid metabolite in the urine is appropriate even if the uptake or metabolism is influenced by other factors.The concentration of BAA in the urine may not be linearly correlated to the absorbed dose, but it may be well correlated to the concentration at the target sites and thus related to the potential toxicity. # Correlation of EGBE Uptake with BAA Excretion BAA was found in the urine of male subjects exposed to EGBE during light physical exercise .The authors concluded that BAA in urine is suitable for biological monitoring of humans exposed to EGBE.However, because of the large variability of BAA concentrations in individuals, the collection of several urine specimens was suggested. # Assessment of Biological Monitoring Results in Various Studies Johanson conducted physiologically-based pharmacokinetic modeling of EGBE inhalation exposure.The model, based on 20 ppm exposures with exercise at 50 W for 2 hr, agreed well with experimental studies conducted in humans .The model predicted the potential for large increases in EGBE uptake with increased workload. In the presence of 1 % blood alcohol (ethanol), the model predicts increased blood concentra tions of EGBE and presumably decreased BAA concentrations in the urine.This finding agrees with previous animal research and may occur because of competitive inhibition of EGBE metabolism by alcohol dehydrogenase, an enzyme involved in the metabolism of ethanol and ethylene glycol ethers.The model also predicted the even distribution of EGBE to body compartments based on water content and linear exposure kinetics at occupationally relevant exposures. Johanson et al. studied the dermal absorption of EGBE in five healthy males who had also participated in inhalation studies .The subjects kept four fingers immersed for 2 hr in a container of undiluted EGBE, which was placed in a ventilated area to eliminate exposure via inhalation.Finger volume, skinfold thickness, and finger diameter were determined for each subject A series of 12 experiments was conducted.At the conclusion of the exposure period, both hands were washed with soap and water. Arterialized capillary blood samples were collected from the unexposed hand before, during, and up to 4 hr after the EGBE exposure, and analyzed for EGBE by gas chromatography using an electron-capture detector.Urine samples were collected as described in Section 4.2 for 24 hr and analyzed for BAA by a high-sensitivity, gas chromatography method developed for this study. The authors concluded that detection of EGBE in the blood of all subjects indicated systemic in vivo dermal absorption.The total percutaneous uptake averaged 384 ^mol/subject with a range of 127 to 1,891 pmol/subject.The subject that showed 1,891 |jmol uptake was included even though two separate repeat doses did not confirm the high uptake.The next highest uptake was 743 pmol/subject.The uptake rate averaged 20 fimol/min with a range of 7.1 to 95.8, including the unconfirmed highest uptake.The next highest uptake rate was 38.5 jimol/min.The urinary excretion rate of BAA increased during the first hour after exposure ended and reached a peak 3 hr after exposure.The excretion rate then declined with an average BAA half-life of 3.1 hr.The accumulated excretion of BAA averaged 94.3 (imol and ranged from 8.7 to 313 |itnol, corresponding to an average percutaneous uptake of 17% with a range of 2.5% to 39%.The relationship between EGBE uptake and total 24-hr BAA excretion was linear (excretion -0.17 x uptake, r - 0.78). The authors noted that the wide variations in uptake rates of EGBE might have been caused by individual differences in the stratum comeum, but they acknowledged that other factors may have also been important.They stated that the uptake rate of EGBE was comparable to that obtained in vitro using human skin .The authors concluded that their study clearly showed that EGBE is absorbed through human skin in vivo and enters the systemic circulation.A comparison of the dermal uptake rate (1 to 16 pmol/min for four fingers exposed to liquid EGBE for 2 hr) with the inhalation uptake rate ( 8 to 14 mol/min in subjects exposed to 20 ppm for 2 hr at 50 W of exercise) suggested that uptake of EGBE by these two exposure routes was approximately equivalent The authors further concluded that both skin and respiratory uptake should be considered when workers are exposed to EGBE.They cautioned that their comparison of uptake rates for dermal and inhalation exposures be used with care because of different uptake rates with different skin areas, interindividual variation in dermal penetration of EGBE, use of other solvents in the workplace, and the small number of subjects used in this study . Studies done by Johanson and Femstrom on the dermal penetration of aqueous solutions of EGBE in guinea pigs may have some significance to human dermal uptake.Aqueous solutions of EGBE between 20% and 80% were more readily absorbed through the skin of guinea pigs than pure EGBE or solutions of less than 20% EGBE.The high water-solubility of EGBE may therefore make it possible for EGBE vapor to be absorbed through wet human skin at a faster rate than pure liquid EGBE. Van Vlem conducted two studies evaluating human exposure to EGBE using the methods of Groeseneken et al. .The first was an experimental laboratory exposure of three male subjects to two levels of EGBE at rest and with exercise.Retention, uptake, and elimination of EGBE and BAA were studied.The second study was an evaluation of occupational exposure of five females performing silk-screening operations ]. In the first study, three male subjects were exposed by face mask to 120 mg/m (25.2 ppm) EGBE at rest, 60 mg/m3 (12.6 ppm) EGBE at rest, and 60 mg/m3 (12.6 ppm) EGBE at 30 W of exercise, 50 min/hr for 4 hr.The experimental design was similar to that of Groeseneken et al. .It is important to note that these exposures were by face mask, in contrast to inhalation chamber exposures conducted by Johanson et al. .Retention averaged 67.0%, 68.9%, and 77.6% for the three exposure conditions (difference not significant). Respiratory elimination of EGBE averaged 0.66% to 0.69% at rest and 0.24% at 30 W. The average percentage of BAA recovered was 27%, 27%, and 13.6% of the absorbed EGBE for the three exposure conditions; wide individual variation was observed.Table 5-1 summarizes the uptake, respiratory elimination, BAA half-life, and total BAA excreted in 62 hr. These results generally agree with those from other Groeseneken studies that examined different ethylene glycol ethers and different exposure concentrations and workloads in the group of five women studied by Veulemans et al. at a silk screening operation. Half-shift personal monitoring was conducted for 5 days.Following a 12-day halt in production, monitoring continued for an additional 7 days.Mean weekly exposures to EGBE averaged 0.65 ppm (3.1 mg/m3). BAA was measured preshift and postshift for each of the work days as described by Veulemans et al. .The urine showed higher postshift concentrations of BAA in all cases compared with preshift concentrations.Preshift concentrations ranged from less than 1 to 5.The author dismissed the value of BAA as an exposure monitor because of the unexplained variability of urinary BAA concentrations, particularly with exercise.The use of three subjects per group does not impart much statistical power to studies of this type, which have been shown to have large individual variability in response.In addition, the author dismissed the value of measuring BAA in urine to monitor occupational exposure.In this study, exposures were very low and uniform, so calculation of a dose-response curve would be difficult The author proposed that BAA may be a good monitor for toxic effects because it exerts adverse hemolytic effects. showed a much lower urinary excretion of BAA than seen by Johanson et al. .The half-lives are remarkably close considering the diversity of exposure routes (inhalation and dermal), exposure conditions (experimental and workplace), ex posure concentrations (0.65 to 25.2 ppm), and sex (male experimental and female work site). If EGBE can be absorbed through wet skin, then exposure-chamber inhalation studies at 50 W continuous exercise for 2 hr might be expected to show greater uptake of EGBE and greater excretion of BAA than inhalation exposures by face mask.Examination of Table 5-2 shows that inhalation chamber exposure to 20 ppm EGBE for 2 hr at 50 W of exercise produced a total uptake of 143 mg EGBE, and a total excretion of 65.5 mg BAA.Assuming linear kinetics, exposure for 4 hr would be expected to produce a corresponding uptake of 284 mg EGBE and a total excretion of 131 mg BAA.These projected values are much higher than those seen for face mask exposure for 200 min to 25.2 ppm EGBE at rest (122 mg uptake, 35.7 mg BAA excretion) and for exposure for 4 hr to 12.6 ppm EGBE at 30 W (132 mg uptake, 19.6 mg BAA excreted).Although exercise increases pulmonary ventilation and uptake, the higher values seen in the chamber study are consistent with the hypothesis that EGBE vapor can be absorbed through wet slán. Uptake is based on the molecular weight (mw) of 1182 g for EGBE and represents total uptake.

Excretion is based on the molecular weight of 132 g for BAA and represents the total amount of BAA excreted during the experiment ^Urine BAA data were estimated from plots in the reference and represent urine specimens collected at the end of exposure.Urine data were estimated from a plot in the cited reference and represent urine specimens collected following 3 days of exposure.Urine data were corrected to a specific gravity of 1.016.Urine BAA data were estimated from a plot in the cited reference and represent a urine specimen collected at the end of exposure.®*Urine BAA data were estimated from a plot in the cited reference and reflect the concentrations in urine samples collected at the end of exposure. # Method for Analyzing Urinary BAA A variety of methods have been developed for the analysis of BAA in human urine.The gas chromatographic procedures employed are based on either fluoranhydride derivatization following the extraction of the acid tetrabutylammonium ion-pair .Groeseneken et al. later developed a method that combined the best attributes of the two basic models.Detailed descriptions of the above methods are presented in Appendix C. # Summary BAA has been shown to produce hematotoxic effects noted for EGBE and EGBEA.Because EGBE can be absorbed through the skin , monitoring of BAA may serve as a measure of EGBE uptake and of potential adverse health effects. BAA may be analyzed by a variety of sensitive and specific methods.The recent method by Groeseneken etal. has sufficient sensitivity to monitor excretion of this metabolite after EGBE or EGBEA exposure at the REL. Exposure of male subjects to EGBE vapor in an inhalation chamber during light physical exercise resulted in 57% retention of inspired EGBE .BAA was rapidly excreted in urine with an elimination half-life of 5.8 hr.Excretion rates varied widely among individuals.Percutaneous exposure of male subjects to EGBE resulted in uptake of EGBE, with BAA excreted in the urine .A comparison of dermal and inhalation uptake suggested that both should be considered when workers are potentially exposed to EGBE . Van Vlem exposed male subjects to EGBE by face mask both at rest and during exercise.BAA was excreted in the urine with an elimination half-life of 6 to 9 hr.Less uptake and elimination were found in this study using mask inhalation exposures compared with the inhalation chamber studies of Johanson et al. performed during light work.This finding provides some evidence for the possible absorption of EGBE vapor through wet skin. Insufficient information is currently available to construct statistically sound guidelines for determining the concentration of BAA in urine that would correlate with an airborne exposure to EGBE or EGBEA.However, biological monitoring should be considered because the metabolite measured is also an indicator of potential toxicity.General guidelines for biological monitoring of EGBE and EGBEA are presented in Appendix D. OSHA adopted the current Federal standard for occupational exposure to EGBE (there is no standard for EGBEA) in 1989.At that time.OSHA lowered the permissible exposure limit (PEL) for EGBE from 50 ppm (240 mg/m ) to 25 ppm (120 mg/m3) as an 8 -hr TWA with a skin notation .OSHA considers the PEL of 25 ppm to reduce the risk of irritant, hematologic, and other systemic effects because this limit is below the concentration at which these toxic effects are observed in animals and humans.This lower limit also prevents the discomfort experienced by workers at concentrations of 40 ppm. In 1946, ACGIH established a maximum allowable concentration (m.a.c.)of 200 ppm for EGBE .Although the value remained unchanged, the term "threshold limit value" (TLV®) was substituted for m.a.c.in 1948.ACGIH lowered the TLV for EGBE from 200 to 50 ppm in 1961 on the basis of a study by Carpenter et al. .These investigators concluded that humans exposed to single 8 -hr exposures of 1 0 0 and 2 0 0 ppm EGBE suffered discomfort and mild irritation . In 1968, the notation "skin" (indicating the potential for skin absorption of toxic amounts of the compound) was added to the TLV for EGBE.In 1981, the ACGIH adopted a TLV of 25 ppm EGBE with a short-term exposure limit (STEL) of 75 ppm.However, the STEL was eliminated in 1987 .The TLV was lowered because of adverse hematologic effects observed in laboratory animals .Exposure to 62 ppm EGBE increased the osmotic fragility of rat erythrocytes, and exposure to 32 ppm EGBE exerted no effect.The ACGIH deemed it prudent to limit chemical exposures to concentrations below those found to cause blood changes in experimental animals . The principal human health effects attributed to EGBE and EGBEA exposure involve the central nervous system, the blood and hematopoietic system, and the kidneys.No evidence from animal studies indicates that EGBE or EGBEA causes adverse reproductive or developmental effects.Summaries of the adverse effects of EGBE and EGBEA on the hematopoietic system are presented in Table 7-1. # CORRELATION OF EXPOSURE AND EFFECTS # EGBE # Studies In Humans Rambourg-Schepens et al. reported hemoglobinuria and erythropenia in a woman who had ingested 250 to 500 ml of a cleaning solution containing 12% EGBE.Gijsenbergh et al. reported a suicide attempt in which a woman ingested a window cleaning agent containing an unknown amount of EGBE.Upon admittance to the hospital, the woman was comatose and suffering from hypotension.Severe metabolic acidosis followed.The patient recovered after forced diuresis and hemodialysis.Human volunteers exposed to 98 to 200 ppm EGBE for 4 to 8 hr reported nasal and ocular irritation and disturbed taste ; no abnormalities were detected in blood pressure, pulse rate, erythrocytic fragility, urinary glucose, or albumin.However, increased osmotic fragility was found in vitro with human erythrocytes.In vitro, EGBE (200,225, and 250 mmol/liter) induced complete lysis of human erythrocytes, whereas 3.75 and 7.5 mmol BAA/liter failed to cause lysis of human erythrocytes .Ghanayem also examined the in vitro effect of BAA on human blood obtained from healthy young male and female volunteers.At 8 mM BAA, there was a slight but significant increase in Hct (P<0.05) followed by slight but significant hemolysis (P<!0.05) of human erythrocytes.No other information is available on the toxic effects of EGBE in humans. # Studies In Animals Data obtained from studies in animals indicate that EGBE and EGBEA do not cause adverse reproductive or developmental effects .However, these compounds do adversely affect the blood and hematopoietic system in animals (see Section 4.3) . A decrease in WBCs, RBCs and Hb, and an increase in MCV, reticulocytes, and MCHb were noted in male rats treated by gavage with 500 or 1,000 mg EGBE/kg per day for 4 days .RBC counts were decreased in male mice treated by gavage with 500, 1,000,2,000, or 4,000 mg EGBE/kg per day, 5 days/wk for 5 wk ; no effects were noted at 62.5,125, or 250 mg/kg per day. demonstrated that adult rats (9 to 13 wk old) were more susceptible to EGBE-induced hematotoxicity than young rats (4 to 5 wk old). Increased numbers of circulating immature granulocytes, reticulocytes, and RBCs, and increased Hct were observed in rats exposed by inhalation to 320 ppm EGBE for 7 hr/day, 5 days/wk for 5 wk . Inhalation studies by Carpenter et al. showed increased osmotic fragility in rats at 54 ppm EGBE, a transitory increase in WBCs and a decrease in Hct in dogs at 100 ppm, and a transitory increase in osmotic fragility and RBCs in monkeys at 100 ppm. Inhalation exposure to 8 6 or 245 ppm EGBE for 6 hr/day for 9 days caused increased numbers of lymphocytes in male rats, and decreased Hb and MCHb and increased Hct and MCV in female rats; no effects were noted at 20 ppm .The effect of EGBE on the hematopoietic system was also assessed by the same investigators in a chronic study of rats exposed to EGBE for 7 hr/day, 5 days/wk for 90 days .No effects were observed at 5 or 25 ppm EGBE.At 77 ppm EGBE, male rats had decreased RBCs, and female rats had decreased RBCs and Hb and increased MCHb. A decrease in RBCs and MCHC, and an increase in MCV and MCHb were noted in rats exposed to 100 or 200 ppm EGBE for 6 hr/day on g.d.6 to 15, whereas no adverse effects were noted at 25 or 50 ppm .The same study showed no effects on the hematopoietic systems of rabbits exposed to 25,50,100, or 200 ppm EGBE for 6 hr/day on g.d.6 to 18. # Basis for Selection of No Observable Adverse Effect Level (NOAEL) Acute toxicity data for EGBE (see Chapter 4, Tables 4-1 and 4 -2) indicate that CNS, kidney, and liver effects occur at higher exposure concentrations than hematotoxic effects.In the Carpenter et al. study, early death in rats exposed to 2,400 and 2,500 mg EGBE/kg was attributed to narcotic effects, and delayed death was attributed to lung and kidney damage.However, in the same study, increases in osmotic fragility occurred at the lower concentrations of 62 and 54 ppm EGBE (see Table 7-1).CNS, kidney, and liver effects occur at higher EGBE exposures than hematotoxic effects.Therefore, limiting exposures to prevent hematotoxic effects will also prevent CNS, kidney, and liver effects. Table 7-1 presents hematotoxic effects resulting from exposure to EGBE.These data include the lowest observable adverse effect level (LOAEL) for mice (500 mg/kg), rats (54 ppm), and dogs and monkeys (100 ppm).In the study by Tyl et al. ,no effects on rabbits were noted at any concentration tested.Thus it appears that on the basis of available data, the rat is the most sensitive species. Data presented in Section 4.3 (see demonstrate that the rat is more susceptible than humans to the hematotoxic effects of EGBE and its metabolite BAA .Whereas 175 mmol EGBE/liter caused complete lysis of rat erythrocytes, 200 mmol EGBE/liter caused complete lysis of human erythrocytes , In the Ghanayem study, 20 mM EGBE caused significant hemolysis of rat erythrocytes.In vitro, 0.5 to 8 mM BAA caused complete lysis of rat erythrocytes.With human erythrocytes in vitro, 8 mM BAA caused a slight but significant increase in Hct (P<,0.05) followed by slight but significant hemolysis (P£0.05) .Because there is a lack of adequate human data and because the rat is the animal species most sensitive to EGBE, it is reasonable to use the rat NOAEL to extrapolate an equivalent dose for humans. The data that demonstrate adverse effects on the blood and hematopoietic system, and the LOAELs and NOAELs presented in Table 7-1 indicate that 50 ppm is the highest NOAEL in rats that is also lower than the lowest LOAEL in rats .NIOSH therefore deems it appropriate to use 50 ppm as the NOAEL for EGBE in rats and to use the body weights of rats studied by Tyl et al. for calculating the daily NOAEL for rats and extrapolating an equivalent dose for humans. # EGBEA Few data are available on the toxicity of EGBEA.Transient hematuria and hemoglobinuria were noted in rabbits exposed by inhalation for 4 hr to 400 ppm EGBEA .The toxic effects of EGBEA are likely to be similar to those caused by EGBE as a result of the metabolism of EGBEA to EGBE (see Section 4.2 for the analogy to EGEEA, EGEE, and EAA).Therefore, it is reasonable to use NOAELs for EGBE to extrapolate the NOAEL for EGBEA. # BASIS FOR THE RECOMMENDED STANDARD FOR EGBE AND EGBEA A limited number of studies describe the effects of EGBE exposure on humans.The following toxic effects have been reported in humans exposed by inhalation to 1 0 0 to 200 ppm EGBE: ocular and nasal irritation, disturbed taste, vomiting, headache, and belching .In separate incidents, two women attempted suicide by ingesting window cleaners containing EGBE .Their symptoms included hemoglobinuria, erythropenia, and hypotension.Both women recovered fully. Experimental results indicate that rats are more susceptible than humans to the hemolytic effects of EGBE and BAA.When rats and men were exposed simultaneously to 200 ppm EGBE, osmotic fragility of rat erythrocytes increased appreciably, but that of human erythrocytes did not .The same study revealed that human erythrocytes have increased osmotic fragility in vitro.Therefore, the osmotic fragility of human erythrocytes would be expected to increase after inhalation of EGBE at concentra tions above 200 ppm.Later investigators demonstrated that in vitro lysis of human erythrocytes requires higher concentrations of EGBE and BAA than lysis of rat erythrocytes . Data obtained from animal studies indicate that EGBE and EGBEA do not cause adverse reproductive or developmental effects .Adult rats appear to be more susceptible to EGBE-induced hematotoxicity than young rats .No significant hematologic effects were observed in young rats receiving 125 mg EGBE/kg, but significant decreases in RBCs, Hct, and Hb were detected in adult rats receiving the same dose of EGBE. Limited data exist to characterize the effects of EGBE on human erythrocytes; however, studies in animals clearly demonstrate that EGBE adversely affects the hematopoietic system and that these effects are age-dependent.Because the rat appears to be more sensitive to hematologic effects than humans, NIOSH deems it appropriate to base the REL on animal data in the absence of sufficient human data.Data from the Tyl et al. study (Table 7-1) were used to determine the human dose corresponding to a 50-ppm NOAEL in rats. No mechanistic models exist to describe the relationship of hematotoxicity to exposure; only empirical models are available to use in a quantitative risk assessment (QRA).Because a threshold is assumed to exist for hematotoxicity, a QRA model is inappropriate since such models assume a no-threshold effect.Therefore, the following method was used to deter mine the REL for EGBE. Both humans and rats were assumed to retain 100% of inhaled EGBE.The retained dose (44.9 mg/kg per day) for rats exposed at the NOAEL (50 ppm ) was calculated by using the inhalation rate and the average body weight of the rats (see Table 7-2): < / 3 v (0.161 m3/day x 0.25 day) , - 241.5 mg/m x ---------¿215 kg = mg/kg per day That dose was converted to an equivalent exposure concentration for humans by assuming a 70-kg body weight and an inhalation rate of 10 m3 in an 8 -hr workday : 44.9 mg/kg per day x 70 kg ". . ,3 . . , , ,-----------=314 mg/m (equivalent daily exposure for humans) 1 0 m /day The adverse hematologic effects observed are reversible , and the available data indicate that humans are less sensitive than *The values in this equation were rounded to obtain 44.9.rats to the hematotoxic effects of EGBE .In consideration of this interspecies variation, an uncertainty factor was not deemed appropriate.In consideration of potential intraspecies variability, an uncertainty factor of 1 0 was applied to the concentration calculated as the human equivalent to the NOAEL for rats.The resulting concentration was converted to parts per million: 314 mg/m x 24.45 _ 1 0 # ppm On the basis of these calculations, NIOSH recommends that occupational exposure to EGBE be limited to a TWA of 5 ppm for up to a 10-hr workshift and a 40-hr workweek. Because any effects of EGBEA would be likely to occur after it is metabolized to EGBE, the same exposure limit is recommended for EGBEA.Both EGBE and EGBEA can be absorbed percutaneously [Dugard et al.1984;; thus skin and eye contact should be avoided through the use of good work practices and personal protective clothing and equipment.On November 21, 1983, OSHA promulgated an occupational safety and health standard entitled "Hazard Communication."Under the provisions of this standard (29 CFR 1910(29 CFR .1200, employers in the manufacturing sector (i.e., SIC Codes 20 through 39) must establish a comprehensive hazard communication program that includes, at a minimum, container labeling, material safety data sheets (MSDSs), and a worker training program.The hazard communication program is to be written and made available to workers and their designated representatives.Chemical manufacturers, importers, and distributors are required to ensure that containers of hazardous chemicals leaving their workplaces are labeled, tagged, or marked to show the identity of the chemical, appropriate hazard warnings, and the name and address of the manufacturer or other responsible party.Employers must ensure that labels on incoming containers of hazardous chemicals are not removed or defaced unless they are immediately replaced with other labels containing the required information. Each container in the workplace must be prominently labeled, tagged, or marked to show the identity of any hazardous chemical it contains and the hazard warnings appropriate for worker protection.If a work area has a number of stationary containers that have similar contents and hazards, the employer may post hazard signs or placards rather than labeling each container.Employers may use various types of standard operating procedures, process sheets, batch tickets, or other written materials as substitutes for individual container labels on stationary process equipment.However, these written materials must contain the same information that is required on the labels and must be readily accessible to workers in the work areas.Pipes or piping systems are exempted altogether from the OSHA labeling requirements, although NIOSH recommends that filler ports and outlets be labeled.In addition, NIOSH recommends that a system be set up to ensure that pipes containing hazardous materials are identified to avoid accidental cutting and discharge of their contents. Employers are not required to label portable containers holding hazardous chemicals that have been transferred from labeled containers and that are intended only for the immediate use of the worker who performs the transfer.

