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# Qualifying Statements for Recommendation 6 Although the identified literature only evaluated hospital-based nurse-led care models, expert opinion supports family physician-led care models.Additionally, family physicians should be included in all survivorship care models.There is no evidence to support timing for when lung cancer survivors can be transitioned into non-specialist care, thus no recommendation can be made for when transition is appropriate. # RECOMMENDATION 7 Smoking cessation counselling is recommended for patients who have completed curativeintent therapy for NSCLC and SCLC.Although verbal cessation advice from a health care professional is of benefit, interventions that involve behavioural and pharmacotherapy support in addition to verbal advice is recommended. # Summary of Key Evidence for Recommendation 7 Systematic reviews that assessed the efficiency of smoking cessation counselling concluded that any intervention is better than no cessation advice from a health care professional (25), and that an intensive intervention that adds further follow-up visits is more effective than brief intervention (25).When pharmacotherapy and behavioural support are added to advice from a health care professional alone, the benefit of the counselling is increased (26).The three systematic reviews and one cohort study that evaluated the benefits of smoking cessation after diagnosis of lung cancer or prior to surgery all concluded that smoking cessation improved clinical outcomes (27)(28)(29)(30).Cohort studies that looked at the association between smoking cessation and QoL found that never-smokers reported the best QoL after curative treatment (31,32).However, patients who quit smoking within one year prior to diagnosis or during follow-up reported better overall QoL and symptom scales, compared with survivors who continued to smoke (31)(32)(33). # Justification for Recommendation 7 Even though none of the identified studies directly evaluated the value of smoking cessation counselling directly, the Working Group members agreed that taken together, the evidence for the benefit of smoking cessation counselling, the evidence for the benefits of cessation in lung cancer survivors and the evidence for the QoL benefits of cessation can be combined to adequately inform this recommendation. # HOW THIS GUIDELINE CONTRIBUTES TO THE CARE OF PATIENTS Studies showing the benefits of surveillance after treatment for lung cancer are fairly new.For this reason, many physicians have not favoured intensive follow-up or advanced imaging because it was thought to be of little value.In the current era, improved treatment options exist, producing a larger population of lung cancer survivors and thus making followup more important.However, there is currently great variability in the follow-up care being provided to lung cancer survivors in Ontario due to a lack of high-quality evidence to support one surveillance schedule.Additionally, there is a lack of high-quality evidence to inform which clinical evaluations should be performed at follow-up visits.The current evidencebased guidance document provides recommendations on appropriate follow-up schedules and evaluations for survivors of NSCLC and SCLC.This guidance document also outlines specific symptoms that may indicate recurrence or progression of lung cancer and that should be further investigated by an appropriate health care professional.Lung cancer survivors have specific post-treatment health-related QOL issues. Physicians and other health care professionals can assist patients with these issues.Finally, health care professionals can positively impact the rate of smoking cessation in lung cancer survivors by ensuring that smoking cessation counselling occurs. # FUTURE RESEARCH High-quality literature for this topic was very limited.As such, many of the recommendations are based on clinical standards and expert opinion.Research into better salvage therapies, as well as detection of recurrent disease and second primary cancers at an earlier stage is greatly needed.Additionally, very little evidence was identified that assessed symptoms of lung cancer recurrence or development of second primary tumours.Research into these areas will allow for better guidance for health care professionals.Additionally, studies that investigate other issues experienced by cancer survivors, such as fear of recurrence, sexual health, return to work and psychosocial coping, have not been addressed in solely lung cancer survivor groups, presenting an area in need of future work.Finally, although survivorship follow-up care plans facilitate continuity of care and may minimise adverse outcomes as survivors transition into non-specialist follow-up care, care plans have not been extensively evaluated in lung cancer survivor populations, presenting another area in need of future research. # RELATED GUIDELINES - PEBC EBS No. The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care.All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol, available on the CCO website at: .