According to the OSHA definition of "immediate use," the container must be under the control of the worker performing the transfer and must be used only during the workshift in which the chemicals are transferred. The OSHA hazard communication standard requires chemical manufacturers and importers to develop an MSDS for each hazardous chemical they produce or import.Employers in the manufacturing sector (which includes paint and allied coating products) are required to obtain or develop an MSDS for each hazardous chemical used in the workplace.The MSDS is required to provide information such as the chemical and common names for the hazardous chemical.For hazardous chemical mixtures, the MSDS must list each hazardous component that constitutes 1% or more of the mixture.Any chemical that is determined to be a carcinogen must be listed if it is present in quantities of 0.1 % or greater.Ingredients present in concentrations of less than 1 % must also be listed if there is evidence that the PEL may be exceeded or if it could present a health hazard in those concentrations.Additional information on the MSDS must include the physical and chemical characteristics of the hazardous chemical, known acute and chronic health effects, precautionary measures, and emergency and first aid procedures.The NIOSH publication entitled A Recommended Standard-An Identification System f o r O ccupationally Hazardous M aterials can be used as a guide when preparing the MSDS.Required information can be recorded on the MSDS shown in Appendix B or on a similar form.Workers should also be trained in methods for detecting the presence or release of hazardous chemicals (e.g., monitoring conducted by the employer, continuous monitoring devices, visual appearance or odor of hazardous chemicals when released, etc.).Training should include information about measures workers can take to protect themselves from exposure to hazardous chemicals (e.g., the use of appropriate work practices, emergency procedures, and personal protective equipment). # WORK PRACTICES # Worker Isolation If feasible, workers should be isolated from direct contact with the work environment by the use of automated equipment operated from a closed control booth or room.The control room should be maintained at a positive pressure so that air flows out of rather than into the room.However, when workers must perform process checks, adjustments, maintenance, or other related operations in work areas where EGBE or EGBEA is present, personal protective clothing and equipment may be necessary, depending on exposure concentrations and the potential for dermal contact. # Storage and Handling Containers of EGBE and EGBEA should be stored in a cool, dry, well ventilated location away from any area containing a fire hazard.Outside or detached storage is preferred.EGBE and EGBEA should be isolated from materials with which they are incompatible; contact with strong oxidizing agents may cause fires and explosions.Containers of solvents, including those that contain EGBG and EGBEA, should be tightly covered at all times except when material is transferred.Working amounts of these solvents should be stored in containers that ( 1) hold no more than 5 gal, (2) have spring-closing lids and spout covers, and ( 3) are designed to safely relieve internal pressure in case of fire.Because small amounts of residue may remain and present a fire hazard, containers that have held solvents should be thoroughly cleaned with steam and then drained and dried before reuse.Fittings should not be struck with tools or other hard objects that may cause sparks.Special spark-resistant tools of nonferrous materials should be used where flammable gases, highly volatile liquids, or other explosive substances are used or stored .In addition, all sources of ignition such as smoking and open heaters should be prohibited except in specified areas.Fire hazards around tank trucks and cars can be reduced by keeping motors turned off during loading or unloading operations.Specific OSHA requirements for the storage and handling of flammable and combustible liquids are given in 29 CFR 1910.106. # Sanitation and Hygiene The preparation, storage, or consumption of food should not be permitted in areas where there is exposure to EGBE and EGBEA.The employer should make handwashing facilities available and encourage the workers to use them before eating, smoking, using the toilet, or leaving the work site.Tools and protective clothing and equipment should be cleaned as needed to maintain sanitary conditions.Toxic wastes should be collected and disposed of in a manner that is not hazardous to workers or the environment.Vacuum pickup or wet mopping should be used to clean the work area at the end of each workshift or more frequently if needed to maintain good housekeeping practices.Collected wastes should be placed in sealed containers that are labeled as to their contents.Cleanup and disposal should be conducted in a manner that enables workers to avoid contact with the waste.Tobacco products should not be carried uncovered, smoked, or chewed in work areas.Workers should be provided with and advised to use facilities for showering and changing clothes at the end of each workshift.Work areas should be kept free of flammable debris.Flammable work materials (rags, solvents, etc.)should be stored in approved safety cans. # Spills and Waste Disposal Procedures for decontamination and waste disposal should be established for materials or equipment contaminated with EGBE and EGBEA.The following procedures are recom mended in the event of an EGBE or EGBEA spill : - Exclude persons not wearing protective clothing and equipment from areas of spills or leaks until cleanup has been completed. -Remove all ignition sources. - Ventilate the area of a spill or leak. - Absorb small spills on paper towels.Allow the vapors to evaporate in a suitable place such as a fume hood, allowing sufficient time for them to clear the hood ductwork.Bum the paper towels in a suitable location away from combustible materials. -Absorb large quantities with sand or other noncombustible absorbent material and atomize the contaminated material in a suitable combustion chamber. -Collect contaminated waste and place in sealed containers for disposal in accord ance with existing regulations of the U.S. Environmental Protection Agency and the U.S. Department of Transportation.State and local regulations may supersede Federal regulations if they are more restrictive. # LABELING AND POSTING In accordance with 29 CFR1910.1200 (Hazard Communication), workers must be informed of chemical exposure hazards, of their potential adverse health effects, and of methods to protect themselves.Labels and signs also provide an initial warning to other workers who may not normally work near processes involving hazardous chemicals such as EGBE and EGBEA.Depending on the process, warning signs may state a need to wear eye protection or a respirator, or they may be used to limit entry to an area without protective equipment For transient nonproduction work, it may be necessary to display warning signs at the work site to inform other workers of the hazards. All labels and warning signs should be printed in both English and the predominant language of workers who do not read English.Workers who cannot read labels or posted signs should be identified so that they may receive information about hazardous areas and be informed of the instructions printed on labels and signs.Airborne concentrations of EGBE and EGBEA can be most effectively controlled at the source of contamination by enclosure of the operation and use of local exhaust ventilation.Enclosures, exhaust hoods, and ductwork should be kept in good repair so that designed airflows are maintained.Measurements of variables such as capture velocity, duct velocity, or static pressure should be made at least semiannually, and preferably monthly, to demonstrate the effectiveness of the mechanical ventilation system.The use of continuous airflow indicators (such as water or oil manometers marked to indicate acceptable airflow) is recommended.The effectiveness of the system should also be measured as soon as possible after any change in production, process, or control that may result in any increase in airborne contaminants. It is essential that any scheme for exhausting air from a work area also provide a positive means of bringing in at least an equal volume of air from the outside, conditioning it, and evenly distributing it throughout the exhausted area.The ventilation system should be designed and operated to prevent the accumulation or recirculation of airborne contaminants in the workplace.To evaluate the use of these materials with EGBEA, users should consult the best available performance data and manufacturer's recommendations.Significant differences have been demonstrated in the chemical resistance of generically similar PPE materials (e.g., butyl) produced by different manufacturers .In addition, the chemical resistance of a mixture may be significantly different from that of any of its neat components .Users should therefore test the candidate material with the chemicals to be used. Any chemical-resistant clothing that is used should be periodically evaluated to determine its effectiveness in preventing dermal contact Safety showers and eye wash stations should be located close to operations that involve EGBE and EGBEA. Splash-proof chemical safety goggles or face shields (20 to 30 cm minimum) should be worn during any operation in which a solvent caustic, or other toxic substance may be splashed into the eyes. In addition to the possible need for wearing protective outer apparel (e.g., aprons, encap sulating suits), workers should wear work uniforms, coveralls, or similar full-body coverings that are laundered each day.Employers should provide lockers or other closed areas to store work and street clothing separately.Employers should collect work clothing at the end of each work shift and provide for its laundering.Laundry personnel should be informed about the potential hazards of handling contaminated clothing and instructed about measures to minimize their health risk. Employers should ensure that protective clothing is inspected and maintained to preserve its effectiveness.Clothing should be kept reasonably free of oil or grease. Workers and persons responsible for worker health and safety should be informed that protective clothing may interfere with the body's heat dissipation, especially during hot weather or in hot industries or work situations (e.g., confined spaces).Additional monitoring is required to prevent heat-related illness when protective clothing is worn under these conditions. # Respiratory Protection Engineering controls should be the primary method used to control exposure to airborne contaminants.Respiratory protection should be used by workers only in the following circumstances: - During the development, installation, or testing of required engineering controls - When engineering controls are not feasible to control exposure to airborne con taminants during short-duration operations such as maintenance and repair # During emergencies Respiratory protection is the least preferred method of controlling worker exposures and should not be used routinely to prevent or minimize exposures.When respirators are used, employers should institute a complete respiratory protection program that includes worker training at regular intervals in the use and limitations of respirators, routine air monitoring, and maintenance, inspection, cleaning, and evaluation of the respirator.Any respiratory protection program must, at a minimum, meet the requirements of 29 CFR 1910.134. Respirators should be used in accordance with the manufacturer's instructions.Each respirator user should be fit-tested and, if possible, receive a quantitative, on-the-job evaluation of his or her respiratory protection factor to confirm the protection factor assumed for that class of respirator.For additional information on the use of respiratory protection, refer to the NIOSH Guide to Ind ustria l Respiratory P rotection and NIOSH Respirator Decision Logic . Selection of the appropriate respirator depends on the types of glycol ethers and their concentrations in the worker's breathing zone.Before a respirator can be selected, an assessment of the work environment is necessary to determine the concentrations of EGBE and EGBEA and other contaminants that may be present.Respirator types should be selected in accordance with the most recent edition of the NIOSH Respirator Decision Logic . The actual respirator selection should be made by a qualified individual, taking into account specific use conditions, including the interaction of contaminants with the filter medium, space restrictions caused by the work location, and the use of any required face and eye protective devices.Respirator selection tables are presented in Chapter 1. # CHEMICAL SUBSTITUTION The substitution of less hazardous materials can be an important measure for reducing worker exposure to hazardous materials. # EXPOSURE MONITORING An occupational health program designed to protect workers from adverse effects caused by exposure to EGBE and EGBEA should include the means for thoroughly identifying all potential hazards.Routine environmental sampling as an indicator of worker exposure is an important part of this program, as it provides a means of assessing the effectiveness of work practices, engineering controls, personal protective clothing and equipment, etc. Prior knowledge of the presence of certain types of interfering compounds in the sampled environment will greatly help the analyst in the selection of the appropriate analytical conditions for sample analysis.This list of compounds can be compiled from the material safety data sheets for the compounds that are used in or around the process where the sampling will take place. Initial and routine worker exposure surveys should be made by competent industrial hygiene and engineering personnel.These surveys are necessary to characterize worker exposures and to ensure that controls already in place are operational and effective.Each worker's exposure should be estimated, whether or not it is measured by a personal sampler.Therefore, the sampling strategy should allow reasonable estimates of each worker's exposure.NIOSH's Occupational Exposure Sampling Strategy M anual may be helpful in developing efficient programs to monitor worker exposure . In work areas where airborne exposures to EGBE or EGBEA may occur, an initial survey should be done to determine the extent of worker exposure.In general, TWA exposures should be determined by collecting samples over a full shift.Measurements to determine worker exposure should be taken so that the average 8 -hr exposure is based on a single 8 -hr sample or on two 4-hr samples.Several short-term interval samples (up to 30 minutes) may also be used to determine the average exposure concentration. When the potential for exposure to EGBE or EGBEA is periodic, short-term samples may be needed to replace or supplement full-shift sampling.Personal sampling (i.e., samples collected in the worker's breathing zone) is preferred over area sampling.If personal sampling is not feasible, area sampling can be substituted only if the results can be used to approximate worker exposure.Sampling should be used to identify the sources of emissions so that effective engineering controls or work practices can be instituted. If a worker is found to be exposed to EGBE or EGBEA concentrations that are below the REL but at or above the action level (one-half of the REL), the exposure of that worker should be monitored at least once every 6 months or as otherwise indicated by a professional industrial hygienist When the work environment contains concentrations exceeding the REL for EGBE or EGBEA, workers must wear respirators for protection until adequate engineering controls or work practices are instituted; exposure monitoring is recommended at 1 -wk intervals.Such monitoring should continue until consecutive determinations at least a week apart indicate that the workers' exposure no longer exceeds the REL. When workers' exposures are greater than the action level but less than the REL, sampling should be conducted after 6 months; if EGBE or EGBEA concentrations are lower than the action level after two consecutive biannual surveys, sampling can then be conducted annually.Exposure monitoring should be conducted whenever changes in production, process, controls, work practices, or weather conditions may result in a change in exposure conditions. # MEDICAL MONITORING # General Requirements Workers exposed to EGBE and EGBEA are at risk of suffering adverse health effects. Medical monitoring as described below should be made available to all workers.The employer should provide the following information to the physician responsible for the medical monitoring program: - Any requirements of the applicable OSHA standard or NIOSH recommended standard - Identification of and extent of exposure to physical and chemical agents that may be encountered by the worker - Any available workplace sampling results that characterize exposures for job categories previously and currently held by the worker - A description of any protective devices or equipment the worker may be required to use - The frequency and nature of any reported illness or injury of a worker - The results of any monitoring of urinary BAA for any worker exposed to unknown concentrations of EGBE or EGBEA during a spill or emergency (see Appendix D). # Medical Examinations The objectives of a medical monitoring program are to augment the primary preventive measures, which include industrial hygiene monitoring of the workplace, the implementa tion of engineering controls, and the use of proper work practices and personal protective equipment.Medical monitoring data may also be used for epidemiologic analysis within large plants and on an industrywide basis; they should be compared with exposure data from industrial hygiene monitoring. Medical examinations are conducted before job placement and periodically thereafter.The preplacement medical examination allows the physician to assess the applicant's functional capacity and inform him or her of how it relates to the physical demands and risks of the job.Furthermore, such an examination provides baseline medical data that can be compared with subsequent health changes.The preplacement examination should also provide information about prior occupational exposures.Periodic medical examinations after job placement are intended to detect work-related changes in health at an early stage. The following factors should be considered during the preplacement medical examination and any periodic medical examinations of the worker: (a) exposure to chemical and physical agents that may produce independent or interactive adverse effects on the worker's health (including exacerbation of preexisting health problems and nonoccupational risk factors such as tobacco use), and (b) potentially hazardous characteristics of the work site (e.g., confined spaces, heat, and proximity to hazards such as explosive atmospheres and toxic chemicals).The type of information that should be gathered is discussed in the following subsections.

# Preplacement Medical Examination # Medical history The medical history should contain information about occupational history, including the number of years worked in each job.Special attention should be given to any history of occupational exposure to hazardous chemical and physical agents . # Clinical examination The preplacement clinical examination should determine the fitness of the worker to perform the intended job assignment.Appropriate pulmonary and musculoskeletal evaluation should be done for workers whose jobs may require extremes of physical exertion or stamina (e.g., heavy lifting), especially those who must wear personal respiratory protection.Because the standard 12-lead electrocardiogram is of little practical value in monitoring for asymptomatic cardiovascular disease, it is not recommended.More valuable diagnostic information is provided by physician interviews of workers that elicit reports of the occurrence and work-relatedness of angina, breathlessness, and other symptoms of chest illnesses.Special attention should also be given to workers who require the use of eyeglasses.These workers must be able to wear simultaneously any equipment needed for respiratory protection, eye protection, and visual acuity, and they must be able to maintain their concurrent use during work activities. The worker's duties may be performed near unrelated operations that generate potentially harmful exposures (e.g., asbestos or cleaning or degreasing solvents).The physician must be aware of these potential exposures to evaluate possible hazards to the individual worker. # Periodic Medical Examination A periodic medical examination should be conducted annually or more frequently, depend ing on age, health status at the time of a prior examination, and reported signs or symptoms associated with exposure to EGBE and EGBEA.The physician should note any trends in health changes revealed by epidemiologic analyses of examination results.The occurrence of an occupationally related disease or other work-related adverse health effects should prompt an immediate evaluation of industrial hygiene control measures and an assessment of the workplace to determine the presence of a previously unrecognized hazard. The physician's interview with the worker is an essential part of a periodic medical examination.The interview gives the physician the opportunity to learn of (1) changes in the work setting (e.g., confined spaces), and (2 ) potentially hazardous workplace exposures that are in the vicinity of the worker but are not related to the worker's job activities. During the periodic medical examination, the physician should reexamine organ systems at risk to note changes from the previous examination. # BIOLOGICAL MONITORING The urinary concentration of BAA (the metabolite of EGBE and EGBEA) may be a useful biological indicator of worker exposure to EGBE and EGBEA.Biological monitoring accounts not only for environmental concentrations and actual respiratory uptake, but also for absorption through the skin.Information about biological monitoring appears in Section 5.4 of this document, and guidelines for biological monitoring are given in Appendix D. Biological monitoring is suggested when the potential exists for exposure to airborne EGBE or EGBEA at or above the REL, or for skin contact resulting from accidental exposure or breakdown of chemical protective clothing (see Section 8 .6 .1).Monitoring of urinary BAA (see Appendix D) should be made available to any worker exposed to unknown concentra tions of EGBE or EGBEA during a spill or other emergency.In the absence of skin exposure, a urinary BAA concentration of 60 mg/g creatinine approximates the concentration that would result from exposure to the REL for EGBE or EGBEA (5 ppm) during an 8 -hr work shift.If a worker's urinary BAA suggests exposure to EGBE or EGBEA above the REL, an effort should be made to ascertain the cause (e.g., failure of engineering controls, poor work practices, or nonoccupational exposures). # RECORDKEEPING Medical records as well as exposure and biological monitoring results must be maintained for workers as specified in Section 1.9 of this document.Such records must be kept for at least 30 years after termination of employment Copies of environmental exposure records for each worker must be included with the medical records.These records must be made available to the past or present workers or to anyone having the specific written consent of a worker, as specified in Section 1.9.4 of this document. # RESEARCH NEEDS The following research is needed to farther reduce the risk of adverse health effects from occupational exposure to EGBE or EGBEA: - Investigations should be conducted in workplaces where exposures have been maintained below the current standards.Evaluations should be made of the relationship of exposure concentrations to urinary metabolite concentrations and toxic effects on the hematopoietic system. -Evaluations should be made to correlate dermal absorption of EGBE or EGBEA with concentrations of the urinary metabolite in populations exposed to these compounds. -Additional data should be collected to determine actual concentrations of EGBE and EGBEA in the workplace. -Physiologically based pharmacokinetic models should be prepared and validated to predict NOAELs for EGBE and EGBEA in humans and animals. -A device should be developed to measure dermal exposure. - Additional studies should be conducted to investigate EGBE and EGBEA for carcinogenicity and mutagenicity. -Studies should be conducted to determine the effect of mixed solvent exposure on the metabolism of EGBE to BAA. 9.Capped charcoal tubes should be packed tightly and padded before they are shipped to minimize tube breakage during shipping. 10.A sample of the bulk material should be submitted to the laboratory in a glass container with a Teflon-lined cap.This sample should not be transported in the same container as the charcoal tubes.ALCOHOLS IV METHOD: 1403 APPLICABILITY: This method may be used to determine two or more analytes simul taneously by varying GC conditions (e.g., temperature programming). INTERFERENCES: High humidity reduces sampling capacity.The methods were validated using a 3 m x 3 mm stainless steel column packed with 10% FFAP on Chromosorb W-AW; other columns with equal or better resolution (e.g., capillary) may be used.Less volatile compounds may displace more volatile compounds on the charcoal. OTHER METHODS: This method combines and replaces Methods S79 , S361 , and S76 . REAGENTS: 1.Eluent: methylene chloride with 5% (v/v) methanol and 0 .2 % (v/v) 1 -heptanol, 0 .1 % (v/v) ethyl benzene or other suitable internal standard.2.Analyte.3.Nitrogen,purified.4.Hydrogen,prepurified.5.Air,compressed,filtered.EQUIPMENT: 1.Sampler: glass tube, 7 cm long, 6 mm OD, 4 mm ID, flame-sealed ends, containing two sections of activated (600°C) coconut shell charcoal (front-100 mg; back-50 mg) separated by a 2 -mm urethane foam plug.A silylated glass wool plug precedes the front section and a 3-mm urethane foam plug follows the back section.Pressure drop across the tube at 1 L/min airflow must be less than 3.4 kPa.Tubes are commercially available.NOTE: If peak area is above the linear range of the working standards, dilute with eluent, reanalyze and apply the appropriate dilution factor in calculations.12.Measure peak area.Divide the peak area of analyte by the peak area of internal standard on the same chromatogram. # CALCULATIONS: Determine the mass, mg (corrected for DE) of analyte found in the sample front (Wf) and back (W^) sorbent sections, and in the average media blank front (Bf) and back (Bjj) sorbent sections.NOTE: Calculate concentration, C, of analyte in the air volume sampled, V (L): If Wb > Wf/10, report breakthrough and possible sample loss. ----------------------------- (2 -ethoxyethanol) and S76 (2-butoxy-ethanol) were issued on February 14,1975 , March 17,1978 , andFebruary 14,1975 , and validated using, respectively, 50-, 6 -and 10-L air samples of atmospheres generated by calibrated syringe drive.Precision and recovery were as shown below, representing non-significant bias in each method: .5.3).The NIOSH method also included an evaluation of 2-butoxyethanol at a range of 124 to 490 mg/m3 for 10-L air samples.NIOSH has no evaluated method for 2-butoxyethyl acetate. " (Wf + Wb -Bf -Bb) - 10 3 C - ' mg/m EVALUATION OF METHOD: Methods S79 (2-methoxyethanol), S361 OSHA has adopted a PEL of 25 ppm few 2-butoxyethanol (Ref.5.4) and currently has no PEL for 2-butoxyethyl acetate.NIOSH is considering issuing recommendations to lower the PEL for 2-butoxyethanol and to establish a PEL at about the same recommended concentration for 2 -butoxyethyl acetate, thus a target concentration of 5 ppm was chosen for both analytes in this evaluation. A number of modifications were made to OSHA Method 79 for this evaluation. Although an RTx-Volatiles (Restek Corp.) capillary column is acceptable for analysis of 2-butoxyethanol, there was less peak-tailing when a Nukol (Supelco, Inc.) capillary column was used.There is no significant peak-tailing for 2-butoxyethyl acetate on either of these columns.In OSHA Method 79, solid anhydrous magnesium sulfate was added to the desorption vials for 2 -methoxyethanol and 2 -ethoxyethanol samples to improve desorption ef ficiency.This was found to be unnecessary for 2-butoxyethanol samples. To ascertain the validity of this method at higher concentrations, the collection efficiency of charcoal sampling tubes was confirmed at 50 ppm for each analyte.The stability and desorption efficiency of the analytes should not be affected at these higher loadings. The effects of overexposure to 2-butoxyethanol and 2-butoxyethyl acetate are similar.Inhalation of vapors may be irritating to the respiratory tract and may cause nausea, headaches, vomiting, dizziness, drowsiness, and unconsciousness.The liquid is readily absorbed through the skin and may cause irritation to the skin and eyes.Ingestion may cause nausea, vomiting, headaches, dizziness, and gastrointestinal irritation.Chronic overexposure may damage the kidneys, liver, and blood (Ref.5.5). 1.1.3.Workplace exposure 2-Butoxyethanol is used as a solvent for nitrocellulose, natural and syn thetic resins, soluble oils, lacquers, varnishes and enamels.It is also used in textile dyeing and printing, in the treatment of leather, in the production of plasticizers, as a stabilizer in metal cleaners and household cleaners, and in hydraulic fluids, insecticides, herbicides and rust removers (Ref.5.6).The detection limits of the analytical procedure are 0.12 and 0.13 ng per injection (1.0-pL injection with a 58:1 split) for 2-butoxyethanol and 2-butoxyethyl acetate respectively.These are the amounts of each analyte that will give peaks with heights approximately 5 times the height of baseline noise (Section 4.1). 1 .2 .2 .Detection limit of the overall procedure The detection limits of the overall procedure are 7.22 and 7.54 ng per sample for 2-butoxyethanol and 2-butoxyethyl acetate respectively.These are the amounts of each analyte spiked on the sampling device that allow recovery of amounts of each analyte equivalent to the detection limits of the analytical procedure.These detection limits correspond to air concentrations of 31 ppb (150 ng/m 3) and 24 ppb (157 pg/m3) for 2-butoxyethanol and 2-butoxyethyl acetate respectively (Section 4.2). # Reliable quantitation limit The reliable quantitation limits are the same as the detection limits of the overall procedure because the desorption efficiencies are essentially 1 0 0 % at these levels.These are the smallest amounts of each analyte that can be quantitated within the requirements of recoveries of at least 75% and precisions (±1.96 SD) of ±25% or better (Section 4.3). The reliable quantitation limits and detection limits reported in the method are based upon optimization of the GC for the smallest possible amounts of each analyte.When the target concentration of an analyte is exceptionally higher than these limits, they may not be attainable at the routine operating parameters. # Instrument response to the analyte The instrument response over the concentration ranges of 0.5 to 2 times the target concentrations is linear for both analytes (Section 4.4). # Recovery The recovery of 2-butoxyethanol and 2-butoxyethyl acetate from samples used in a 15-day storage test remained above 98 and 8 6 % respectively when the samples were stored at ambient temperatures (Section 4.5, from regres sion lines shown in Figures 4.5.1.2 and 4.5.2.2). 1.2.6.Precision (analytical procedure) The pooled coefficients of variation obtained from replicate injections of analytical standards at 0.5,1 and 2 times the target concentrations are 0.004 and 0 .0 0 2 for 2 -butoxyethanol and 2 -butoxyethyl acetate respectively (Section 4.6). 1.2.7.Precision (overall procedure) The precisions at the 95% confidence level for the ambient temperature 15-day storage tests are +10.1 and +10.8% for 2-butoxyethanol and 2-butoxyethyl acetate respectively.These include an additional +5 % for pump error.The overall procedure must provide results at the target concentration that are +25% or better at the 95% confidence level (Section 4.7). # Reproducibility Six samples for each analyte collected from controlled test atmospheres and a draft copy of this procedure were given to a chemist unassociated with this evaluation. # Sampler capacity Sampler capacity is determined by measuring how much air can be sampled before breakthrough of analyte occurs, i.e., the sampler capacity is exceeded.Individual breakthrough studies were performed on each of the analytes by monitoring the effluent from sampling tubes containing only the 1 0 0 -mg section of charcoal while sampling at 0.1 L/min from atmospheres containing 50 ppm analyte.The atmos pheres were at approximately 80% relative humidity and 20-25°C.No breakthrough was detected in any of the studies after sampling for more than 8 h (>48 L). 2.5.Desorption efficiency 2.5.1.The average desorption efficiencies of 2-butoxyethanol and 2-butoxyethyl acetate from SKC Inc. Lot 120 charcoal are 99.0 and 101.5% respectively over the range of 0.5 to 2 times the target concentrations (Section 4.9.). 3.1.4.Two-milliliter vials with Teflon-lined caps. 3.1.5.A dispenser capable of delivering 1.0 mL to prepare standards and samples.If a dispenser is not available, a 1.0-mL volumetric pipet may be used. 3.1.6.Syringes of various sizes for preparation of standards. 3.1.7.Volumetric flasks and pipets to dilute the pure analytes in preparation of standards.3.6.Interferences (analytical) 3.6.1.Any compound that produces a flame ionization detector response and has a similar retention time as the analyte or internal standard is a potential interference.Any potential interferences reported to the laboratory by the industrial hygienist should be considered before samples are desorbed. 3.6.2.GC parameters (i.e., column and column temperature) may be changed to possibly circumvent interferences. 3.6.3.Retention time on a single column is not considered proof of chemical identity.Analyte identity should be confirmed by GC/mass spectrometer if possible. # Calculations The analyte concentration for samples is obtained from the appropriate calibration curve in terms of micrograms per sample, uncorrected for desorption efficiency.The air concentration is calculated using the following formulae.The back (50-mg) section is analyzed primarily to determine if there was any breakthrough from the front (100-mg) section during sampling.If a significant amount of analyte is found on the back section (e.g., greater than 25% of the amount found on the front section), this fact should be reported with sample results.If any analyte is found on the back section, it is added to the amount found on the front section.This total amount is then corrected by subtracting the total amount (if any) found on the blank.The injection size listed in the analytical procedure (1.0 nL with a 58:1 split) was used in the determination of the detection limits of the analytical procedure.The detection limits of 0.12 and 0.13 ng were determined by making injections of 7.22 and 7.54 ng/pL standards for 2-butoxyethanol and 2-butoxyethyl acetate, respec tively.These amounts were judged to produce peaks with heights approximately 5 times the baseline noise.A chromatogram of such an injection is shown in Figure 4.1. Six samples for each analyte were prepared by injecting 7.22 Mg of 2-butoxyethanol and 7.54 |ig of 2-butoxyethyl acetate into the 100-mg section of charcoal tubes.The detection limits of the overall procedure correspond to air concentra tions of 31 ppb (150 Mg/m3) and 24 ppb (157 Mg/®3) f°r 2-butoxyethanol and 2-butoxyethyl acetate, respectively.The results are given in Tables 4.2.1 and 4.2.2.The reliable quantitation limits were determined by analyzing charcoal tubes spiked with loadings equivalent to the detection limits of the analytical procedure.Samples were prepared by injecting 7.22 Mg of 2-butoxyethanol and 7.54 Mg of 2-butoxyethyl acetate into the 100-mg section of charcoal tubes.These amounts The instrument response to the analytes over the range of 0.5 to 2 times the target concentrations was determined from multiple injections of analytical standards.These data are given in Tables 4.4 Storage samples are normally generated by sampling the recommended air volume at the recommended sampling rate from test atmospheres at 80% relative humidity containing the analyte at the target concentration.Because this would require generation of 8-h samples, in the interest of time, samples were generated by sampling from atmospheres containing the analytes at about 4 times the target concentrations for 60 min at 0.2 L/min (12-L samples).For each set of 36 samples for each analyte, six samples were analyzed immediately after generation, fifteen were stored in a refrigerator at 0°C, and fifteen were stored in a closed drawer at ambient temperatures of 20-28°C.Six samples, three from refrigerated and three from ambient storage, were analyzed at intervals over a period of fifteen days.The results are given in Tables 4.S. 1 and 4.5.2 and shown graphically in Figures 4.5.1.1,4.5.1.2,4.5.2.1 and 4.5.2.2.The loss of analyte on the 2-butoxyethyl acetate samples was due to hydrolysis of the ester to 2-butoxyethanol and acetic acid.This was supported by the fact that amounts of 2-butoxyethanol were found on these samples which corresponded to the loss of 2-butoxyethyl acetate.The loss of analyte in this study after 15 days was about 3% for refrigerated storage and about 10% for ambient storage.If possible, stored 2-butoxyethyl acetate samples should be refrigerated to reduce hydrolysis.The precision of the analytical procedure for each analyte is the pooled coefficient of variation determined from replicate injections of standards.The precision of the analytical procedure for each analyte is given in Tables 4.6.1 and 4.6.2.These tables are based on the data presented in Section 4.4.The precision of the overall procedure is determined from the storage data.

The determination of the standard error of estimate (SEE) for a regression line plotted through the graphed storage data allows the inclusion of storage time as one of the factors affecting overall precision.The SEE is similar to the standard deviation, except it is a measure of dispersion of data about a regression line instead of about a mean.It is determined with the following equation: # Detection limit of the overall procedure where n -total no.of data points k -2 for linear regression k » 3 for quadratic regression Yobs -observed % recovery at a given time _ estimated % recovery from the regression line at the same given time An additional 5 % for pump error is added to the SEE by the addition of variances.The SEEs are 5.2% and 5.5% for 2-butoxyethanol and 2-butoxyethyl acetate respectively.The precision of the overall procedure is the precision at the 95% confidence level, which is obtained by multiplying the SEE (with pump error included) by 1.96 (the z-statistic from the standard normal distribution at the 95% confidence level).The 95% confidence intervals are drawn about their respective regression lines in the storage graphs. The stability of desorbed samples was checked by reanalyzing the target con centration samples from Section 4.9.one day later using fresh standards.The sample vials were resealed with new septa after the original analyses and were allowed to stand at room temperature until reanalyzed.The results are given in Table 4.10. Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature.Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. The "%" may be the approximate percentage by weight or volume (indicate basis) that each hazardous ingredient of the mixture bears to the whole mixture.This may be indicated as a range or maximum amount (i.e., 10% to 40% vol.or 10% max.wt.)to avoid disclosure of trade secrets. Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used (e.g., "100 ppm LC50-rat," "25 mg/kg LD50-skin-rabbit," "75 ppm LC man," "permissible exposure from 29 CFR 1910.1000") or, if not available, from other sources such as NIOSH RELs and publications of the American Conference of Governmental Industrial Hygienists (ACGIH) or the American National Standards Institute, Inc. (ANSI).Flashpoint, shock sensitivity, or similar descriptive data may be used to indicate flammability, reactivity, or similar hazardous properties of the material. # B.3 SECTION III.PHYSICAL DATA The data in Section III should be for the total mixture and should include the boiling point and melting point in degrees Fahrenheit (Celsius in parentheses); vapor pressure, in conventional millimeters of mercury (mm Hg); vapor density of gas or vapor (air - 1); solubility in water, in parts per hundred parts of water by weight; specific gravity (water " 1); percent volatiles (indicated if by weight or volume) at 70°F (21.1°C); evaporation rate for liquids or sublimable solids, relative to butyl acetate; and appearance and odor.These data are useful for the control of toxic substances.Boiling point, vapor density, percent volatiles, vapor pressure, and evaporation are useful for designing proper ventilation equipment.This information is also useful for design and deployment of adequate fire and spill containment equipment.The appearance and odor may facilitate identification of spilled substances or substances stored in improperly marked containers. # B.4 SECTION IV.FIRE AND EXPLOSION DATA Section IV should contain complete fire and explosion data for the product, including flashpoint and autoignition temperature in degrees Fahrenheit (Celsius in parentheses); flammable limits, in percent by volume in air; suitable extinguishing media or materials; special fire fighting procedures; and unusual fire and explosion hazard information.If the product presents no fire hazard, insert "NO FIRE HAZARD" on the line labeled "Extin guishing Media." # B.5 SECTION V. HEALTH HAZARD INFORMATION The "Health Hazard Data" should be a combined estimate of the hazard of the total product.This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard.Other data are acceptable, such as lowest LD^q if multiple components are involved. Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question.Comments should indicate the severity of the effect and the basis for the statement if possible.The basis might be animal studies, analogy with similar products, or human experiences.Comments such as "yes" or "possible" are not helpful.Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation. Eye Contact-some pain and mild transient irritation; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical person nel or individuals trained in first aid. Information in the "Notes to Physician" section should include any special medical infor mation that would be of assistance to an attending physician, including required or recom mended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed workers. # B.6 SECTION VI.REACTIVITY DATA The comments in Section VI relate to safe storage and handling of hazardous, unstable substances.It is particularly important to highlight instability or incompatibility to common substances or circumstances such as water, direct sunlight, steel or copper piping, acids, alkalies, etc. "Hazardous Decomposition Products" shall include those products released under fire conditions.It must also include dangerous products produced by aging, such as peroxides in the case of some ethers.Where applicable, shelf life should also be indicated. # B.7 SECTION VII.SPILL OR LEAK PROCEDURES Detailed procedures for cleanup and disposal should be listed with emphasis on precautions to be taken to protect workers assigned to cleanup detail.Specific neutralizing chemicals or procedures should be described in detail.Disposal methods should be explicit, including proper labeling of containers holding residues and ultimate disposal methods such as "sanitary landfill" or "incineration."Warnings such as "comply with local, State, and Federal antipollution ordinances" are proper but not sufficient.Specific procedures shall be identified. # B.8 SECTION VIII.SPECIAL PROTECTION INFORMATION Section VIII requires specific information.Statements such as "yes," "no," or "if necessary" are not informative.Ventilation requirements should be specific as to type and preferred methods.Respirators shall be specified as to type and NIOSH or MSHA approval class (i.e., "supplied air," "organic vapor canister," etc.).Protective equipment must be specified as to type and materials of construction. # B.9 SECTION IX.SPECIAL PRECAUTIONS "Precautionary Statements" shall consist of the label statements selected for use on the container or placard.Additional information on any aspect of safety or health not covered in other sections should be inserted in Section IX.The lower block can contain references to published guides or in-house procedures for handling and storage.Department of Transportation markings and classifications and other freight, handling, or storage require ments and environmental controls can be noted. # B.10 SIGNATURE AND FILING Finally, enter the name and address of the responsible person who completed the MSDS and the date of completion.This will facilitate correction of errors and identify a source of additional information. The MSDS shall be filed in a location readily accessible to workers exposed to the hazardous substance.The MSDS can be used as a training aid and basis for discussion during safety meetings and training of new workers.It should assist management by directing attention to the need for specific control engineering, work practices, and protective measures to ensure safe handling and use of the material.It will aid the safety and health staff in planning a safe and healthful work environment and in suggesting appropriate emergency procedures and sources of help in the event of harmful exposure of workers.The procedure developed by Groeseneken et al. was described as follows.Urine was adjusted to pH 7; 1 ml was placed in small vials with 3-chloropropionic acid (internal standard) and lyophilized overnight.The dry residue was redissolved in methanol contain ing PFBB, and the vials were capped.The vials were heated at 90°C for 3 hr.After cooling, sample cleanup was performed by adding distilled water and extracting the pentafluorobenzyl esters (PFB esters) with methylene chloride.The methylene chloride extract was analyzed by gas chromatography using FID.A fused silica capillary column was used (CP Sil 5, 25 m x 0.32 mm id, 0.21-|jm film thickness) with a split ratio of 5.1.Temperature programming was employed.All PFB esters showed baseline resolution; retention times of 11.66 min (BAA) and 8.59 min (internal standard) were observed.A typical gas chromatographic run, including cool-down and equilibration times, required about 30 min. Optimization studies were performed for reagent concentrations as well as for urinary pH and reaction time.After correction for the partial solubility of methylene chloride in the 50:50 methanol: urine phase, recovery of BAA from urine averaged 95.1 %.The yield for the derivatization reaction averaged 101.3 % for BAA.Standard curves were set up in urine and were linear over the range of 0.1 to 200 mg/liter.The limit of detection, at a signal to noise ratio of 5, was 0.03 mg/liter.Precision of the method, calculated from triplicate injections of 40 urine samples, averaged 3.5%, ranging from 1.1% at 25 mg/liter to 20% at 0.1 mg/liter.The method of Groeseneken et al. is the preferred method for analysis of the alkoxyacetic acid metabolites in urine. Carpenter et al.used paper chromatography (which is not as quantitatively accurate as modem chromatographic techniques) and because these investigators did not give data for the peak urinary (end of shift) concentration of BAA, concentrations were calculated from the other three sources, as follows. # D.2.1 Johanson et al. , The estimated BAA in urine was determined after a 2-hr exposure to 20 ppm EGBE, with a 50-W workload (see Table D -1).BAA excretion rates for the seven subjects were taken from Johanson et al. (Figure 5).The y-axis values were measured in mm, converted into iimol/min, and then converted into mg BAA excreted per 2 hr, for each subject.Johanson et al. do not give the creatinine values for these subjects, so a physiologi cally "normal" value of 1.5 g creatinine/day was assumed . Therefore, a 2-hr exposure to 20 ppm EGBE with a 50-W workload, is expected to yield urinary BAA concentrations of 64,84,114, and 90 mg BAA/g creatinine at 2,4,6, and 8 hr, respectively.The urinary BAA from an 8-hr exposure to 20 ppm EGBE with a 50-W workload can be estimated by "superpositioning" the urinary BAA profiles of four 2-hr exposures.For the 8-hr "end of shift" timepoint, the result is equal to the sum of the concentrations from the four 2-hr exposures given above; therefore, the expected urinary BAA concentration is64 + 84+ 114 + 90 -352 mg BAA/g creatinine.This can be extrapolated to a 5-ppm EGBE exposure by multiplying by 5/20 for a yield of 88 mg BAA/g creatinine. ,pp.1-54. # D.2.2 Van Vlem An estimate of BAA excretion from 4-hr EGBE exposures was determined from data by Van Vlem , Appendix 3, Figure 2.10 (page 43).The exposures were 50 min/hr Experiments I and II were performed with the subjects in a "resting" condition, while experiment HI was done under a 30-W workload.Because of the very limited number of subjects, a separate estimate of BAA excretion was made for each of the three experiments, and the three estimates were averaged to give one overall estimate of BAA excretion. The y-axis values in Figure 2.10 were measured (in mm) for the 4-and 8-hr time points and converted to ng BAA/min.Assuming a normal physiological level of creatinine excretion (1.5 g/day), BAA concentrations in urine at 4 and 8 hr after the beginning of an 8-hr EGBE exposure were calculated as shown in Table D-2.The urinary BAA concentrations predicted (by "superpositioning" two 4-hr exposures) for an 8-hr end-of-shift urine sample are 87, 51, and 61 mg BAA/g creatinine for experiments I, II, and HI, respectively.For a work setting, the values in experiments I and II should be approximately doubled to reflect the increased pulmonary uptake expected under nonresting conditions.Proportionally adjusting these values to a 5-ppm EGBE exposure results in predicted urinary BAA values of 41,49, and 29 mg BAA/g creatinine for experiments I, II, and El, respectively.The arithmetic average of these three estimates is 39.6 mg BAA/g creatinine, or (rounding off) 40 mg BAA/g creatinine.The average estimate-40 mg BAA/g creatinine-is the best overall estimate of BAA excretion that can be prepared from this data set. ,pp.55-72. # D.2.3 Van Vlem These data were taken from Van Vlem , Appendix 3, pp.55-72.Van Vlem reports the average exposure to EGBE for the five women to be 3.1 mg/m3 (0.65 ppm), resulting in a BAA value of 8.1 mg/liter at the end of the workday: 8.1 mg/liter x 1.2 liter urine/day x 1 day/1.5 g creatinine -6.48 mg BAA/g creatinine Adjusting this to a 5-ppm exposure yields: 6.48 x (5/0.65) -49.8 mg BAA/g creatinine, or (rounded) 50 mg BAA/g creatinine The BAA estimates from Johanson et al. and Van Vlem can be averaged to provide a single "best" estimate as follows: (88 + 40 + 50)/3 - 59.3, or (rounded) 60 mg BAA/g creatinine # D.4 LIMITATIONS OF ESTIMATING BAA All of these studies have some limitations.Johanson et al. is an excellent laboratoty study; however, the seven subjects were male.The 50-W exercise level used in this study may exceed the actual workplace energy expenditure of many workers in "light" industries, leading to an overestimate of actual EGBE uptake (under working conditions).Furthermore, the experimental protocol utilized 2-hr exposures; this is a rather short exposure from which to extrapolate uptake during an 8-hr workday. The Van Vlem laboratory studies used only three (male) subjects; this is far too few to compensate for individual variations in uptake and metabolism.Because the same three subjects were used for all three experiments, it is possible that the results of these experiments may be systematically biased (either high or low) by the presence of even one unusual EGBE metabolizer.In addition, the experiments were conducted using inhalation by face mask; this neglects any possible contribution from dermal absorption (caused by possible dermal deposition of EGBE vapor on the subject's skin).Because the subjects were exercising, and most likely sweating, the deposition of the highly water-soluble EGBE on the wet skin may conceivably be significant. Urine samples from the Veulemans et al.study were analyzed for BAA by Van Vlem .They represent samples from five female workers under actual working conditions.The exposures were for five working days, so that the time of exposure was more than adequate.However, the average EGBE exposure concentration was only 0.65 ppm, and the exposure was to a mixture of solvents.Therefore, a substantial extrapolation is involved in using these data to project the results to a 5-ppm exposure to EGBE alone, and the possibility that the other solvents involved may have altered the metabolism of EGBE (most likely reducing BAA excretion) cannot be excluded.In addition, a dermal component of the EGBE uptake (tinder actual working conditions) cannot be ruled out. In all, the published data on which this BAA estimation is based are not as complete and consistent as might be desired.It is clear that further studies of EGBE uptake (either laboratory or field studies) would be advantageous, and that the existing data do not allow an absolutely rigorous determination of a BAA concentration for corresponding to 5 ppm EGBE.However, publication of the estimated BAA concentration simply as a guideline may be of some use in situations where a mixed exposure (inhalation plus dermal) may occur.Under such conditions, a workplace standard based entirely on ambient air concentra tion may grossly underestimate the total uptake of EGBE (by neglecting the dermal D.3 OVERALL ESTIMATE OF BAA component), whereas biological monitoring for BAA will reflect both the pulmonary and the dermal exposure routes. # D.5 JUSTIFICATION FOR RECOMMENDING BIOLOGICAL MONITORING The following factors justify NIOSH recommendations for biological monitoring: - Biological monitoring for EGBE and EGBEA exposure is recommended even though no validated guidelines can be provided concerning the relationship be tween airborne exposure to these ethylene glycol ethers and their urinary metabo lite, BAA.This metabolite is both an index of exposure or uptake of EGBE by the worker and an index of potential adverse health effects from this ethylene glycol ether. - Dermal absorption may be a major route of exposure to EGBE or EGBEA.The potential also exists for absorption of their vapors through wet skin. - The influence of workload is significant for inhalation exposure.Doubling the workload results in twice the uptake of EGBE and EGBEA. # APPENDIX E MEDICAL ASPECTS OF WEARING RESPIRATORS* In recommending medical evaluation criteria for respirator use, one should apply rigorous decision-making principles ; tests used should be chosen for operating characteristics such as sensitivity, specificity, and predictive value.Unfortunately, many knowledge gaps exist in this area.The problem is complicated by the large variety of respirators, their conditions of use, and individual differences in the physiologic and psychologic responses to them.For these reasons, the following guidelines are to be considered as informed suggestions rather than established NIOSH policy recommenda tions.They are intended primarily to assist the physician in developing medical evaluation criteria for respirator use. # E.1 BACKGROUND INFORMATION Brief descriptions of the health effects associated with wearing respirators are summarized below.More detailed analyses of the data are available in recent reviews by James and Raven et al. .