# GUIDELINE OBJECTIVES This guideline aims: -To describe the role of active surveillance (AS) as a management strategy for patients with localized prostate cancer.-To identify patients with prostate cancer that would most benefit from AS. -To develop an evidence-based protocol for AS in localized prostate cancer and to identify the factors affecting the offer of, acceptance of, and adherence to AS.-To understand the role of 5-alpha reductase inhibitors (5ARI) (e.g., finasteride and dutasteride) in patients with localized prostate cancer undergoing AS.-To identify which physician is responsible for managing the AS protocol and if any other human resources required to offer AS (e.g., genitourinary pathologist, psychosocial specialist, etc.)would need specific training. # TARGET POPULATION Men with clinically localized prostate cancer (stage T1 and T2, Gleason score ≤7). # INTENDED USERS Clinicians and specialists providing care to patients with prostate cancer (i.e. urologists and radiation oncologists). Prostate cancer is often a slowly progressive or nonprogressive indolent disease diagnosed at an early stage with localized tumours that are unlikely to cause morbidity or death (1).Standard active treatments for prostate cancer include radiotherapy (RT) or radical prostatectomy (RP).However, harms from overdiagnosis and overtreatment are a significant concern and the risks of active treatment may outweigh the benefits in many patients, particularly those with low-grade disease.To address these concerns, AS is increasingly being considered as a management strategy to avoid or delay the potential harm caused by unnecessary radical treatment (2) in those patients with prostate cancers that are unlikely to progress. There are no published randomized controlled trials (RCTs) comparing AS to active interventions.Some of the evidence used in this guideline comes from trials comparing active intervention (such as RP) to watchful waiting (WW) or observation.AS differs from WW or observation in both intent and in the utilization of serial biopsy strategies.The intent of WW or observation is to avoid active intervention in patients with limited long-term survival expectancy by providing delayed noncurative therapy for patients who experience metastatic progression.Patients with Gleason ≤6 prostate cancer rarely experience metastatic progression on WW or observation and therefore the members of the Working Group and Expert Panel feel that the results from these trials give important natural history information and the results can be used to inform this guideline on AS. The intent of AS is curative, allowing the option of active treatment for those patients on AS who are reclassified to higher risk or who show disease progression.AS involves regular follow-up testing for prostate-specific antigen (PSA), digital rectal examination (DRE), repeat prostate biopsy, and use of prostate imaging, when indicated.The goal of this strategy is to monitor cancers at low risk of future progression to select patients with occult cancers of higher grade and risk who require timely therapy, while maintaining surveillance on patients who remain classified as having low-risk cancers (1). The majority of prostate cancers at low risk of future progression are the low-grade cancers which have the most favourable outcomes.The Gleason grading system is effective in predicting the biological behaviour and prognosis of these cancers.In combination with measurements of tumour extent, Gleason score is the most meaningful pathologic determinant of eligibility for AS protocols.Modifications to the Gleason scoring system in recent years have enabled the identification of more homogeneous, truly low-grade Gleason <6 prostate cancers (3).Pure Gleason 6 cancers defined according to these criteria showed lymph node metastases in only 0.48% of patients in a recent meta-analysis of 21960 RP specimens (4). In Ontario, the selection of patients and the protocols used for AS vary across the province, and the importance of establishing a standardized protocol for AS has led to the development of these evidence-based recommendations.The term "low-risk" prostate cancer as used in this guideline is defined as the risk status for patients who have Gleason score ≤6, PSA <10, and ≤ stage T2A. The Working Group and Expert Panel have defined our target populations for AS recommendations by Gleason score ≤6 and also Gleason score 3+4. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION # RECOMMENDATION 1 For patients with low-risk (Gleason score ≤6) localized prostate cancer, AS is the preferred disease management strategy. # Summary of Key Evidence for Recommendation 1 -Eight noncomparative studies of low-risk patients undergoing AS reported prostate cancer survival rates of 100% (5-12) and another two noncomparative studies reported high prostate cancer survival rates of 97% ( 13) and 98% respectively ( 14). -Studies comparing immediate RP with delayed RP in patients undergoing AS detected no significant differences in biochemical recurrence rate, positive surgical margins, extraprostatic extension (15)(16)(17), and risk of incurable cancer (18)(19). # RECOMMENDATION 3 The AS protocol should include the following tests: -PSA test every 3 to 6 months. -DRE every year. -12-to 14-core confirmatory transrectal ultrasound (TRUS) biopsy (including anterior directed cores) within 6 to 12 months, then serial biopsy a minimum of every 3 to 5 years thereafter.The AS protocol may include the following test: -Multiparametric MRI (mpMRI).This is indicated when a patient's clinical findings are discordant with the pathologic findings and it is useful in identifying occult cancers or changes indicative of tumour progression in patients at risk. (36,37).Multiparametric MRI also had a negative predictive value of 83% to 100% (38) in one study that used transperineal template mapping saturation biopsy as a reference standard, and which included patients with a PSA range of 0.9 to 29 (median 7).One study also showed mpMRI to be a predictor of high-risk disease in the AS context (37). # Summary of Key Evidence for # Justification for Recommendation 3 -This recommendation is consistent with the AS protocol presented in most of the studies reviewed for this guideline.Since most studies employed PSA testing, DRE, and biopsy, these can be considered the three most important components of an AS protocol.