# E.1.1 Pulmonary Effects In general, the added inspiratory and expiratory resistances and dead space of most respirators cause an increase in tidal volume and a decrease in respiratory rate and ventilation (including a small decrease in alveolar ventilation).These respirator effects have usually been small both among healthy individuals and, in limited studies, among individuals with impaired lung function .This generalization is applicable to most respirators when resistances (particularly expiratory resistance) are low . While most studies report minimal physiologic effects during submaximal exercise, the resistances commonly lead to reduced endurance and reduced maximal exercise perfor mance .The dead space of a respirator (reflecting the amount of expired air that must be rebreathed before fresh air is obtained) tends to cause increased ventilation.At least one study has shown substantially increased ventilation with a full-face respirator, a type that can have a large effective dead space .However, the net effect of a Adapted from NIOSH Respirator Decision Logic . respirator's added resistances and dead space is visually a small decrease in ventilation . The potential for adverse effects, particularly decreased cardiac output, from the positive pressure feature of some respirators has been reported .However, several recent studies suggest that this is not a practical concern, at least not in healthy individuals . Theoretically, the increased fluctuations in thoracic pressure caused by breathing with a respirator might constitute an increased risk to subjects with a history of spontaneous pneumothorax.Few data are available in this area.While an individual is using a negative-pressure respirator with relatively high resistance during very heavy exercise, the usual maximal-peak negative oral pressure during inhalation is about 15 to 17 cm of water .Similarly, the usual maximal-peak positive oral pressure during exhalation is about 15 to 17 cm of water, which might occur with a respirator in a positive-pressure mode, again during very heavy exercise , By comparison, maximal positive pressures such as those during a vigorous cough can generate 200 cm of water pressure .The normal maximal negative pleural pressure at full inspiration is -40 cm of water , and normal subjects can generate -80 to -160 cm of negative water pressure .Thus while vigorous exercise with a respirator does alter pleural pressures, the risk of barotrauma would seem to be substantially less than that of coughing. In some asthmatics, an asthmatic attack may be exacerbated or induced by a variety of factors including exercise, cold air, and stress, all of which may be associated with wearing a respirator.While most asthmatics who are able to control their condition should not have problems with respirators, a physician's judgment and a field trial may be needed in selected cases. # E.1.2 Cardiac Effects The added work of breathing from respirators is small and could not be detected in several studies .A typical respirator might double the work of breathing (from 3% to 6% of the total oxygen consumption), but this is probably not of clinical significance .In concordance with this view, several other studies indicated that at the same workloads heart rate does not change with the wearing of a respirator . In contrast, the added cardiac stress due to the weight of a heavy respirator may be considerable.A self-contained breathing apparatus (SCBA) may weigh up to 35 lb.Heavier respirators can reduce maximum external workloads by 20% and similarly increase heart rate at a given submaximal workload .In addition, it should be noted that many uses of SCBA (e.g., for firefighting and hazardous waste site work) also necessitate the wearing of 10 to 25 lb of protective clothing.Raven et al. found statistically significant higher systolic and/or diastolic blood pressures during exercise for persons wearing respirators.Arborelius et al. did not find significant differences for persons wearing respirators during exercise. # E.1.3 Body Temperature Effects Proper regulation of body temperature is primarily of concern with the closed circuit SCBA that produces oxygen via an exothermic chemical reaction.Inspired air within these respirators may reach 120°F (49°C), thus depriving the wearer of a minor cooling mechanism and causing discomfort Obviously this can be more of a problem with heavy exercise and when ambient conditions and/or protective clothing further reduce the body's ability to lose heat The increase in heart rate because of increasing temperature represents an additional cardiac stress. Closed-circuit breathing units of any type have the potential for causing heat stress since warm expired gases (after exothermic carbon dioxide removal with or without oxygen addition) are rebreathed.Respirators with large dead spaces also have this potential problem, again because of partial rebreathing of warmed expired air . # E.1.4 Sensory Effects Respirators may reduce visual fields, decrease voice clarity and loudness, and decrease hearing ability.Besides the potential for reduced productivity, these effects may result in reduced industrial safety.These factors may also contribute to a general feeling of stress . # E.1.5 Psychologic Effects This important topic is discussed in recent reviews by Morgan [Morgan 1983a[Morgan , 1983b. There is little doubt that virtually everyone suffers some discomfort when wearing a respirator.The large variability and the subjective nature of the psycho-physiologic aspects of wearing a respirator, however, make studies and specific recommendations difficult Fit testing obviously serves an important additional function by providing a trial to determine if the wearer can psychologically tolerate the respirator.The great majority of workers can tolerate respirators, and experience in wearing them aids in this tolerance .However, some individuals are likely to remain psychologically unfit for wearing respirators. # E.1.6 Local Irritation Effects Allergic skin reactions may occur occasionally from wearing a respirator, and skin occlusion may cause irritation or exacerbation of preexisting conditions such as pseudofolliculitis barbae.Facial discomfort from the pressure of the mask may occur, particularly when the fit is unsatisfactory. In addition to the health effects (described above) associated with wearing respirators, specific groups of respirator wearers may be affected by the following factors: a. Perforated Tympanic Membrane While inhalation of toxic materials through a perforated tympanic membrane (ear drum) is possible, recent evidence indicates that the airflow would be minimal and rarely if ever of clinical importance .In highly toxic or unknown atmospheres, use of positive pressure respirators should ensure adequate protection .b. Contact Lenses Contact lenses are generally not recommended for use with respirators, although little documented evidence exists to support this viewpoint .Several possible reasons for this recommendation are noted below: (1) Comeal Irritation or Abrasion Comeal irritation or abrasion might occur with the exposure.This would, of course, be a problem primarily with quarter-and half-face masks, especially with particulate exposures.However, exposures could occur with full-face respirators because of leaks or inadvisable removal of the respirator for any reason.While comeal irritation or abrasion might also occur without contact lenses, their presence is known to substantially increase this risk. (2) Loss or Misplacement of a Contact Lens The loss or misplacement of a contact lens by an individual wearing a respirator might prompt the wearer to remove the respirator, thereby resulting in exposure to the hazard as well as to the potential problems noted above. # 3) Eye Irritation from Respirator Airflow The constant airflow of some respirators, such as powered, air-purifying respirators (PAPRs) or continuous flow, air-line respirators, might irritate the eyes of a contact lens wearer. # E.2 SUGGESTED MEDICAL EVALUATION AND CRITERIA FOR RESPIRATOR USE The following NIOSH recommendations allow latitude for the physician in determining a medical evaluation for a specific situation.More specific guidelines may become available as knowledge increases regarding human stresses from the complex interactions of worker E.1.7 Miscellaneous Health Effects health status, respirator usage, and job tasks.While some of the following recommendations should be part of any medical evaluation of workers who wear respirators, others are applicable for specific situations. - A physician should determine fitness to wear a respirator by considering the worker's health, the type of respirator, and the conditions of respirator use. The recommendation above leaves the final decision of an individual's fitness to wear a respirator to the person who is best qualified to evaluate the multiple clinical and other variables.Much of the clinical and other data could be gathered by other personnel.It should be emphasized that the clinical examination alone is only one part of the fitness determination.Collaboration with foremen, industrial hygienists, and others may often be needed to better assess the work conditions and other factors that affect an individual's fitness to wear a respirator. - A medical history and at least a limited physical examination are recommended. The medical history and physical examination should emphasize the evaluation of the cardiopulmonary system and should elicit any history of respirator use.The history is an important tool in medical diagnosis and can be used to detect most problems that might require further evaluation.Objectives of the physical examination should be to confirm the clinical impression based on the history and to detect important medical conditions (such as hypertension) that may be essentially asymptomatic. - While chest X-ray and/or spirometry may be medically indicated in some fitness determinations, these should not be routinely performed. In most cases, the hazardous situations requiring the wearing of respirators will also mandate periodic chest X-rays and/or spirometry for exposed workers.When such information is available, it should be used in the determination of fitness to wear respirators. Data from routine chest X-rays and spirometry are not recommended solely for determining if a respirator should be worn.In most cases, with an essentially normal clinical examination (history and physical) these data are unlikely to influence the respirator fitness determina tion; additionally, the X-ray would be an unnecessary source of radiation exposure to the worker.Chest X-rays in general do not accurately reflect a person's cardiopulmonary physiologic status, and limited studies suggest that mild to moderate impairment detected by spirometry would not preclude the wearing of respirators in most cases.Thus it is recommended that chest X-rays and/or spirometry be done only when clinically indicated. - The recommended periodicity of medical fitness determinations varies according to several factors but could be as infrequent as every 5 years. Federal or other applicable regulations shall be followed regarding the frequency of respirator fitness determinations.The guidelines for most work conditions for which respirators are required are shown in These guidelines are similar to those recommended by ANSI, which recommends annual determinations after age 45 .The more frequent examinations with advancing age relate to the increased prevalence of most diseases in older people.More frequent examinations are recommended for individuals performing strenuous work involving the use of a SCBA.These guidelines are based on clinical judgment and, like the other recommendations in this section, should be adjusted as clinically indicated. - The respirator wearer should be observed during a trial period to evaluate potential physiological problems. In addition to considering the physical effects of wearing respirators, the physician should determine if wearing a given respirator would cause extreme anxiety or claustrophobic reaction in the individual.This could be done during training while the worker is wearing the respirator and is engaged in some exercise that approximates the actual work situation. Present OSHA regulations state that a worker should be provided the opportunity to wear the respirator "in normal air for a long familiarity period ..." .This trial period should also be used to evaluate the ability and tolerance of the worker to wear the respirator .This trial period need not be associated with respirator fit testing and should not compromise the effectiveness of the vital fit testing procedure. - Examining physicians should realize that the main stress of heavy exercise while using a respirator is usually on the cardiovascular system and that heavy respirators (e.g., SCBA) can substantially increase this stress.Accordingly, physicians may want to consider exercise stress tests with electrocardiographic monitoring when heavy respirators are used, when cardiovascular risk factors are present, or when extremely stressful conditions are expected. Some respirators may weigh up to 35 lb and may increase workloads by 20%.Although a lower activity level could compensate for this added stress , a lower activity level might not always be possible.Physicians should also be aware of other added stresses, such as heavy protective clothing and intense ambient heat, that would increase the worker's cardiac demand.As an extreme example, firefighters who use a SCBA inside burning buildings may work at maximal exercise levels under life-threatening conditions.In such cases, the detection of occult cardiac disease, which might manifest itself during heavy stress, may be important.Some authors have either recommended stress testing or at least its consideration in the fitness determination .Kilbom has recommended stress testing at 5-year intervals for firefighters below age 40 who use SCBAs and at 2-year intervals for those aged 40 to 50.He further suggested that firemen over age 50 not be allowed to wear SCBAs. Exercise stress testing has not been recommended for medical screening for coronary artery disease in the general population .It has an estimated sensitivity and specificity of 78% and 69%, respectively, when the disease is defined by coronary angiography , In a recent 6-year prospective study, stress testing to determine the potential for heart attacks indicated a positive predictive value of 27% when the prevalence of disease was 3.5% .While stress testing has limited effectiveness in medical screening, it could detect individuals who may not be able to complete the heavy exercise required in some jobs. A definitive recommendation regarding exercise stress testing cannot be made at this time. Further research may determine whether this is a useful tool in selected circumstances. - An important concept is that "general work limitations and restrictions identified for other work activities also shall apply for respirator use" . In most situations, a worker who can physically do an assigned job without a respirator can perform the same job without increased risk while wearing a respirator. - Because of the variability in the types of respirators, work conditions, and workers' health status, many employers may wish to designate categories of fitness to wear respirators, thereby excluding some workers from strenuous work situations in volving the wearing of respirators. Depending on the various circumstances, several permissible categories of respirator usage are possible.One conceivable scheme would consist of three overall categories: full respirator use, no respirator use, and limited respirator use including "escape only" respirators.The latter category excludes heavy respirators and strenuous work conditions.Before identifying the conditions that would be used to classify workers into various categories, it is critical that the physician be aware that these conditions have not been validated and are presented only for consideration.The physician should modify the use of these conditions based on actual experience, further research, and individual worker sen sitivities.He may also wish to consider the following conditions in selecting or permitting the use of respirators: - History of spontaneous pneumothorax - Claustrophobia/anxiety reaction 132 - Use of contact lenses (for some respirators) - Moderate or severe pulmonary disease - Angina pectoris, significant arrhythmias, recent myocardial infarction - Symptomatic or uncontrolled hypertension, and - Advanced age Wearing a respirator would probably not play a significant role in causing lung damage such as pneumothorax.However, without good evidence that wearing a respirator would not cause such lung damage, the physician would be prudent to prohibit the individual with a history of spontaneous pneumothorax from wearing a respirator. Moderate lung disease is defined by the Intermountain Thoracic Society as being present when the following conditions exist-a forced expiratory volume in one second (FEVj) divided by the forced vital capacity (FVC) (i.e., FEVj/FVC) of 0.45 to 0.60, or an FVC of 51 % to 65 % of the predicted FVC value.Similar arbitrary limits could be set for age and hypertension.It would seem more reasonable, however, to combine several risk factors into an overall estimate of fitness to wear respirators under certain conditions.Here the judgment and clinical experience of the physician are needed.Many impaired workers would even be able to work safely while wearing respirators if they could control their own work pace, including having sufficient time to rest. # E.3 CONCLUSIONS Individual judgment is needed to determine the factors affecting an individual's fitness to wear a respirator.While many of the preceding guidelines are based on limited evidence, they should provide a useful starting point for a respirator fitness screening program.Further research is needed to validate these and other recommendations currently in use.Of particular interest would be laboratory studies involving physiologically unpaired in dividuals and field studies conducted under actual day-to-day work conditions. # APPENDIX A METHODS FOR SAMPLING AND ANALYSIS OF EGBE AND EGBEA IN AIR- A.1 GENERAL REQUIREMENTS FOR SAMPLING The air samples collected represent the air a worker breathes while performing each job or operation.It is advisable to maintain records of the date, time, rate, duration, volume, and location of sampling. # A.2 COLLECTION AND SHIPPING OF SAMPLES 1.Immediately before sampling, break the ends of the sampling tube to provide an opening at least one-half the internal diameter of the tube ( 2 mm). The following items of information that are applicable to a product or material shall be provided in the appropriate block of the material safety data sheet (MSDS). Insert the product designation in the block in the upper left comer of the first page to facilitate filing and retrieval.Print in upper case letters as large as possible.The MSDS should be printed to read upright with the sheet turned sideways.The product designation is the name or code that appears on the label, or the name by which the product is sold, or the name known by workers.The relative numerical hazard ratings and key statements are those determined by the rules in Chapter V, Part B, of the NIOSH publication entitled A Recom mended Standard: An Identification System for Occupationally Hazardous Materials .

The company identification may be printed in the upper right comer if desired. # B.1 SECTION I. PRODUCTION IDENTIFICATION Insert the manufacturer's name, address, and regular and emergency telephone numbers (including area code) in the appropriate blocks of Section I. The company listed should be a source of detailed backup information on the hazards of the materials) covered by the MSDS.The listing of suppliers or wholesale distributors is discouraged.The trade name should be the product designation or common name associated with the material.The synonyms are those commonly used for the product, especially formal chemical nomenclature.Every known chemical designation or competitor's trade name need not be listed. # B.2 SECTION II.HAZARDOUS INGREDIENTS The "materials" listed in Section II shall be those substances that are part of the hazardous product covered by the MSDS and individually meet any of the criteria defining a hazardous material.Thus one component of a multicomponent product might be listed because of its toxicity, another component because of its flammability, and a third component could be included both for its toxicity and its reactivity.Note that the MSDS for a single component product must have the name of the material repeated in this section to avoid giving the impression that there are no hazardous ingredients. Johanson et al. modified the method of Smallwood et al. to determine BAA in urine.An internal standard for pentoxyacetic acid was added to acidified urine.After extraction with methylene chloride, an alkaline solution of tetrabutylammonium hydrogen sulfate was added.Pentafluorobenzyl bromide (PFBB) was also added and the mixture shaken vigorously for 1 hr.Gas chromatography with a flame ionization detector (FID) was performed on a fused silica capillary column (BP-10, 12 m x 0.22 mm id) using a 1:100 split ratio.The limits of detection for BAA in urine and recovery data were not presented.Reproducibility was reported as 7.6%. # I l l # Appendix B Material Safety Data Sheet Johanson et al. modified the method used previously for BAA in urine by performing the phase transfer catalysis derivatization at pH 6 to avoid hydrolysis of potential conjugates and by using an electron capture detector to increase sensitivity.Urine (200 jil), tetrabutylammonium hydrogen sulfate, sodium phosphate buffer, pentoxyacetic acid (pH 6) (internal standard), methylene chloride, and PFBB were added to a screw-capped culture tube.The culture tube was vigorously shaken and then rotated for 1 hr at room temperature.The methylene chloride layer was evaporated to dryness and the residue taken up in hexane. A gas chromatograph equipped with an Ni63 electron capture detector and an autosampler was used for separation and quantitation of BAA.A fused silica capillary column (Oribond SE-30, 25 m x 0.32 mm id) was used in the split/splitless mode.The analytical range of the method was 5 to 500 ^mol/liter (0.66 to 66 mg/liter).Although limits of detection were not given, they can be assumed to be lower than the standard (0.6 mg/liter).Reproducibility was stated as 14% (RSD) based on the analysis of 60 duplicate urine samples. Groeseneken et al. further evaluated the existing methods for alkoxyacetic acids and concluded that the phase transfer catalysis procedures had the required specificity without the production of artifacts, but they lacked sufficient sensitivity to detect these metabolites at low occupational exposure concentrations.On the other hand, the methods utilizing diazomethane derivatization had the required sensitivity but lacked the specificity.There fore, Groeseneken et al. developed an improved method that combined the best attributes of the two basic existing methods.Because background interference in urine samples can be troublesome when using the electron capture detector, the method published by was not cited even though it has the required sensitivity and specificity for BAA. # APPENDIX D GUIDELINES FOR BIOLOGICAL MONITORING Compliance with the NIOSH REL alone may not ensure that workers are protected from overexposure to EGBE and EGBEA.In addition to inhalation, dermal absorption is a significant route of entry for these chemicals.As a result, biological monitoring of workers should be done routinely on the basis of work practices. # D.1 MONITORING FOR BAA IN URINE To conduct biological monitoring, urine samples should be evaluated for BAA using the method of Groeseneken et al. or an equivalent method.Expression of results as milligrams of metabolite per gram of creatinine (mg/m creatinine) is suggested.Factors that may affect the urinary concentration of BAA include ethanol consumption (which lowers urinary metabolite concentrations), dermal contact, heavy workloads, and nonoccupational exposures. Urine samples should be collected at the end of the workshift following at least 2 days of typical exposure.Such specimens reflect absorption (dermal and inhalation) during the day and possibly some residual BAA from the previous day's exposure.In case of an accident or spill, urine samples should be collected 3 hr later, when peak BAA excretion occurs.Four sources (presented in Sections 4.3 and 5.2) were investigated for quantitative data relating EGBE exposure to urinary excretion of BAA: Johanson et al. ,Van Vlem , pp.1-54, Van Vlem , pp.55-72, and Carpenter et al. .Because

In August 2013, the Food and Drug Administration (FDA) permitted marketing of the Xpert MTB/RIF assay (Cepheid, Sunnyvale, California) to detect DNA of the Mycobacterium tuberculosis complex (MTBC) and genetic mutations associated with resistance to rifampin (RMP) in unprocessed sputum and concentrated sputum sediments (1).Along with clinical, radiographic, and other laboratory findings, results of the assay aid in the diagnosis of pulmonary tuberculosis (TB).The assay is a nucleic acid amplification-based (NAA)- test using a disposable cartridge in conjunction with the GeneXpert Instrument System.Sensitivity and specificity of the Xpert MTB/RIF assay for detection of MTBC appear to be comparable with other FDA-approved NAA assays for this use, although direct comparison studies have not been performed.Sensitivity of detection of RMP resistance was 95% and specificity 99% in a multicenter study using archived and prospective specimens from subjects aged ≥18 years suspected of having TB who had 0-3 days of antituberculous treatment (1).CDC continues to recommend following published U.S. guidelines for TB diagnosis and infection control practice, including the use and interpretation of NAA test results (2)(3)(4).Providers and laboratories need to ensure that specimens are available for other recommended mycobacteriological testing.The Xpert MTB/RIF assay aids in the prompt diagnosis of TB and RMPresistant disease.RMP resistance most often coexists with isoniazid (INH) resistance; TB that is resistant to both drugs is multidrug-resistant (MDR) † TB.Because the prevalence of RMP resistance is low in the United States (about 1.8% of TB cases) (5), a positive result indicating a mutation in the rpoB gene of MTBC should be confirmed by rapid DNA sequencing for prompt reassessment of the treatment regimen and followed by growth-based drug susceptibility testing (DST) (1,6,7).CDC offers these services free of charge. §The World Health Organization has published guidance on use of the Xpert MTB/RIF assay aimed primarily at settings where the prevalence of TB and drug-resistant disease is much higher than in the United States (8). # Detection of MTBC In 2008, the Association of Public Health Laboratories and CDC convened a panel ¶ that recommended NAA testing as standard practice in the United States to aid in the initial diagnosis of patients with suspected TB.On the basis of the panel report (7) and consultation with the Advisory Council for the Elimination of TB, CDC published revised NAA guidelines, including a detailed testing and interpretation algorithm for initial diagnosis (4).Recent studies further support NAA test use in the United States to avoid delays in diagnosis and treatment, especially for patients with suspected TB and sputum smears negative for acid-fast bacilli on microscopy.Because of rapid results, NAA testing can help avoid unnecessary respiratory isolation, treatment, and contact investigation of patients without TB (9) and can contribute to system cost savings in patients with HIV infection, homelessness, or substance abuse, compared with smear microscopy alone (9). CDC recommends that NAA testing be performed on at least one (preferably the first) respiratory specimen from each patient suspected of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established, and for whom the test result would alter case management or TB Please note: An erratum has been published for this issue.To view the erratum, please click here. control activities (4).The recommendation emphasizes the need for NAA testing in the initial diagnosis and for triaging public health interventions such as contact investigations and infection control decisions.Parallel guidance for the use of NAA TB testing in patients infected with HIV has been published (10).NAA testing does not replace the need for culture; all patients suspected of TB should have specimens collected for mycobacterial culture (4). # Practical Considerations for Use of the Xpert MTB/RIF Assay for Detection of Mutations Associated with RMP Resistance CDC presents these interim practical considerations for incorporation of the Xpert MTB/RIF assay into diagnostic algorithms.For any test, even with high sensitivity and specificity (including NAA testing, DNA sequencing, and growth-based DST), the positive predictive value is low for a rare condition; accordingly, health-care providers should consult with their public health laboratory for confirmation by rapid molecular detection of mutations associated with drug resistance.To confirm a positive result, genetic loci associated with RMP resistance (to include rpoB), as well as INH resistance (to include inhA and katG) should be sequenced to assess for MDR TB.If mutations associated with RMP resistance are confirmed, rapid molecular testing for other known mutations associated with drug resistance (to first-line and second-line drugs) is needed for health-care providers to select an optimally effective treatment regimen.All molecular testing should prompt growth-based DST (6,7).Laboratories should report an Xpert MTB/RIF assay positive for RMP resistance pending confirmatory results (Table 1).Note that although an Xpert MTB/RIF assay result positive for MTBC and negative for RMP resistance has high negative predictive value † † for ruling out RMP resistance, growth-based DST to first-line TB drugs is still necessary.Consultation with a TB expert is recommended if the clinician is not experienced in the interpretation of NAA and other molecular test results or the diagnosis and treatment of TB.This is especially important in cases of suspected drug resistance (3). # Considerations for Infection Control CDC recommends airborne infection isolation (AII) precautions for patients with suspected TB disease of the lungs, airway, or larynx in health-care settings (3,10).AII precautions may be discontinued when contagious TB disease is considered unlikely and either 1) another diagnosis is made that explains the clinical syndrome or 2) the patient has three consecutive sputum smears negative for acid-fast bacilli on microscopy.Because of the intermittent presence of TB bacilli in the sputum of patients with TB, three specimens separated in time † † Approximately 5% of RMP resistance is not associated with rpoB mutations. Combined with a RMP resistance prevalence of about 1.8% in United States, the negative predictive value is high for RMP resistance when rpoB mutations are not found.Because culture-based DST is recommended for all cases of TB, almost all RMP resistance can be detected. have been recommended to have a sufficiently high predictive value for excluding contagious disease. Because NAA testing, including that with the Xpert MTB/RIF assay, is significantly more sensitive and specific for the detection of MTBC than microscopy alone, substitution of Xpert MTB/RIF assay results that are negative for MTBC for microscopy results increases the negative predictive value for MTBC.Therefore, in ruling out contagious TB, specimens can be tested by microscopy, NAA, or a combination of the two (Table 2) (2,10).Three sputum specimens, each collected 8-24 hours apart, with one being an early morning specimen, should be collected to inform decisions regarding the discontinuation of AII precautions for patients with suspected TB in health-care settings.For patients with a diagnosis of TB, decisions regarding discontinuation of AII precautions should be based on microscopy (i.e., three consecutive negative smears) and other clinical criteria (10). sputum samples that are negative on acid-fast bacilli microscopy, and to obtain isolates for drug susceptibility testing and genotyping. †CDC suggested minimum language for the laboratory report.Laboratories are encouraged to enhance and customize this basic language in accordance with the capabilities or referral systems of their institution. §Might refer to more than one mutation. ¶Because of the low positive predictive value of RMP resistance results in low prevalence populations, in the United States, confirmatory testing should include prompt DNA sequencing and subsequent phenotypic drug susceptibility testing of cultured isolates.DNA sequencing of direct patient samples (or if not available, isolates) with possible RMP resistance should include genetic loci associated with resistance to RMP (to include rpoB) as well as isoniazid (to include inhA and katG) to assess for multidrug-resistant tuberculosis; rpoB mutations detected by the Xpert MTB/RIF assay might be silent mutations that do not affect RMP susceptibility.DNA sequencing can distinguish silent mutations, which in this context refer to synonymous single nucleotide polymorphisms (also known as sSNPs). # Reported by # Div of Tuberculosis Elimination The MMWR series of publications is published by the Center for Surveillance, Epidemiology, and Laboratory Services (proposed), Centers for Disease Control # TABLE 2.Analysis of results of SS and NAA testing for infection control in health-care settings involving patients with suspected tuberculosis (TB) -United States, 2013 Results of combinations of SS and NAA testing on a total of at least three specimens, each collected 8-24 hours apart, with one being an early morning specimen # Decisional analysis SS results # NAA test results All SS tests are negative.All NAA tests are negative for the detection of MTBC. In combination with other requirements,- supports discontinuation of airborne infection isolation (AII) precautions.

These guidelines replace CDC's 1994 guidelines, HIV Counseling, Testing, and Referral Standards and Guidelines, and contain recommendations for public-and private-sector policy makers and service providers of human immunodeficiency virus (HIV) counseling, testing, and referral (CTR).To develop these guidelines, CDC used an evidence-based approach advocated by the U.S. Preventive Services Task Force and public health practice guidelines.The recommendations are based on evidence from all available scientific sources; where evidence is lacking, opinion of "best practices" by specialists in the field has been used.This revision was prompted by scientific and programmatic advances in HIV CTR, as well as advances in prevention and the treatment and care of HIV-infected persons.These advances include a) demonstrated efficacy of HIV prevention counseling models aimed at behavioral risk reduction; b) effective treatments for HIV infection and opportunistic infections; c) effective treatment regimens for preventing perinatal transmission; and d) new test technologies.Although the new guidelines include many aspects of the previous ones (e.g., encouragement of confidential and anonymous voluntary HIV testing, need for informed consent, and provision of HIV prevention counseling that focuses on the client's own risk), the new guidelines differ in several respects, including - giving guidance to all providers of voluntary HIV CTR in the public and private sectors; - using an evidence-based approach to provide specific recommendations for CTR; - underscoring the importance of early knowledge of HIV status and making testing more accessible and available; - acknowledging providers' need for flexibility in implementing the guidelines, given their particular client base, setting HIV prevalence level, and available resources; - recommending that CTR be targeted efficiently through risk screening and other strategies; and - addressing ways to improve the quality and provision of HIV CTR.#INTRODUCTION # Purpose of the Guidelines These guidelines were developed for policy makers and service providers in the many settings that offer voluntary human immunodeficiency virus (HIV) counseling, testing, and referral (CTR) -public and private, urban and rural, and those with high and low HIV prevalence (Box 1).The guidelines are intended to be used to develop CTR services and policies in traditional clinical settings (e.g., sexually transmitted disease ), which can be important places to provide access to CTR to persons at increased HIV risk.The Public Health Service is responsible for ensuring the quality of services in publicly funded programs, and many aspects of these guidelines focus on such programs.The guidelines could also be useful for CTR in other settings (e.g., for insurance, military, and blood donation purposes). Recommendations should be tailored to fit the needs of clients, communities, and programs within local, state, and federal rules and regulations. # Evolution of the Guidelines These guidelines revise and update several sets of CDC guidelines for HIV CTR.The first CDC guidelines, published in 1986, highlighted the importance of offering voluntary testing and counseling and maintaining confidential records (1 ).In 1987, new guidelines emphasized the need to decrease barriers to counseling and testing, especially disclosure of personal information (2 ).In 1993, an additional report described the model of HIV prevention counseling currently recommended -an interactive rather than didactic model focusing on a personalized HIV risk-reduction plan (3 ).In 1994, HIV Counseling, Testing and Referral Standards and Guidelines focused on standard counseling and testing procedures and reiterated the importance of the HIV prevention counseling model and the need for confidentiality of counseling (4 ). - Publish electronically and in hard copy.Single copies of this report are available from CDC's National Prevention Information Network (NPIN) website at or by calling (800) 458-5231.The guidelines are also available at the HIV Counseling, Testing, and Referral website at .They will be updated and posted periodically. # Similarities and Differences Between Current and Previous Guidelines Aspects of previous CDC HIV guidelines that are unchanged include - encouraging availability of anonymous as well as confidential HIV testing; - ensuring that HIV testing is informed, voluntary, and consented; - emphasizing access to testing and effective provision of test results; - advocating routine recommendation of HIV CTR in settings (e.g., publicly funded clinics) serving clients at increased behavioral or clinical risk for HIV infection; - recommending use of a prevention counseling approach aimed at personal risk reduction for HIV-infected persons and persons at increased risk for HIV; and - stressing the need to provide information regarding the HIV test to all who take the test. # MMWR November 9, 2001 Differences in the new guidelines include - giving guidance to all providers of voluntary HIV CTR in the public and private sectors; - using an evidence-based approach to provide specific recommendations for CTR; - underscoring the importance of early knowledge of HIV status and making HIV testing more accessible and available;

Recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation Summary CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients.The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health.For the purposes of this report, HSCT is defined as any transplantation of blood-or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood).Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients.These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety.The diseasespecific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients.The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients.The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals.For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation.Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.#INTRODUCTION In 1992, the Institute of Medicine (1 ) recommended that CDC lead a global effort to detect and control emerging infectious agents.In response, CDC published a plan (2 ) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons.During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3)(4)(5).Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations.An informal survey of hematology, oncology, and infectious disease specialists at transplant centers Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998). HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells.Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient.Such transplants are the most effective treatment for persons with severe aplastic anemia (13 ) and offer the only curative therapy for persons with chronic myelogenous leukemia (12 ).Allogeneic donors might be a blood relative or an unrelated donor.Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling.However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14)(15)(16).Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18 ).However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19 ).These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19 ).To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft.Although the recipients of T-lymphocyte-depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20 ). The patient's own cells are used in an autologous HSCT.Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor.Autologous HSCTs are preferred for patients who require high-level or marrowablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows.Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial.Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21 ).Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD. Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth.These harvested cells are used primarily for allogeneic transplants among children.Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22)(23)(24).However, immune system function after UCB transplants has not been well-studied. HSCT is also evolving rapidly in other areas.For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colonystimulating factors (e.g., granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor ) are being used increasingly among autologous recipients (25 ) and are under investigation for use among allogeneic HSCT.Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients.A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration. GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them.Although the use of intravenous immunoglobulin (IVIG) in the MMWR October 20, 2000 routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26 ) and because of the development of other strategies for GVHD prophylaxis (27 ).For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s.Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27 ).Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed. Although survival rates for certain autologous recipients have improved (28,29 ), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29 ).Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987-November 1990, a total of 66% had died by 1991 (15 ).Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15 ).- Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health.A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30 ).In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31 ). # Immune System Recovery After HSCT During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease.Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity.The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteriacarrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens.Virtually all HSCT recipients rapidly lose all T-and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines.Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients. During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers.Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements.These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci ) (32,33 ). Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm 3 and sustained platelet count of ³20,000, lasting ³3 consecutive days without transfusions.Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6-84 days) (15 ).In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections.However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment.For example, although allogeneic recipients might have normal total lymphocyte counts within ³2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27 ).They might also have immunoglobulin G (IgG) 2 , IgG 4 , and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32 ).Immune system recovery might be delayed further by CMV infection (34 ). During the first ³2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I-IV (32,35,36 ).Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37 ), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants.GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19 ).Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38 ). Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39 ).Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40 ) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41 ), poor response to vaccination (42)(43)(44), and severe mucositis (19 ).Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40 ), and a history of acute GVHD (24,45 ).Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19 ).Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41 ), they experience longlasting IgA, IgG, and IgG subclass deficiencies (41,46,47 ) and poor opsonization and impaired reticuloendothelial function.Consequently, they are at even greater risk for infections (32,39 ), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre.pneumoniae , Ha.influenzae , or Ne.meningitidis ).After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored. # Opportunistic Pathogens After HSCT HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure).Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. # Toxoplasma gondii # Aspergillus species Aspergillus species # Strongyloides stercoralis Phase I is the preengraftment phase (100 days after HSCT).Prevention strategies should be based on these three phases and the following information: - Phase I, preengraftment.During the first month posttransplant, HSCT recipients have two critical risk factors for infection -prolonged neutropenia and breaks in the mucocutaneous barrier resulting from the HSCT preparative regimens and frequent vascular access required for patient care.Consequently, oral, gastro-intestinal, and skin flora are sources of infection.Prevalent pathogens include Candida species, and as neutropenia continues, Aspergillus species.Additionally, herpes simplex virus (HSV) reactivation can occur during this phase.During preengraftment, the risks for infection are the same for autologous or allogeneic patients, and OIs can appear as febrile neutropenia.Although a recipient's first fever during preengraftment is probably caused by a bacterial pathogen, rarely is an organism or site of infection identified.Instead, such infections are usually treated preemptively or empirically (48 ) until the neutropenia resolves (49 ).Growth factors can be administered during phase I to decrease neutropenia duration and complications (e.g., febrile neutropenia) (50 ). - Phase II, postengraftment.Phase II is dominated by impaired cell-mediated immunity for allogeneic or autologous recipients.Scope and impact of this defect for allogeneic recipients are determined by the extent of GVHD and its immunosuppressive therapy.After engraftment, the herpes viruses, particularly CMV, are critical pathogens.At 30-100 days after HSCT, CMV causes pneumonia, hepatitis, and colitis and potentiates superinfection with opportunistic pathogens, particularly among patients with active GVHD.Other dominant pathogens during this phase include Pneumocystis carinii and Aspergillus species. - Phase III, late phase.During phase III, autologous recipients usually have more rapid recovery of immune system function and, therefore, a lower risk for OIs than do allogeneic recipients.Because of cell-mediated and humoral immunity defects and impaired reticuloendothelial system function, allogeneic patients with chronic GVHD and recipients of alternate donor allogeneic transplants are at risk for certain infections during this phase.Alternate donors include matched unrelated, UCB, or mismatched family-related donors.These patients are at risk for infections that include CMV, varicella-zoster virus (VZV), EBV-related posttransplant lymphoproliferative disease, community-acquired respiratory viruses (CRV), and infections with encapsulated bacteria (e.g., Ha.influenzae and Stre.pneumoniae). Risk for these infections is approximately proportional to the severity of the patient's GVHD during phases II and III.Patients receiving mismatched allogeneic transplants have a higher attack rate and severity of GVHD and, therefore, a higher risk for OIs during phases II and III than do patients receiving matched allogeneic HSCTs.In contrast, patients undergoing autologous transplantation are primarily at risk for infection during phase I. Preventing infections among HSCT recipients is preferable to treating infections.However, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients.Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain # BACTERIAL INFECTIONS # General Recommendations Preventing Exposure Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII). # Preventing Disease Preventing Early Disease (0-100 Days After HSCT).Routine gut decontamination is not recommended for HSCT candidates (51-53 ) (DIII).Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients.Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51 ), infection-related fatality rates are not reduced (52 ).If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII).The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es.coli (51,52 ), vancomycin-intermediate Sta.aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54 ).Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII).Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55 ); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease. Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention.Researchers have recommended routine IVIG- use to prevent bacterial infections among the approximately 20%-25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG 400-500 mg/dl (58 ) (BII).Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix). Preventing Late Disease (>100 Days After HSCT).Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre.pneumoniae, Ha.influenzae, or Ne.meningitidis ) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59 ) (BIII).Antibiotic selection should be guided by local antibiotic resistance patterns.In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels 90 days after HSCT is not recommended (60 ) (DI) as a means of preventing bacterial infections. Other Disease Prevention Recommendations.Routine use of IVIG among autologous recipients is not recommended (61 ) (DII).Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients. # Recommendations Regarding Stre.pneumoniae Preventing Exposure Appropriate care precautions should be taken with hospitalized patients infected with Stre.pneumoniae (62,63 ) (BIII) to prevent exposure among HSCT recipients. # Preventing Disease Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients.However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64-66 ) (BIII).No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made. Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre.pneumoniae , Ha.influenzae , and Ne.

meningitidis ) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59 ) (BIII).Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections.However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre.pneumoniae disease.Certain strains of Stre.pneumoniae are resistant to TMP-SMZ and penicillin.Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients. As with adults, pediatric HSCT recipients aged ³2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII).However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI).No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made. # Recommendations Regarding Streptococci viridans Preventing Exposure Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known. # Preventing Disease Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia.Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67 ) (AIII). Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII).No data were found that demonstrate efficacy of prophylactic antibiotics for this infection.Furthermore, such use might select antibioticresistant bacteria, and in fact, penicillin-and vancomycin-resistant strains of Streptococci viridans have been reported (68 ).However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII).Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII). HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII).Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69 ). # Recommendations Regarding Ha.influenzae type b Preventing Exposure Adults with Ha.influenzae type b (Hib) pneumonia require standard precautions (62 ) to prevent exposing the HSCT recipient to Hib.Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions.Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71 ); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix).This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72)(73)(74).Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII). # Preventing Disease Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII).This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies ³4 months after HSCT (75 ), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77 ).HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70 ) (BIII) (Appendix). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre.pneumoniae, Ha.influenzae, or Ne.meningitidis ) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59 ) (BIII).Antibiotic selection should be guided by local antibiotic-resistance patterns.Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients.Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70 ) (BIII).Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71 ) (Appendix). # VIRAL INFECTIONS # Recommendations Regarding Cytomegalovirus Preventing Exposure HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII).Only Food and Drug Administration (FDA) licensed or approved tests should be used.HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII). Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII).However, even long-time monogamous pairs can be discordant for CMV infections.Therefore, during periods of immunocompromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). # MMWR October 20, 2000 After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII).CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 10 6 leukocytes/unit) to prevent transfusion-associated CMV infection (78 ) (AI).However, insufficient data were found to recommend use of leukocyte-reduced or CMVseronegative red cells and platelets among CMV-seronegative recipients who have CMVseropositive donors (i.e., R-negative or D-positive). All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients.HSCT patients who are known to excrete CMV should be placed under standard precautions (62 ) for the duration of CMV excretion to avoid possible transmission to CMVseronegative HSCT recipients and candidates (AIII).Physicians are cautioned that CMV excretion can be episodic or prolonged. # Preventing Disease and Disease Recurrence HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI).Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI).In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability. Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT).The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix). Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII).Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT.It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected.Allogeneic recipients at risk should be screened ³1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII). HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment.Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80 ) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79)(80)(81).Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) ( 82) is very sensitive but has a low positive predictive value (79 ).Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing. Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83 ) or routine culture (84,85 ) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests.Also, rapid shell-viral cultures require ³48 hours and routine viral cultures can require weeks to obtain final results.Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests.HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86 ) (BII).Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 or CMV pp67 viral RNA detection) ( 88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made. Allogeneic recipients £100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has ³2 consecutively positive CMV-DNA PCR tests (BIII).After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix).Antigen or PCR tests should be negative when ganciclovir is stopped.Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89-91 ) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII). Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII).No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress.One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92 ), but no recommendation can be made regarding this strategy because of limited data.Patients who are ganciclovir-intolerant should be administered foscarnet instead (93 ) (BII) (Appendix).HSCT recipients receiving ganciclovir should have ANCs checked ³2 times/week (BIII).Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94 ) or temporarily stopping ganciclovir for ³2 days if the patient's ANC is 5 days after ganciclovir has been stopped (CIII) (Appendix).Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII). Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III).However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII).Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell-depleted HSCTs who are at high risk (95)(96)(97)(98)(99).If CMV is still detectable by routine screening ³100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI).If low-grade CMV antigenemia (<5 positive cells/ slide) is detected on routine screening, the antigenemia test should be repeated in 3 days MMWR October 20, 2000 (BIII).If CMV antigenemia indicates ³5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix).Ganciclovir should also be started if the patient has had ³2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT).Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function. If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected.If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100 ) or stopping ganciclovir and starting foscarnet (CIII).Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93 ). Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made.Although, in a substantial cooperative study, highdose acyclovir has had certain efficacy for preventing CMV disease (101 ), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102 ).Acyclovir is not effective in preventing CMV disease after autologous HSCT (103 ) and is, therefore, not recommended for CMV preemptive therapy (DII).Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII). Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI).Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis.The drug's major disadvantage is nephrotoxicity.Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made. Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease.However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII).Researchers report that CMVseropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII).This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80 ) or quantitative PCR (BII). Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of ³5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80 ), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix).Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients.Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults. # Recommendations Regarding EBV Preventing Exposure All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII).For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing and avoiding the sharing of cups, glasses, and eating utensils with others) (104 ) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104 ) (AII). # Preventing Disease Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell-depleted unrelated or mismatched allogeneic recipients (105,106 ).However, insufficient data were found to recommend its use.Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108 ) (DII). # Recommendations Regarding HSV Preventing Exposure HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary.Only FDA-licensed or -approved tests should be used.All HSCT candidates, particularly those who are HSVseronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII).HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII).Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII).However, even long-time monogamous pairs can be discordant for HSV infections.Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody.If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62 ) (AI) to prevent transmission of HSV to HSCT recipients. # Preventing Disease and Disease Recurrence Acyclovir.Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109-113 ) (AI).Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix).

Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII).Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII).Researchers have proposed administration of ganciclovir prophylaxis alone (86 ) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114 ), although ganciclovir has not been approved for use against HSV. Valacyclovir.Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome among HSCT recipients (115 ).Controlled trial data among HSCT recipients are limited (115 ), and the FDA has not approved valacyclovir for use among recipients.Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix). Foscarnet.Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII). Famciclovir.Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made. # Other Recommendations HSV prophylaxis lasting >30 days after HSCT might be considered for persons with frequent recurrent HSV (CIII) (Appendix).Acyclovir can be used during phase I for administration to HSV-seropositive autologous recipients who are likely to experience substantial mucositis from the conditioning regimen (CIII).Antiviral prophylaxis doses should be modified for use among children (Appendix), but no published data were found regarding valacyclovir safety and efficacy among children. # Recommendations Regarding VZV Preventing Exposure HSCT candidates should be tested for the presence of serum anti-VZV IgG antibodies (AIII).However, these tests are not 100% reliable, particularly among severely immunosuppressed patients.Researchers recommend that a past history of varicella accompanied by a positive titer is more likely to indicate the presence of immunity to VZV than a low positive titer alone.All HSCT candidates and recipients, particularly those who are VZV-seronegative, should be informed of the potential seriousness of VZV disease among immunocompromised persons and advised of strategies to decrease their risk for VZV exposure (116)(117)(118)(119)(120)(121)(122) # (AII). Although researchers report that the majority of VZV disease after HSCT is caused by reactivation of endogenous VZV, HSCT candidates and recipients who are VZVseronegative, or VZV-seropositive and immunocompromised, should avoid exposure to persons with active VZV infections (123 ) (AII).HCWs, family members, household contacts, and visitors who are healthy and do not have a reported history of varicella infection or who are VZV-seronegative should receive VZV vaccination before being allowed to visit or have direct contact with an HSCT recipient (AIII).Ideally, VZV-susceptible family members, household contacts, and potential visitors of immunocompromised HSCT recipients should be vaccinated as soon as the decision is made to perform HSCT.The vaccination dose or doses should be completed ³4 weeks before the conditioning regimen begins or ³6 weeks (42 days) before the HSCT is performed (BIII). HSCT recipients and candidates undergoing conditioning therapy should avoid contact with any VZV vaccine recipient who experiences a rash after vaccination (BIII).When this rash occurs, it usually appears 14-21 days after VZV vaccination (median: 22 days; range: 5-35 days) (personal communication from Robert G. Sharrar, M.D., Merck & Co., Inc.).However, to date, no serious disease has been reported among immunocompromised patients from transmission of VZV vaccine virus, and the VZV vaccine strain is susceptible to acyclovir. All HSCT recipients with VZV disease should be placed under airborne and contact precautions (62 ) (AII) to prevent transmission to other HSCT recipients.Contact precautions should be continued until all skin lesions are crusted.Airborne precautions should be instituted 10 days after exposure to VZV and continued until 21 days after last exposure or 28 days postexposure if the patient received varicella-zoster immunoglobulin (VZIG)- (62 ) (AI) because a person infected with VZV can be infectious before the rash appears. # Preventing Disease VZIG.VZV-seronegative HSCT recipients should be administered VZIG as soon as possible but ideally within 96 hours after close or household contact with a person having either chickenpox or shingles if the HSCT recipient is not immunocompetent (i.e., allogeneic patient <24 months after HSCT, ³24 months after HSCT and on immunosuppressive therapy, or having chronic GVHD) (AII).Researchers report VZIG administration for VZV exposure as described for HSCT recipients who were VZV-seropositive before HSCT (CIII). Because of the high morbidity of VZV-associated disease among severely immunocompromised HSCT recipients and until further data are published, HSCT physicians should administer VZIG to all VZV-seronegative HSCT recipients or candidates undergoing conditioning therapy who are exposed to a VZV vaccinee having a varicellalike rash (BIII).Researchers also report VZIG administration for this situation for VZVseropositive HSCT recipients and candidates undergoing conditioning therapy (CIII).These recommendations are made because the vaccinee might be unknowingly incubating wild-type varicella, particularly during the first 14 days after varicella vaccination, and because vaccine-strain VZV has been rarely transmitted by VZV vaccinees with vesicular rashes postvaccination (121 ). If VZV-seronegative HSCT recipients or candidates undergoing conditioning therapy are closely exposed to varicella >3 weeks after receiving VZIG, they should be administered another dose of VZIG (120 ) Antiviral Drugs.Any HSCT recipient or candidate undergoing conditioning therapy who experiences a VZV-like rash (particularly after exposure to a person with wild-type varicella or shingles) should receive preemptive intravenous acyclovir until ³2 days after all lesions have crusted (BIII) (Appendix).Any HSCT recipient or candidate undergoing conditioning therapy who experiences a VZV-like rash after exposure to a VZV vaccinee with a rash should be administered intravenous acyclovir preemptively to prevent severe, disseminated VZV disease (BII).Acyclovir should be administered until 2 days after all lesions have crusted. Long-term acyclovir prophylaxis to prevent recurrent VZV infection (e.g., during the first 6 months after HSCT) is not routinely recommended (124-126 ) (DIII); however, this therapy could be considered for use among HSCT recipients with severe, long-term immunodeficiency (CIII).When acyclovir resistance occurs among patients, HSCT physicians should use foscarnet for preemptive treatment of VZV disease (127 ) (BIII).Researchers report valacyclovir use for preventing HSV among HSCT recipients (CIII).However, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115 ).Controlled trial data regarding HSCT recipients are limited (115 ), and the FDA has not approved valacyclovir for use among HSCT recipients.Physicians wishing to use valacyclovir among HSCT recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).No data were found demonstrating safety and efficacy of preemptive treatment of famciclovir against herpes zoster among HSCT recipients.Consequently, no recommendation for its use can be made. Live-Attenuated VZV Vaccine.VZV vaccine use is contraindicated among HSCT recipients <24 months after HSCT (128 ) (EIII).Use of VZV vaccine among HSCT recipients is restricted to research protocols for recipients ³24 months after HSCT who are presumed immunocompetent.Further research is needed to determine the safety, immunogenicity, and efficacy of VZV vaccine among HSCT recipients. # Other Recommendations An inactivated VZV vaccine has been used investigationally among HSCT recipients (129 ); however, more studies are needed before a recommendation regarding its use can be made.Recommendations for VZV prevention are the same for allogeneic or autologous recipients.Recommendations for preventing VZV disease among pediatric or adult HSCT recipients are the same, except that appropriate dose adjustments for VZIG should be made for pediatric HSCT recipients (AIII) (Appendix). # Recommendations Regarding CRV Infections: Influenza, Respiratory Syncytial Virus, Parainfluenza Virus, and Adenovirus Preventing Exposure Preventing CRV exposure is critical in preventing CRV disease (130,131 ).To prevent nosocomial CRV transmission, HSCT recipients and their HCWs should always follow HSCT infection control guidelines (AIII).To minimize the risk for CRV transmission, HCWs and visitors with upper respiratory infection (URI) symptoms should be restricted from contact with HSCT recipients and HSCT candidates undergoing conditioning therapy (AIII).At a minimum, active clinical surveillance for CRV disease should be conducted on all hospitalized HSCT recipients and candidates undergoing conditioning therapy; this clinical surveillance should include daily screening for signs and symptoms of CRV (e.g., URI or lower respiratory infection ) (AIII).Viral cultures of asymptomatic HSCT candidates are unlikely to be useful.HSCT recipients with URI or LRI symptoms should be placed under contact precautions to avoid transmitting infection to other HSCT candidates and recipients, HCWs, and visitors until the etiology of illness is identified (62 ) (BIII).Optimal isolation precautions should be modified as needed after the etiology is identified (AIII).HSCT recipients and candidates, their family members and visitors, and all HCWs should be informed regarding CRV infection control measures and the potential severity of CRV infections among HSCT recipients (130-140 ) (BIII).Physicians have routinely conducted culture-based CRV surveillance among HSCT recipients; however, the cost effectiveness of this approach has not been evaluated. Influenza vaccination of family members and close or household contacts is strongly recommended during each influenza season (i.e., October-May) starting the season before HSCT and continuing ³24 months after HSCT (141 ) (AI) to prevent influenza exposure among the recipients or candidates.All family members and close or household contacts of HSCT recipients who remain immunocompromised ³24 months after HSCT should continue to be vaccinated annually as long as the HSCT recipient's immunocompromise persists (141 ) (AI).Seasonal influenza vaccination is strongly recommended for all HCWs of HSCT recipients (142,143 ) (AI). If HCWs, family members, or other close contacts of HSCT recipients receive influenza vaccination during an influenza A outbreak, they should receive amantadine or rimantadine chemoprophylaxis for 2 weeks after influenza vaccination (BI) while the vaccinee experiences an immunologic response to the vaccine.Such a strategy is likely to prevent transmission of influenza A to HCWs and other close contacts of HSCT recipients, which could prevent influenza A transmission to HSCT recipients themselves.However, if a nosocomial outbreak occurs with an influenza A strain that is not contained in the available influenza vaccine, all healthy family members, close and household contacts, and HCWs of HSCT recipients and candidates should be administered influenza A chemoprophylaxis with amantadine or rimantadine until the end of the outbreak (141 ) (BIII). In 1999, two neuroaminidase inhibitors (zanamivir and oseltamivir) were approved for treatment of influenza, but are not currently approved for prophylaxis.To date, experience is limited regarding use of zanamivir or oseltamivir in the treatment or prophylaxis of influenza among HSCT settings.However, HCWs, family members, or other close contacts can be offered a neuroaminidase inhibitor (e.g., zanamivir or oseltamivir) using the same strategies outlined previously, if a) rimantadine or amantadine cannot be tolerated, b) the outbreak strain of influenza A is amantadine or rimantadine-resistant, or c) the outbreak strain is influenza B (144-147 ) (BI).Zanamivir can be administered to persons aged ³12 years, and oseltamivir can be administered to persons aged ³18 years.Patients with influenza should be placed under droplet and standard precautions (AIII) to prevent transmission of influenza to HSCT recipients.HCWs with influenza should be excused from patient care until they are no longer infectious (AIII). # Preventing Disease HSCT physicians should determine the etiology of a URI in an HSCT recipient or candidate undergoing conditioning therapy, if possible, because respiratory syncytial Recommendations Regarding Influenza.Life-long seasonal influenza vaccination is recommended for all HSCT candidates and recipients, beginning during the influenza season before HSCT and resuming ³6 months after HSCT (142 ) (BIII).Influenza vaccinations administered to HSCT recipients 24 months after HSCT and still substantially immunocompromised (i.e., receiving immunosuppressive therapy, have had a relapse of their underlying disease, or have GVHD) and who have not yet received a current influenza vaccination, should be vaccinated against influenza immediately (BIII).Additionally, to allow sufficient time for the patient to experience an immunologic response to influenza vaccine, chemoprophylaxis with amantadine or rimantadine can be used for these HSCT recipients for 2 weeks after vaccination during a nosocomial or community influenza A outbreak (CIII).Influenza A chemoprophylaxis with amantadine or rimantadine has been recommended for all influenza A-exposed HSCT recipients <24 months after HSCT or ³24 months after HSCT and substantially immunocompromised regardless of vaccination history, because of their likely suboptimal immunologic response to influenza vaccine (142,143 ).However, no recommendation regarding such chemoprophylaxis can be made because of lack of data. To prevent severe disease, early preemptive therapy with amantadine or rimantadine has been reported for HSCT recipients with unexplained acute URI or LRI symptoms during a community or nosocomial outbreak of influenza A (141 ).However, the effectiveness in preventing influenza-related complications and the safety of this strategy have not been evaluated among HSCT recipients.Therefore, data are insufficient to make a recommendation. Neuroaminidase inhibitors (zanimivir and oseltamivir), intravenous and aerosol ribavirin, and combination drug therapy (e.g., rimantadine or amantadine with ribavirin or interferon) (143,(150)(151)(152)(153) have been proposed for investigational, preemptive treatment to prevent severe influenza disease among HSCT recipients.However, because of lack of data, no recommendation for use of these strategies among HSCT recipients can be made. # Recommendations Regarding RSV. Respiratory secretions of any hospitalized HSCT candidate or recipient who experiences signs or symptoms of CRV infection should be tested promptly by viral culture and rapid diagnostic tests for RSV (BIII).If two diagnostic samples taken ³2 days apart do not identify a respiratory pathogen despite persistence of respiratory symptoms, BAL and further testing are advised (BIII).This testing is critical because of the high morbidity and case fatality of RSV disease among HSCT recipients (154,155 ).HSCT recipients, particularly those who are preengraftment and at highest risk for severe RSV pneumonia, should have their illness diagnosed early (i.e., during RSV URI), and their illness should be treated aggressively to prevent fatal RSV disease (BIII). Although a definitive, uniformly effective preemptive therapy for RSV infection among HSCT recipients has not been identified, certain strategies have been proposed, including use of aerosolized ribavirin (155,156 ), RSV antibodies (i.e., passive immunization with high RSV-titered IVIG or RSV immunoglobulin) in combination with aerosolized ribavirin (137,157 ), and RSV monoclonal antibody (158 ).Clinical trials are currently underway to evaluate the efficacy of these strategies.No recommendation regarding the optimal method for RSV prevention and preemptive therapy can be made because of limited data.Further, current data do not support use of intravenous ribavirin for preemptive therapy for RSV pneumonia among HSCT recipients (60 ) (DIII), and no commercially licensed vaccines against RSV are currently available. Recommendations Regarding Parainfluenza Virus and Adenovirus.Immunoprophylaxis, chemoprophylaxis, and preemptive treatment for parainfluenza virus and adenovirus infections among HSCT recipients have been proposed (159,160 ).However, no recommendation can be made in these guidelines because of insufficient data.No commercially licensed vaccines against parainfluenza or adenovirus are currently available. # Other Disease Prevention Recommendations The recommendations for preventing CRV infections and their recurrence are the same for allogeneic or autologous recipients.Generally, these recommendations apply to children or adults (161)(162)(163)(164), but with appropriate adjustments in antiviral drug and influenza vaccine doses for children (Appendix). For pediatric HSCT recipients and candidates aged >6 months, annual seasonal influenza vaccination is recommended HSCT (BIII).Children aged <9 years who are receiving influenza vaccination for the first time require two doses administered ³1 months apart (AI).Healthy children who receive influenza vaccination for the first time might not generate protective antibodies until 2 weeks after receipt of the second dose of influenza vaccine.Therefore, during an influenza A outbreak, pediatric recipients aged <9 years, ³6 months after HSCT, and receiving their first influenza vaccination, should be administered ³6 weeks of influenza A chemoprophylaxis after the first dose of influenza vaccine (141 ) (BIII) (Appendix).Amantadine and rimantadine are not FDA-approved for children aged <1 year (141,161 ) (DIII). To prevent RSV disease, researchers report substituting RSV-IVIG for IVIG during RSV season (i.e., November-April) for pediatric recipients (i.e., children aged <18 years) who receive routine IVIG therapy (164 ) (i.e., those with hypogammaglobulinemia) (CIII) (Appendix).Other researchers report that pediatric recipients with RSV can be considered for preemptive therapy (e.g., during URI or early LRI) with aerosolized ribavirin (CIII), although this therapy remains controversial (164 ) (Appendix).Droplet and contact precautions for the duration of illness are required for pediatric recipients for the duration of adenovirus (62 ) (AIII). # MMWR October 20, 2000 FUNGAL INFECTIONS General Recommendations Preventing Exposure Limited data were found that demonstrate to what extent preventing fungal exposures is effective in preventing infection and disease.However, HSCT recipients and candidates undergoing conditioning therapy have been advised to avoid contact with certain areas and substances, including foods, that might increase a patient's risk for fungal exposures (CII).Specific precautions have included avoiding areas of high dust exposure (e.g., excavation sites, areas of building construction or renovation, chicken coops, and caves), occupations involving soil, and foods that contain molds (e.g., blue cheese). # Preventing Disease Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (165 ); however, no data were found that indicate which growth factors effectively reduce the attack rate of invasive fungal disease.Therefore, no recommendation for use of growth factors solely for prophylaxis against invasive fungal disease can be made. Topical antifungal drugs, which are applied to the skin or mucosa (e.g., nystatin or clotrimazole), might reduce fungal colonization in the area of application.However, these agents have not been proven to prevent generation of locally invasive or disseminated yeast infections (e.g., candidiasis) or mold infections (e.g., aspergillosis) and are not recommended for their prophylaxis (DII).Performing fungal surveillance cultures is not indicated for asymptomatic HSCT recipients (166,167 ) (DII), but cultures should be obtained from symptomatic HSCT recipients (BIII). # Recommendations Regarding Yeast Infections Preventing Exposure Invasive candidiasis is usually caused by dissemination of endogenous Candida species that have colonized a patient's gastrointestinal tract (168 ).

Consequently, methods of preventing exogenous yeast exposure usually do not prevent invasive yeast infections after HSCT.However, because Candida species can be carried on the hands, HCWs and others in contact with HSCT recipients should follow appropriate hand-washing practices to safeguard patients from exposure (AIII). # Preventing Disease Allogeneic recipients should be administered fluconazole prophylaxis to prevent invasive disease with fluconazole-susceptible Candida species during neutropenia, particularly among centers where Can.albicans is the predominant cause of invasive fungal disease preengraftment (AI) (Appendix).Because candidiasis occurs during phase I (169 ), fluconazole (400 mg/day by mouth or intravenously) should be administered (169,170 ) from the day of HSCT until engraftment (AII).However, fluconazole is not effective against certain Candida species, including Can.krusei (171 ) and Can.glabrata and is, therefore, not recommended for their prevention (DI).Further studies are needed to determine the optimal duration of fluconazole prophylaxis.Preliminary studies have reported that low-dose fluconazole prophylaxis (100-200 mg/day by mouth) among neutropenic patients has variable efficacy in preventing candidiasis (172 ).Therefore, this therapy is not recommended for HSCT recipients (DII).Oral, nonabsorbable antifungal drugs, including oral amphotericin B (500 mg suspension every 6 hours), nystatin, and clotrimazole troches, might reduce superficial colonization and control local mucosal candidiasis, but have not been demonstrated to reduce invasive candidiasis (CIII). # Other Recommendations HSCT candidates with candidemia or invasive candidiasis can safely receive transplants ( 173) if a) their infection was diagnosed early and treated immediately and aggressively with amphotericin B or alternatively with appropriate doses of fluconazole if the organism is susceptible; and b) evidence of disease control is reported (e.g., by serial computed tomography scans) before the transplant (BIII).Such patients should continue receiving therapeutic doses of an appropriate antifungal drug throughout phase I (BII) and until a careful review of clinical, laboratory, and serial computed tomography scans verifies resolution of candidiasis (BII). Because autologous recipients generally have an overall lower risk for invasive fungal infection than allogeneic recipients, certain autologous recipients do not require routine antiyeast prophylaxis (DIII).However, researchers recommend administering antiyeast prophylaxis to a subpopulation of autologous recipients with underlying hematologic malignancies (e.g., lymphoma or leukemia) and who have or will have prolonged neutropenia and mucosal damage from intense conditioning regimens or graft manipulation, or have received fludarabine or 2-CDA recently (BIII).Recommendations regarding preventing invasive yeast infections among pediatric or adult HSCT recipients are the same, except that appropriate dose adjustments for prophylactic drugs should be made for pediatric recipients (Appendix). # Recommendations Regarding Mold Infections Preventing Exposure Nosocomial mold infections among HSCT recipients result primarily from respiratory exposure to and direct contact with fungal spores (174 ).Ongoing hospital construction and renovation have been associated with an increased risk for nosocomial mold infection, particularly aspergillosis, among severely immunocompromised patients (175-177 ).Therefore, whenever possible, HSCT recipients who remain immunocompromised should avoid hospital construction or renovation areas (AIII).When constructing new HSCT centers or renovating old ones, hospital planners should ensure that rooms for HSCT patients have an adequate capacity to minimize fungal spore counts through use of - correctly sealed rooms, including correctly sealed windows and electrical outlets (140 ) (BIII); - high rates of room air exchange (i.e., >12 air changes/hour) (140,178 ) (BIII); and - barriers between patient care and renovation or construction areas (e.g., sealed plastic) that prevent dust from entering patient care areas and that are impermeable to Aspergillus species (175,179 ) (BIII). Additionally, HSCT centers should be cleaned with care, particularly after hospital renovation or construction, to avoid exposing HSCT recipients and candidates to mold spores (174,176 ) (BIII). # Preventing Disease No regimen has been reported to be clearly effective or superior in preventing aspergillosis, and therefore, no recommendation can be made.Further studies are needed to determine the optimal strategy for aspergillosis prevention.Moderate-dose (0.5 mg/kg/day) amphotericin B (181-184 ), low-dose (0.1-0.25 mg/kg/day) amphotericin B (185-187 ), intranasal amphotericin B spray (188 ), lipid formulations of amphotericin B (182,189 ), and aerosolized amphotericin B (190 ) have been administered for aspergillosis prophylaxis, but data are limited regarding the safety and efficacy of these formulations among HSCT recipients.Additionally, itraconazole capsules are not recommended for fungal prophylaxis among HSCT recipients (191 ) (DII) for three reasons.First, itraconazole capsules are poorly absorbed gastrointestinally, particularly among patients who are fasting (192 ) or receiving cytotoxic agents (193 ).Second, persons taking itraconazole capsules do not achieve steady-state serum levels for 2 weeks (188,194 ), and when achieved, these levels are lower than the average Aspergillus species minimum inhibitory concentration (MIC) among HSCT recipients (195 ).Third, itraconazole has adverse interactions with other drugs (e.g., antiepileptics, rifampin, oral hypoglycemics, protease inhibitors, vinca alkaloids, cyclosporine, methylprednisolone, and warfarin-like anticoagulants) (196 ).Trials assessing the efficacy of the recently licensed cyclodextrin oral solution and intravenous formulations of itraconazole in preventing invasive fungal disease among HSCT recipients are in progress; however, no recommendations regarding its use for Aspergillus species infection prophylaxis can be made.For HSCT recipients whose respiratory specimens are culture positive for Aspergillus species, acute invasive aspergillosis should be diagnosed presumptively (197 ) and treated preemptively and aggressively (e.g., with intravenous amphotericin) (AIII). The risk for aspergillosis recurrence has been high among allogeneic recipients with preexisting invasive aspergillosis.Previously, allogeneic HSCTs were avoided among persons with uncontrolled, proven aspergillosis.However, HSCT center personnel have recently reported successful allogeneic or autologous HSCT among a limited number of persons who have had successfully treated, prior invasive pulmonary aspergillosis (198)(199)(200).Because of limited data, no recommendations regarding strategies for preventing aspergillosis recurrence can be made. # MMWR 25 PROTOZOAL AND HELMINTHIC INFECTIONS # Recommendations Regarding PCP Preventing Exposure Although a possible cause of PCP is reactivation of latent infection among immunocompromised persons, cases of person-to-person transmission of PCP have been reported (201)(202)(203)(204)(205)(206).Generally, standard precautions should be used for patients with PCP (62 ) (BIII), but researchers have reported patients with PCP being isolated (201,204 ) and contact precautions being used if evidence existed of person-to-person transmission in the institution (CIII).This subject remains controversial, and until further data are published, HSCT recipients should avoid exposure to persons with PCP (62 ) (CIII). # Preventing Disease and Disease Recurrence Physicians should prescribe PCP prophylaxis for allogeneic recipients throughout all periods of immunocompromise ( 207) after engraftment.Prophylaxis should be administered from engraftment until 6 months after HSCT (AII) for all patients, and >6 months after HSCT for the duration of immunosuppression for those who a) are receiving immunosuppressive therapy (e.g. prednisone or cyclosporine) (AI), or b) have chronic GVHD (BII).However, PCP prophylaxis can be initiated before engraftment if engraftment is delayed (CIII).Researchers report an additional 1-to 2-week course of PCP prophylaxis before HSCT (i.e., day -14 to day -2) (CIII). Preferred PCP prophylaxis is TMP-SMZ (AII); however, if TMP-SMZ is administered before engraftment, the associated myelosuppression could delay engraftment, and patients might experience sensitivity to the drug.Every effort should be made to keep such patients on the drug, including assessment of desensitization therapy, although data regarding this technique among HSCT recipients are limited.For patients who cannot tolerate TMP-SMZ, physicians can choose to use alternative PCP prophylaxis regimens (e.g., dapsone) (208 ) (BIII).Use of aerosolized pentamidine ( 209) is associated with the lowest PCP prevention rates and should only be used if other agents cannot be tolerated.Atovaquone is a possible alternative drug for PCP prophylaxis among dapsoneintolerant persons with HIV infection (210 ); however, no recommendation regarding use of atovaquone among HSCT recipients can be made because of lack of data.Although data are limited, concomitant use of leucovorin (folinic acid) and TMP-SMZ is not recommended (211,212 ) (DIII).A patient's history of PCP should not be regarded as a contraindication to HSCT (213 ) (DIII). Recurrent PCP among HSCT recipients is rare; however, patients with continued immunosuppression should remain on PCP prophylaxis until their immunosuppression is resolved (AI).The regimen recommended for preventing toxoplasmosis recurrence among HSCT recipients (i.e., TMP-SMZ) will also prevent PCP recurrence. # Other Recommendations PCP prophylaxis should be considered for autologous recipients who have underlying hematologic malignancies (i.e., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-CDA MMWR October 20, 2000 (207,214 ) (BIII).PCP prophylaxis should be administered ³6 months after HSCT if substantial immunosuppression or immunosuppressive therapy (e.g., steroids) persists (CIII).Use of PCP prophylaxis among other autologous recipients is controversial (CIII).Generally, indications for PCP prophylaxis are the same among children or adults, but pediatric doses should be used (Appendix). # Recommendations Regarding Toxoplasma gondii Preventing Exposure All HSCT recipients should be provided information regarding strategies to reduce their risk for Toxoplasma species exposure.Researchers report that potential donors for allogeneic HSCT be tested for To.gondii antibodies (215,216 ) by using FDA-licensed or -approved screening tests that include IgG antibody testing because To.gondii has been reported to be transmitted by leukocyte transfusion (217 ) and HSCT (218,219 ) (CIII). # Preventing Disease and Disease Recurrence Because most toxoplasmosis among HSCT recipients is caused by disease reactivation, researchers report that candidates for allogeneic HSCT can be tested for IgG antibody to determine whether they are at risk for disease reactivation after HSCT (215,216,218 ) (CIII).However, the value of such testing is controversial because a limited number of patients who were seronegative for To.gondii pretransplant experienced the infection posttransplant (220 ).If testing is performed, only FDA-licensed or -approved screening tests should be used. Researchers recommend toxoplasmosis prophylaxis for seropositive allogeneic recipients with active GVHD or a prior history of toxoplasmic chorioretinitis (221,222 ), but data demonstrating efficacy are limited (CIII).The optimal prophylactic regimen for toxoplasmosis among HSCT recipients has not been determined, but a proposed drug is TMP-SMZ (BII), although allogeneic recipients have experienced break-through clinical disease despite TMP-SMZ prophylaxis (218 ).For patients who are TMP-SMZ-intolerant, a combination of clindamycin, pyramethamine, and leucovorin can be substituted for To.gondii prophylaxis (Appendix).After therapy for toxoplasmosis, HSCT recipients should continue receiving suppressive doses of TMP-SMZ or an alternate regimen for the duration of their immunosuppression (BIII) (Appendix). # Other Recommendations Recipients of autologous transplants are at negligible risk for toxoplasmosis reactivation (218 ).No prophylaxis or screening for toxoplasmosis infection is recommended for such patients (DIII).Indications for toxoplasmosis prophylaxis are the same among children or adults, but pediatric doses should be used among children (Appendix). # Recommendations Regarding Strongyloides stercoralis Preventing Exposure Allogeneic recipients should avoid contact with outhouses and cutaneous exposure to soil or other surfaces that might be contaminated with human feces (223 ) (AIII).Allogeneic recipients who work in settings (e.g., hospitals or institutions) where they could be exposed to fecal matter should wear gloves when working with patients or in areas with potential fecal contamination (AIII). # Preventing Disease and Disease Recurrence Travel and residence histories should be obtained for all patients before HSCT to determine any exposures to high-risk areas (e.g., such moist temperate areas as the tropics, subtropics, or the southeastern United States and Europe) (223 ) (BIII).HSCT candidates who have unexplained peripheral eosinophilia or who have resided in or traveled to areas endemic for strongyloidiasis, even during the distant past, should be screened for asymptomatic strongyloidiasis before HSCT (BIII).Serologic testing with an enzyme-linked immunosorbent assay is the preferred screening method and has a sensitivity and specificity of >90% (223,224 ) (BIII).FDA-licensed or -approved screening tests should be used.Although stool examinations for strongyloidiasis are specific, the sensitivity obtained from ³3 stool examinations is 60%-70%; the sensitivity obtained from concentrated stool exams is, at best, 80% (223 ).A total of ³3 stool examinations should be performed if serologic tests are unavailable or if strongyloidiasis is clinically suspected in a seronegative patient (BIII). HSCT candidates whose screening tests before HSCT are positive for Strongyloides species, and those with an unexplained eosinophilia and a travel or residence history indicative of exposure to Strongyloides stercoralis should be empirically treated before transplantation (225,226 ), preferably with ivermectin (BIII), even if seronegative or stoolnegative (Appendix). To prevent recurrence among HSCT candidates with parasitologically confirmed strongyloidiasis, cure after therapy should be verified with ³3 consecutive negative stool examinations before proceeding with HSCT (AIII).Data are insufficient to recommend a drug prophylaxis regimen after HSCT to prevent recurrence of strongyloidiasis.HSCT recipients who had strongyloidiasis before or after HSCT should be monitored carefully for signs and symptoms of recurrent infection for 6 months after treatment (BIII). # Other Recommendations Hyperinfection strongyloidiasis has not been reported after autologous HSCT; however, the same screening precautions should be used among autologous recipients (BIII).Indications for empiric treatment for strongyloidiasis before HSCT are the same among children or adults except for children weighing <15 kg, for whom the preferred drug is thiabendazole (BIII) (Appendix). # Recommendations Regarding Trypanosoma cruzi Preventing Exposure HSCT physicians should be aware that Trypanosoma cruzi , the etiologic agent of Chagas' disease, can be transmitted congenitally, through blood transfusion (227 ), and possibly through HSCT.Additionally, treatment for persons infected with Tr.cruzi is not always effective, even during the acute stage of infection (227 ).Therefore, potential donors who were born, received a blood transfusion, or ever lived for ³6 months in a Chagas' disease endemic area (e.g., parts of South and Central America and Mexico) should be screened serologically for anti-Tr.cruzi serum IgG antibody ( 228 # Preventing Disease HSCT candidates who are at risk for being infected with Tr.cruzi should be screened for serum IgG anti-Tr.cruzi antibody (228 ) (BIII).Tr.cruzi seropositivity is not a contraindication to HSCT (228,230 ).However, if an acute illness occurs in a Tr.cruzi-seropositive HSCT recipient, particularly during neutropenia, Tr.cruzi reactivation should be included in the differential diagnosis (230 ) (BIII).Researchers have proposed use of beznidazole or nifurtimox for preemptive therapy or prophylaxis of recurrent Tr.cruzi among seropositive HSCT recipients (230,231 ), but insufficient data were found to make a recommendation.* # Other Recommendations Recommendations are the same for autologous or allogeneic recipients.However, recurrence of Chagas' disease is probably less likely to occur among autologous recipients because of the shorter duration of immunosuppression.Recommendations are the same among children or adults. # HOSPITAL INFECTION CONTROL # Room Ventilation HSCT center personnel should follow published guidelines for hospital room design and ventilation (140,180 ) (BIII).HSCT centers should also prevent birds from gaining access to hospital air-intake ducts (140,174 ) (AII).All allogeneic recipients should be placed in rooms with >12 air exchanges/hour (232,233 ) and point-of-use HEPA filters that are capable of removing particles ³0.3 µm in diameter (140,178,180,233 ) # (AIII). Correct filtration is critical in HSCT centers with ongoing construction and renovation (179 ).When portable HEPA filters are used as adjuncts to the primary ventilation system, they must be placed centrally in patient rooms so that space is available around all surfaces to allow free air circulation (BIII).The need for environmental HEPA filtration for autologous recipients has not been established.However, HEPA-filtered rooms should be evaluated for autologous recipients if they experience prolonged neutropenia, a substantial risk factor for nosocomial aspergillosis (CIII). A laminar air flow (LAF) room contains filtered air that moves in parallel, unidirectional flow -the air enters the room from one wall and exits the room on the opposite wall (232 ).Although LAF has been demonstrated to protect patients from infection during aspergillosis outbreaks related to hospital construction (234,235 ), the value of routine LAF room use for all HSCT recipients is doubtful because substantial overall survival benefit has not been reported (236 ).During 1983, LAF rooms were preferred for allogeneic recipients with aplastic anemia and HLA-identical sibling donors because use of regular rooms was associated with a mortality rate that was approximately four times higher than for those recipients treated in LAF rooms (237 ).However, the survival of aplastic anemia HSCT recipients during the late 1990s exceeds that reported during the early 1980s, and no studies have been done to determine whether HSCT recipients with aplastic anemia still have an improved survival rate when treated in an LAF room.Therefore, HSCT centers need not construct LAF rooms for each HSCT recipient.Use of LAF rooms, if available, is optional (CII). Hospital rooms should have directed airflow so that air intake occurs at one side of the room and air exhaust occurs at the opposite side (140 ) (BIII).Each hospital room should also be well-sealed (e.g, around windows and electrical outlets) (140 ) (BIII).To provide consistent positive pressure in the recipient's room, HSCT centers should maintain consistent pressure differentials between the patient's room and the hallway or anteroom at >2.5 Pa (i.e., 0.01 inches by water gauge) (232,233 ) (BIII).Generally, hospital rooms for HSCT recipients should have positive room air pressure when compared with any adjoining hallways, toilets, and anterooms, if present. Anterooms should have positive air pressure compared with hallways ( 180).An exception is the HSCT recipient with an active disease that has airborne transmission (e.g., pulmonary or laryngeal Mycobacteria tuberculosis or measles).These HSCT patients should be placed in negative isolation rooms (62 ) (BIII), and a room with an anteroom is recommended for such patients (180 ) (BIII). Whenever possible, HSCT centers should have self-closing doors to maintain constant pressure differentials among the HSCT recipients' room and anterooms, if available, and hallways (233 ) (BIII).To enable the nursing staff to observe the HSCT recipient even when the doors are closed, windows can be installed in either the door or the wall of the HSCT recipient's room (233 ) (CIII). HSCT centers should provide backup emergency power and redundant air-handling and pressurization systems to maintain a constant number of air exchanges and room pressurization in the center when the central ventilation system is shut off for maintenance and repair (238 ) (BIII).

Additionally, infection control personnel should work with maintenance personnel to develop protocols to protect HSCT centers at all times from bursts of mold spores that might occur when air-handling systems are restarted after routine maintenance shut-downs (BIII). # Construction, Renovation, and Building Cleaning Construction and Renovation Hospital construction and renovation have been associated with an increased risk for nosocomial fungal infection, particularly aspergillosis, among severely immunocompromised patients (175,176 ).Therefore, persons responsible for HSCT center Whenever possible, HSCT recipients, HCWs, and visitors should avoid construction or renovation areas (240 ) (AIII).Also, equipment and supplies used by HSCT recipients or their HCWs should not be exposed to construction or renovation areas (240 ).When planning for construction or renovation, the HSCT center should include plans for intensified aspergillosis-control measures (AIII).Construction and renovation infection control planning committees should include engineers, architects, housekeeping staff, infection control personnel, the director of the HSCT center, the administration, and safety officers (241 ) (BIII). When constructing new HSCT centers, planners should ensure that patient rooms will have adequate capacity to minimize fungal spore counts by following room ventilation recommendations.During outdoor construction and demolition, the intake air should be sealed (BIII), if possible; if not, filters should be checked frequently.Additionally, to protect HSCT patient care areas during fire drills and emergencies, weather stripping should be placed around stairwell doors, or alternatively, the stairwell air should be filtered to the level of safety of the adjacent hospital air (BIII).False ceilings should be avoided whenever possible (174 ) (BII).If use of false ceilings cannot be avoided, the area above false ceilings should be vacuumed routinely to minimize dust and, therefore, fungal exposure to patients (174 ) (BIII). During hospital construction or renovation, hospitals should construct rigid, dustproof barriers with airtight seals (242 ) between patient care and construction or renovation areas to prevent dust from entering patient care areas; these barriers (i.e., sealed drywall) should be impermeable to Aspergillus species (140,175,176,179,240 ) (BIII).If impervious barriers cannot be created around the construction or renovation area, patients should be moved from the area until renovation or construction is complete and the area has been cleaned appropriately (176 ) (BIII).HSCT centers should direct pedestrian traffic occurring near construction or renovation areas away from patient care areas to limit the opening and closing of doors or other barriers that might cause dust dispersion, entry of contaminated air, or tracking of dust into patient areas (140 ), particularly those in the HSCT center (176 ) (BIII).If possible, specific corridors, entrances, and exits should be dedicated to construction use only (240 ).An elevator to which patients do not have access also should be dedicated to construction use only (240 ).Construction workers, whose clothing might be contaminated with Aspergillus species spores, should use the construction elevator and avoid contact with patients, patient care areas, other elevators, and nonconstruction areas (BIII). Hospital construction or renovation areas should have negative air pressure relative to that in adjacent patient care areas, if no contraindications exist for such pressure differential (140,176,179,240,242 ) (BIII).Ideally, air from the construction or renovation areas should be exhausted to the outside of the hospital (176 ) (BIII) or if recirculated, it should be HEPA-filtered first (BIII). Researchers have proposed that HSCT recipients wear the N95 respirator to prevent mold exposure during transportation near hospital construction or renovation areas (CIII) because the N95 respirators are regarded as effective against any aerosol.However, to be maximally effective, N95 respirators must be fit-tested and all users must be trained.With correct personnel fit-testing and training, N95 respirators reliably reduce aerosol exposure by 90%.Without fit-testing and training, aerosol exposure would be reduced but not necessarily by 90% (243 ).For patients who cannot use or tolerate an N95 respirator, researchers have proposed using the powered air purifying respirator (244,245 ), which can be used by patients in wheelchairs.Limitations of the powered air purifying respirator include its cost and that it is not appropriate for young children and infants.General limitations of using respirators are that no commercially available respirator, including N95, has been tested specifically for its efficacy in reducing exposure to Aspergillus species in hospital construction or renovation areas, and no studies have been done that assess the usefulness and acceptability of using respirators among HSCT recipients.Standard surgical masks provide negligible protection against mold spores and are not recommended for this indication (DIII). Newly constructed or renovated areas should be cleaned before patients are allowed to enter them (140,176 ) (AIII).Decontamination of fungal-contaminated areas that cannot be extracted and replaced should be done using copper-8-quinolate (179 ) (BIII).Also, areas above false ceilings located under or adjacent to construction areas should be vacuumed (174 ) (BIII).Additionally, the ventilation, direction of airflow, and room pressurization should be tested and correctly adjusted before patients are allowed to enter (BIII). # Cleaning HSCT centers should be cleaned ³1 times/day with special attention to dust control (BIII).Exhaust vents, window sills, and all horizontal surfaces should be cleaned with cloths and mop heads that have been premoistened with an FDA-or Environmental Protection Agency (EPA)-registered hospital disinfectant (BIII).Thorough cleaning during and after any construction activity, including minor renovation projects, is critical (BIII). HSCT center personnel should prohibit exposures of patients to such activities as vacuuming or other floor or carpet vacuuming that could cause aerosolization of fungal spores (e.g., Aspergillus species) (140 ) (AIII).Accordingly, doors to patient rooms should be closed when vacuuming HSCT center corridors.All vacuum cleaners used in the HSCT center should be fitted with HEPA filters.An FDA-or EPA-registered disinfectant (246,247 ) should be used daily for environmental disinfection and when wet vacuuming is performed in the HSCT center (BIII).If an HSCT center provides care for infants, phenolic disinfectants can be used to clean the floors only if the compound is diluted according to the product label; but phenolic compounds should not be used to clean basinets or incubators (246 ) # (DIII). Water leaks should be cleaned up and repaired as soon as possible but within 72 hours to prevent mold proliferation in floor and wall coverings, ceiling tiles, and cabinetry in and around all HSCT patients care areas (BIII).If cleanup and repair are delayed ³72 hours after the water leak, the involved materials should be assumed to contain fungi and handled accordingly.Use of a moisture meter to detect water penetration of walls should be used whenever possible to guide decision-making (238 ) (BIII).For example, if the wall does not have <20% moisture content ³72 hours after water penetration, it should be removed (BIII).Design and selection of furnishings should focus on creating and maintaining a dust-free environment.Flooring and finishes (i.e., wall coverings, window shades, and countertops) used in HSCT centers should be scrubbable, nonporous, easily disinfected, and they should collect minimal dust (BIII). # Isolation and Barrier Precautions HSCT center personnel should follow published guidelines for hospital isolation practices, including CDC guidelines for preventing nosocomial infections (62,140,248 ) (AIII). # MMWR October 20, 2000 However, the efficacy of specific isolation and barrier precautions in preventing nosocomial infections among HSCT recipients has not been evaluated.HSCT recipients should be placed in private (i.e., single-patient) rooms (BIII).If contact with body fluids is anticipated, standard precautions should be followed (AIII).These precautions include hand washing and wearing appropriate gloves, surgical masks or eye and face protection, and gowns during procedures and activities that are likely to generate splashes or sprays of blood, body fluids, secretions or excretions, or cause soiling of clothing (62 ).When indicated, HSCT recipients should also be placed on airborne, droplet, or contact precautions in addition to standard precautions (62 ) (AIII).Careful observation of isolation precautions is critical in preventing transmission of infectious agents among HSCT recipients, HCWs, visitors, and other HSCT recipients.Physicians are cautioned that HSCT recipients might have a prolonged or episodic excretion of organisms (e.g., CMV). Researchers have proposed that HSCT recipients wear surgical mask and gloves when exiting their hospital rooms before engraftment (CIII).All HSCT recipients who are immunocompromised (phases I-III of immune system recovery) and candidates undergoing conditioning therapy should minimize the time spent in crowded areas of the hospital (e.g., waiting areas and elevators) (BIII) to minimize potential exposure to persons with CRV infections. # Hand Hygiene Hand washing is the single-most critical and effective procedure for preventing nosocomial infection (62 ).All persons, but particularly HCWs, should wash their hands before entering and after leaving the rooms of HSCT recipients and candidates undergoing conditioning therapy (62,249 ) or before and after any direct contact with patients regardless of whether they were soiled from the patient, environment, or objects (AI).HSCT recipients should be encouraged to practice safe hand hygiene (e.g., washing hands before eating, after using the toilet, and before and after touching a wound) (BIII).Hand washing should be done with an antimicrobial soap and water (AIII); alternatively, use of hygienic hand rubs is another acceptable means of maintaining hand hygiene (250,251 ).If gloves are worn, HCWs should put them on in the patient's room after hand washing and then discard them in the same patient's room before washing hands again after exiting the room.When worn, gloves should always be changed between patients or when soiled before touching a clean area (e.g., change gloves after touching the perineum and before going to a "clean" area) (AIII).Appropriate gloves should be used by all persons when handling potentially contaminated biological materials (AII).Items worn on the hands and fingers (e.g., rings or artificial nails ) and adhesive bandage strips, can create a nidus for pathogenic organisms that is difficult to clean.Thus, HCWs should avoid wearing such items whenever possible (BII). # Equipment All HSCT center personnel should sterilize or disinfect and maintain equipment and devices using only EPA-registered compounds as directed by established guidelines (140,180,246,247,(253)(254)(255)(256) (AIII).HSCT center personnel should monitor opened and unopened wound-dressing supplies (e.g., adhesive bandages and surgical and elastic adhesive tape ) to detect mold contamination and prevent subsequent cutaneous transmission to patients (BII). Monitoring should consist of discarding all bandages and wound dressings that are out of date, have damaged packaging, or are visually contaminated by construction debris or moisture (BIII).When arm boards are used to provide support for intravenous lines, only sterile dressing materials should be used (260 ), and arm boards should be changed frequently (e.g., daily) (BIII).Additionally, unsterile tongue depressors inserted into a piece of foam tubing should not be used as splints for intravenous and arterial catheter sites because these have been associated with an outbreak of fatal invasive nosocomial Rhizopus microsporus among preterm (i.e., very low-birth-weight) infants (261 ) (DII).HSCT centers should not install carpeting in hallways outside (DII) or in patient rooms (DIII) because contaminated carpeting has been associated with outbreaks of aspergillosis among HSCT recipients (262,263 ). # Plants, Play Areas, and Toys Although to date, exposure to plants and flowers has not been conclusively reported to cause fungal infections among HSCT recipients, most researchers strongly recommend that plants and dried or fresh flowers should not be allowed in the rooms of hospitalized HSCT candidates undergoing conditioning therapy and HSCT recipients (phases I-III of immune system recovery) because Aspergillus species have been isolated from the soil of potted ornamental plants (e.g., cacti), the surface of dried flower arrangements, and fresh flowers (140,174,178,264 ) (BIII). Play areas for pediatric HSCT recipients and candidates undergoing conditioning therapy should be cleaned and disinfected ³1 times/week and as needed (BIII).Only toys, games, and videos that can be kept clean and disinfected should be allowed in the HSCT center (BIII).HSCT centers should follow published recommendations for washing and disinfecting toys (265 ) (BIII).All HSCT center toys, games, and videos should be routinely and thoroughly washed or wiped down when brought into the HSCT center and thereafter ³1 times/week and as needed by using a nontoxic FDA-or EPA-registered disinfectant (246,247,265 ) followed by a water rinse (BIII).Cloth or plush toys should be washed in a hot cycle of a washing machine or dry-cleaned ³1 times/week and as needed (BIII).Alternatively, machine washing in a cold cycle is acceptable if laundry chemicals for cold water washing are used in proper concentration (265 ).Hard plastic toys should be scrubbed with warm soapy water using a brush to clean crevices, rinsed in clean water, immersed in a mild bleach solution, which should be made fresh daily, for 10-20 minutes, rinsed again, and allowed to air dry (246 ).Alternatively, hard plastic toys can be washed in a dishwasher or hot cycle of a washing machine (BIII).Broviac dolls- should be disassembled upon completion of play and washed with a nontoxic FDA-or EPA-registered disinfectant (246,247 ), rinsed with tap water, and allowed to air dry before other children are allowed to play with them (BIII).Toys that cannot be washed, disinfected, or drycleaned after use should be avoided (BIII).Infants, toddlers, and children who put toys in their mouths should not share toys (265 ) (DIII).For children in isolation, researchers recommend the following: - Disposable play items should be offered whenever possible (BIII). - Before returning a washable toy used in an isolation room to the pediatric play room for use by another child, it should be cleaned again as previously described (BIII). *Broviac dolls are used to demonstrate medical procedures (e.g., insertion of catheters) to children to lessen their fears. # MMWR October 20, 2000 - When a child is taken out of isolation, toys, games, and videos used during the period of isolation and that might serve as fomites for infection should be thoroughly disinfected with a nontoxic FDA-or EPA-registered disinfectant (246,247,265 ) (BIII).After use in isolation rooms, cloth or plush toys should be placed in a plastic bag and separated from unused toys.All cloth or plush toys used in isolation rooms should be washed in a washing machine or dry-cleaned before being used in a nonisolation room (BIII).Toys that cannot be disinfected or dry-cleaned after use in an isolation room should be discarded (BIII). Water-retaining bath toys have been associated with an outbreak of Pseudomonas aeruginosa in a pediatric oncology ward (266 ); therefore, these toys should not be used by immunocompromised HSCT recipients and candidates (DII).Occupational and physical therapy items should be cleaned and disinfected as previously described (BIII).Soil-based materials (e.g., clay or potting soil) should be avoided (BIII). # HCWs HSCT center personnel should have a written comprehensive policy regarding their immunizations and vaccinations, and that policy should meet current CDC, Advisory Committee on Immunization Practices, and Healthcare Infection Control Practices Advisory Committee recommendations (267 ) (BIII).Immunizations are needed to prevent transmission of vaccine-preventable diseases to HSCT recipients and candidates undergoing conditioning therapy.All HCWs with diseases transmissible by air, droplet, and direct contact (e.g., VZV, infectious gastroenteritis, HSV lesions of lips or fingers, and URIs) should be restricted from patient contact and temporarily reassigned to other duties (AI).HSCT center personnel should follow published recommendations regarding the duration of work restrictions for HCWs with infectious diseases (268,269 ) (BIII).HSCT center HCWs with bloodborne viruses (e.g., HIV or hepatitis B or C viruses) should not be restricted from patient contact (DIII) as long as they do not perform procedures that pose a high risk for injury that could result in patient exposure to the HCW's blood or body fluids.Work exclusion policies should be designed to encourage HCWs to report their illnesses or exposures (AII). # HSCT Center Visitors Hospitals should have written policies for screening HSCT center visitors, particularly children, for potentially infectious conditions.Such screening should be performed by clinically trained HCWs (BII).Visitors who might have communicable infectious diseases (e.g., URIs, flu-like illnesses, recent exposure to communicable diseases, an active shingles rash whether covered or not, a VZV-like rash within 6 weeks of receiving a liveattenuated VZV vaccine, or a history of receiving an oral polio vaccine within the previous 3-6 weeks) should not be allowed in the HSCT center or allowed to have direct contact with HSCT recipients or candidates undergoing conditioning therapy (AII).No absolute minimum age requirement for HSCT center visitors exists; however, all visitors must be able to understand and follow appropriate hand washing and isolation precautions (AIII).The number of HSCT center visitors at any one time should be restricted to a number that permits the nursing staff to perform appropriate screening for contagious diseases and adequate instruction and supervision of hand washing, glove and mask use, and biosafety precautions (BIII). # Patient Skin and Oral Care To optimize skin care, HSCT recipients should take daily showers or baths during and after transplantation (BIII), using a mild soap (BIII).Skin care during neutropenia should also include daily inspection of skin sites likely to be portals of infection (e.g., the perineum and intravascular access sites) (BIII).HSCT recipients and candidates undergoing conditioning therapy should maintain good perineal hygiene to minimize loss of skin integrity and risk for infection (BIII).To facilitate this precaution, HSCT center personnel should develop protocols for patient perineal care, including recommendations for gentle but thorough perineal cleaning after each bowel movement and thorough drying of the perineum after each urination (BIII).Females should always wipe the perineum from front to back after using the toilet to prevent fecal contamination of the urethra and urinary tract infections (AIII).Moreover, to prevent vaginal irritation, menstruating immunocompromised HSCT recipients should not use tampons (DIII) to avoid the risk for cervical and vaginal abrasions.Additionally, the use of rectal thermometers, enemas, suppositories, and rectal exams are contraindicated among HSCT recipients to avoid skin or mucosal breakdown (DIII). All HSCT candidates and their caregivers should be educated regarding the importance of maintaining good oral and dental hygiene for at least the first year after HSCT to reduce the risk for oral and dental infections (AIII).

For example, HSCT candidates should be informed that establishment of the best possible periodontal health before HSCT is a substantial step in avoiding short-and long-term oral infections and that maintenance of safe oral hygiene after HSCT can minimize the severity of infections and facilitate healing of mucositis, particularly before engraftment (BIII). All HSCT candidates should receive a dental evaluation and relevant treatment before conditioning therapy begins (270,271 ) (AIII).Likely sources of dental infection should be vigorously eliminated (271 ) (AIII).For example, teeth with moderate to severe caries should be restored; ill-fitting dental prostheses should be repaired; and teeth compromised by moderate to severe periodontal disease should be extracted (271 ).Ideally, 10-14 days should elapse between the completion of tissue-invasive oral procedures and onset of conditioning therapy to allow for adequate healing and monitoring for postsurgical complications (AIII). HSCT recipients with mucositis and HSCT candidates undergoing conditioning therapy should maintain safe oral hygiene by performing oral rinses 4-6 times/day with sterile water, normal saline, or sodium bicarbonate solutions (270 ) (AIII).HSCT recipients and candidates should brush their teeth ³2 times/day with a soft regular toothbrush (270 ) (BIII).If the recipient cannot tolerate these brushings, use of an ultrasoft toothbrush or toothette (i.e., foam swab on a stick), can be used (CIII), but physicians should be aware that using the latter products are less desirable than using soft regular or ultrasoft toothbrushes because the toothettes remove less dental debris (270 ).Using toothpaste is optional, depending on the recipient's tolerance (270 ) (CIII).HSCT recipients and candidates undergoing conditioning therapy who are skilled at dental flossing should floss daily if this can be done without trauma (BIII).Routine dental supervision is advised to monitor and guide the patient's maintenance of oral and dental hygiene (BIII).To decrease the risk for mechanical trauma and infection of oral mucosa, fixed orthodontic appliances and space maintainers should not be worn from the start of conditioning therapy until preengraftment mucositis resolves, and these devices should not be worn during any subsequent periods of mucositis ( 270 the patient's community dentist should coordinate removal of these appliances and longterm rehabilitation of any oral lesions (BIII).However, patients who normally wear removable dental prostheses might be able to wear them during conditioning therapy before HSCT and during mucositis after HSCT, depending on the degree of tissue integrity at the denture-bearing sites and the ability of the patient to maintain denture hygiene on a daily basis (CIII). # Preventing Bacterial Intravascular Catheter-Related Infections HSCT center personnel are advised to implement published guidelines for preventing intravascular device-related infections (33 ) (AIII).Contact with tap water at the central venous catheter site should be avoided (BIII).For long-term central venous access among children, HSCT physicians can use a totally implantable device among children aged 30 days (CII).However, such a device among children aged <4 years is not generally used as the actual HSCT infusion site because a) problems with skin fragility contraindicate repeated punctures over the port site and b) the port device might have an insufficient number of lumens for optimal patient management immediately after HSCT. To prevent bloodstream infections associated with needleless intravenous access devices, HSCT recipients should a) cover and protect the catheter tip or end cap during bathing or showering to protect it from tap water contamination, b) change the device in accordance with manufacturers' recommendations, if available, and c) have a caregiver perform intravenous infusions whenever possible (272,273 ) (BII).Also, HSCT recipients and their caregivers should be educated regarding proper care of needleless intravenous access devices (272 ) (BII).No recommendation regarding the use of antibioticimpregnated central venous catheters among HSCT recipients can be made because of lack of data. # Control of Specific Nosocomial Infections Recommendations Regarding Legionella Species HSCT physicians should always include Legionnaires' disease (LD) in the differential diagnosis of pneumonia among HSCT recipients (140 ) (AIII).Appropriate tests to confirm LD include a) culturing sputum, BAL, and tissue specimens; b) testing BAL specimens for Legionellae by direct fluorescent antibody; and c) testing for Legionella pneumophila serogroup 1 antigen in urine.The incubation period for LD is usually 2-10 days; thus, laboratory-confirmed legionellosis that occurs in a patient who has been hospitalized continuously for ³10 days before the onset of illness is regarded as a definite case of nosocomial LD, and a laboratory-confirmed infection that occurs 2-9 days after hospital admission is a possible case of nosocomial LD (140 ).When a case of laboratoryconfirmed nosocomial LD (274,275 ) is identified in a person who was in the inpatient HSCT center during all or part of the 2-10 days before illness onset, or if two or more cases of laboratory-confirmed LD occur among patients who had visited an outpatient HSCT center, hospital personnel should - report the case(s) to the local or state health department if the disease is reportable in that state or if assistance is needed (140 ) (AIII); and - in consultation with the hospital infection control team, conduct a thorough epidemiologic and environmental investigation to determine the likely environmental source(s) of Legionella species (e.g., showers, tap water faucets, cooling towers, and hot water tanks) (274,276 ) (AI). The source of Legionella infection should be identified and decontaminated or removed (AIII).Extensive hospital investigations of an isolated case of possible nosocomial LD might not be indicated if the patient has had limited contact with the inpatient center during most of the incubation period (CIII).Because HSCT recipients are at much higher risk for disease and death from legionellosis compared with other hospitalized persons (274 ), periodic routine culturing for Legionellae in water samples from the center's potable water supply could be regarded as part of an overall strategy for preventing LD in HSCT centers (CIII).However, the optimal methodology (i.e., frequency or number of sites) for environmental surveillance cultures in HSCT centers has not been determined, and the cost-effectiveness of this strategy has not been evaluated.Because HSCT recipients are at high risk for LD and no data were found to determine a safe concentration of Legionellae organisms in potable water, the goal, if environmental surveillance for Legionellae is undertaken, should be to maintain water systems with no detectable organisms (AIII).Physicians should suspect legionellosis among HSCT recipients with nosocomial pneumonia even when environmental surveillance cultures do not yield Legionellae (AIII).If Legionella species are detected in the water supplying an HSCT center, the following should be done until Legionella species are no longer detected by culture: - The water supply should be decontaminated (140 ) (AII). - HSCT recipients should be given sponge baths with water that is not contaminated with Legionella species (e.g., not with the HSCT center's Legionella species-contaminated potable water system) (BIII). - Patients should not take showers in LD-contaminated water (DIII). - Water from faucets containing LD-contaminated water should not be used in patient rooms or the HSCT center and outpatient clinic to avoid creating infectious aerosols (CIII). - HSCT recipients should be given sterile water instead of tap water for drinking, brushing teeth, or flushing nasogastric tubes during Legionellosis outbreaks (BIII). HSCT center personnel should use only sterile water (i.e., not distilled unsterile water) for rinsing nebulization devices and other semicritical respiratory-care equipment after cleaning or disinfecting and for filling reservoirs of nebulization devices (140 ) (BII).HSCT centers should not use large-volume room air humidifiers that create aerosols (e.g., by Venturi principle, ultrasound, or spinning disk) and, thus, are actually nebulizers (140 ) (DI) unless these humidifier or nebulizers are sterilized or subjected to daily highlevel disinfection and filled with sterile water only (140 ) (CIII). When a new hospital with an HSCT center is constructed, the cooling towers should be placed so that the tower drift is directed away from the hospital's air-intake system, and the cooling towers should be designed so that the volume of aerosol drift is minimized (140 ) (BII).For operational hospital cooling towers, hospitals should # install drift eliminators, # MMWR October 20, 2000 - regularly use an effective biocide, - maintain cooling towers according to the manufacturer's recommendations, and - keep adequate maintenance records (140 ) (BII). HSCT physicians are encouraged to consult published recommendations regarding preventing nosocomial Legionellosis (140,277 ) (BIII).No data were found to determine whether drinking tap water poses a risk for Legionella exposure among HSCT recipients in the absence of an outbreak. # Recommendations Regarding Methicillin-Resistant Sta.aureus HSCT center HCWs should follow basic infection control practices (e.g., hand washing between patients and use of barrier precautions, including wearing gloves whenever entering the methicillin-resistant Sta.aureus infected or colonized patient's room); these practices are essential for MRSA control (62 ) (AII).If MRSA is a substantial problem in the HSCT center and evidence exists of ongoing MRSA transmission, MRSA infected or colonized patients should be treated as a cohort (e.g., cared for exclusively by a limited number of HCWs) (BIII).HSCT transplant recipients with recurrent Sta.aureus infections should undergo extensive evaluation for persistent colonization, including cultures of nares, groin, axilla, and ostomy sites (e.g., tracheostomy or gastrointestinal tube) (BIII).For patients with recurrent MRSA infection, elimination of the carrier state should be attempted by applying a 2% mupirocin calcium ointment to the nares (BIII), although this strategy has been only marginally effective in certain institutions (278 ) (Appendix).High-level mupirocin-resistant MRSA has been reported in Europe, the Middle East, and South America (279-283 ) but is uncommon in the United States.As with any antibiotic, incorrect or overuse of mupirocin can result in mupirocin-resistant Staphylococci ; therefore, mupirocin use should be reserved for infection control strategies only (279,280 ).For patients who fail mupirocin, physicians have used bacitracin, TMP-SMZ, or rifampin administered with another antibiotic, but no standardized protocol using these drugs for this indication has been evaluated and no recommendations can be made because of lack of data.Selection of a systemic antibiotic should be guided by susceptibility patterns. Intravascular cannulas or other implantable devices that are infected or colonized with MRSA should be removed (AIII).Patients with MRSA should be placed under contact precautions until all antibiotics are discontinued and until three consecutive cultures, taken ³1 weeks apart, are negative (62 ) (BIII).Screening cultures for MRSA include the anterior nares, any body site previously positive for MRSA, and any wounds or surgical sites. # Recommendations Regarding Staphylococcus Species with Reduced Susceptibility to Vancomycin All HSCT centers should have sufficient laboratory capability to identify all Staphylococci isolates and their susceptibility patterns to antibiotics, including vancomycin (284,285 ) (AIII).Additionally, all HSCT center personnel should conduct routine surveillance for the emergence of Staphylococcus species strains with reduced susceptibility to vancomycin (285,286 ) (AIII).Reduced susceptibility should be considered for all Sta.aureus strains that have a vancomycin MIC of ³4 µg/mL and all coagulase-negative Staphylococci that have a vancomycin MIC of ³8 µg/mL. If repeat testing of the organism in pure culture confirms the genus, species, and elevated vancomycin MICs, the following steps should be taken ( 287 isolation among HSCT recipients can be made because of lack of data.To control VRE exposure, strict adherence to the following standard infection control measures is necessary (292 ) (AI): - Wash hands with antibacterial soap before entering and after leaving HSCT recipients' rooms, particularly those who have VRE colonization or infection; alternatively, wash hands with a waterless antiseptic agent (e.g., an alcoholbased rinse or gel) (250 ). - Whenever possible, treat as a cohort patients who are known to be colonized or infected with VRE (290 ). - Disinfect patient rooms and equipment (291,293 ), including surfaces of the hospital ward environment (e.g., floors, walls, bed frames, doors, bathroom surfaces) with an FDA-or EPA-registered disinfectant (246,247 ).A nontoxic disinfectant should be used for pediatric areas (BIII). - Place patients with VRE under contact precautions until all antibiotics are discontinued (CIII) and repeated cultures are negative (62 ) (BIII).HCWs should always wear gloves when in the VRE patient or carrier's room and discard gloves in the patient's room before exiting. No evidence exists that treating VRE carriers is beneficial; therefore, chronic antibiotic treatment of carriers is not recommended (DIII).HSCT recipients and candidates should be screened for VRE colonization at the time of interfacility transfer to allow for immediate institution of appropriate infection control practices and to minimize transmission of VRE between and within facilities (294 ) (BII).However, the role of outpatient surveillance in VRE control is unknown; such surveillance is costly and should not be undertaken in nonoutbreak settings (DIII).A history of having resolved VRE bacteremia or being a VRE carrier are not contraindications to HSCT (BIII). # Recommendations Regarding Cl.difficile HSCT physicians should follow published recommendations for preventing and controlling Cl.difficile disease, including minimizing the duration of antibiotic therapy and number of antibiotics used for any indication (295,296 ) (AIII).All patients with Cl.difficile disease should be placed under contact precautions for the duration of illness (62 ) (AII).All HCWs who anticipate contact with a Cl.difficile -infected patient or the patient's environment or possessions should put on gloves before entering the patient's room (62,(295)(296)(297)(298) and before handling the patient's secretions and excretions (AI).During Cl.difficile outbreaks, HSCT center personnel should restrict use of antibiotics (e.g., clindamycin) (299 ) (BII).To prevent transmission of Cl.difficile to patients during nosocomial Cl.difficile outbreaks, HSCT center HCWs should a) use disposable rectal thermometers or tympanic thermometers; b) disinfect gastrointestinal endoscopes with 2% glutaraldehyde immersion for 10 minutes or use an equivalent disinfectant strategy (255,256 ); and c) perform surface sterilization of the hospital ward environment (e.g., floors, walls, bed frames, doors, bathroom surfaces) with an FDA-or EPA-registered sterilant (e.g., phosphate-buffered sodium hypochlorite solution ; unbuffered hypochlorite solution ; 0.04% formaldehyde and 0.03% glutaraldehyde ; or ethylene oxide ) (BII).Additionally, physicians should treat patients with Cl.difficile disease with antibiotics as recommended in published reports (62,295 ) (BII). Certain researchers also recommend antibiotic treatment of Cl.difficile carriers (301 ).However, other researchers have reported that treatment of asymptomatic Cl.difficile carriers with metronidazole is not effective and that treatment with vancomycin is only effective temporarily (i.e., <2 months after treatment) (302 ).Consequently, no recommendation regarding treatment of asymptomatic Cl.difficile carriers can be made.Similarly, although symptomatic Cl.difficile disease recurrence or relapse occurs among 7%-20% of patients (295 ), data are insufficient to make a recommendation for preventing multiple Cl.difficile relapses. The following practices are not recommended for Cl.difficile control: - routine stool surveillance cultures for Cl.difficile for asymptomatic patients or HCWs, even during outbreaks (DIII); - culturing HCWs' hands for Cl.difficile (DIII); or - treating patients presumptively for Cl.difficile disease pending toxin results (DIII), unless the patient is very sick with a compatible syndrome or the hospital has a high prevalence of Cl.difficile (CIII). Prophylactic use of lyophilized Saccharomyces boulardii to reduce diarrhea among antibiotic recipients is not recommended because this therapy is not associated with a substantial reduction in diarrhea associated with Cl.difficile disease (303 ) and has been associated with Saccharomyces boulardii fungemia (304 ) (DII). # Recommendations Regarding CRV Infections Physicians should institute appropriate precautions and infection control measures for preventing nosocomial pneumonia among hospitalized HSCT recipients and candidates undergoing conditioning therapy, particularly during community or nosocomial CRV outbreaks (140 ) (AIII).Patients with URI or LRI symptoms should be placed under a) contact precautions for most viral respiratory infections including varicella; b) droplet precautions for influenza or adenovirus; or c) airborne precautions for measles or varicella to avoid transmitting infection to other HSCT candidates and recipients as well as to HCWs and visitors (BIII).Identifying HSCT recipients with RSV infection and placing them under contact precautions immediately (AIII) to prevent nosocomial transmission is critical.When suctioning the respiratory tract of patients with URI or LRI symptoms, HCWs should wear gowns, surgical masks, and eye protection to avoid contamination from the patient's respiratory secretions.All protective clothing (e.g., gown, gloves, surgical mask, and eye protection) should be put on when entering a patient's room and discarded in the same room before exiting; protective clothing should always be changed between patient rooms (140 ) (AIII).When caring for an HSCT recipient or candidate undergoing conditioning therapy with URI or LRI, HCWs and visitors should change gloves and wash hands a) after contact with a patient; b) after handling respiratory secretions or objects contaminated with secretions from one patient and before contact with another patient, object, or environmental surface; and c) between contacts with a contaminated body site and the respiratory tract of or respiratory device used on the same patient (140 ) (AII).This practice is critical because most respiratory infections are usually transmitted by contact, particularly by hand to nose and eye.Therefore just wearing a mask, without appropriate hand washing, glove-wearing, or use of eye protection is insufficient to prevent transmission of CRV infections. # MMWR October 20, 2000 Researchers have proposed that HSCT recipients or candidates undergoing conditioning therapy be placed under contact precautions during nosocomial outbreaks (131 ) (CIII).Even when no nosocomial or community outbreak of CRV infections exists, all persons who enter the HSCT center should be screened daily for URI symptoms, including visitors and HCWs (BIII).Researchers also describe systems where HCWs provide daily verification (e.g., using sign-in sheets) that they are free of URI symptoms before being allowed to provide HSCT patient care.HCWs and visitors with URI symptoms should be restricted from contact with HSCT recipients and candidates undergoing conditioning therapy to minimize the risk for CRV transmission (131 ) (AIII).All HCWs with URI symptoms should be restricted from patient contact and reassigned to nonpatient care duties until the HCW's symptoms resolve (BIII).Visitors with URI symptoms should be asked to defer their visit to the HSCT center (131 ) until their URI symptoms resolve (BIII).