-Although many studies reviewed here followed a repeat biopsy frequency of 1 to 2 years in their AS protocol, the study with the most mature cohort of patients undergoing AS (13) and two other studies opted for a repeat biopsy frequency of 2 to 4 years (8,11) and found similarly high prostate-cancer survival rates of 97% to 100%. -Current evidence shows that PSA kinetics does not reliably predict disease stability or reclassification to higher risk state.-Although one correlational study detected that patients from multidisciplinary clinics were more likely to receive AS than patients under the care of individual practitioners (39), there is insufficient evidence to address the factors affecting the offer of, acceptance of, and adherence to AS. Qualifying Statements for Recommendation 3 -Decisions about frequency of biopsy need to take into consideration individual patient factors including age, risk of progression, comorbidities, etc.The repeat biopsy frequency recommendation of a minimum of once every 3 to 5 years is based on the series reported by Klotz et al (40), which included 450 patients on AS with a median follow-up of 6.8 years (range, 1 to 13 years).Overall survival rate was 78.6%.The 10year prostate cancer actuarial survival rate was 97.2%.Compared with shorter repeat biopsy intervals, this recommended frequency potentially reduces the risk of complications that are associated with TRUS biopsy, including urosepsis (41,42), without negatively affecting outcomes.A shorter interval between biopsies may be reasonable in selected patients and should be at the discretion of the ordering physician in consultation with the patient.Serial biopsy should not continue past the age of 80.-The role of magnetic resonance imaging (MRI) in AS is evolving.Prospective multicentre trials reporting utility of MRI on entrance into AS or in reclassification of disease risk are lacking.Single-centre publications looking at all men undergoing biopsy have found that mpMRI can reclassify patients when combined with systematic biopsy by identifying tumour targets missed with systematic biopsy (38).Multiparametric MRI is useful in identifying anterior and higher volume tumours, and it is good in identifying findings that predict disease reclassification (36,37).Whether this should be done on all patients or only on those in whom there is discordance between clinical findings such as PSA and DRE is an open question.However, being cognizant of both the high cost of mpMRI and its promise, it is recommended that when a patient's clinical findings are discordant with the pathologic findings, a mpMRI is indicated.When indicated, it may be considered at entry or during follow-up.-Discordant findings between a patient's clinical course and pathologic findings can include rapidly rising PSA, PSA density over 0.2, higher PSA than expected for prostate size, DRE abnormality, and very low PSA free/total ratio.Presence of these findings requires further investigation with mpMRI or earlier repeat biopsy. # RECOMMENDATION 4 Daily 5-alpha reductase inhibitors may have a role in men on AS. # Summary of Key Evidence for Recommendation 4 -An RCT found that in men with very low-risk prostate cancer undergoing AS and followed for 3 years, daily dutasteride delayed disease reclassification (hazard ratio 0.62; confidence interval 0.43 to 0.89) and improved quality of life at 18 months (28). # Justification for Recommendation 4 -Evidence from a high-quality RCT detected a benefit for dutasteride administered to patients undergoing AS (28). Qualifying Statements for Recommendation 4 -It should be noted that the RCT had short follow-up of 3 years and detected no difference between groups in survival rate outcomes (28).-Dutasteride is the only 5ARI that has been tested in an RCT.However, it is the opinion of the Expert Panel that the evidence likely demonstrates a drug class effect and that finasteride may also have a role in men on AS.-While the U.S. Food and Drug Administration (FDA) has issued a warning about a possible low but increased risk for high-grade prostate cancer with the use of 5ARIs based on two RCTs that did not meet inclusion criteria for this guideline (43), it is the opinion of the Expert Panel members that the benefits of 5ARIs outweigh the risks and they can be prescribed to a patient undergoing AS as long as the patient is adequately informed about the risk and benefits of treatment.This is consistent with the Canadian Consensus Conference statement (44). # RECOMMENDATION 5 For patients undergoing AS who are reclassified to a higher risk category, defined by repeat biopsy showing Gleason score >7 and/or significant increases in the volume of Gleason 6 tumour, consideration should be given to active therapy (e.g., RP or RT). # Summary of Key Evidence for Recommendation 5 -Based on RCTs of treatment versus observation, the patients who benefitted most from therapy had Gleason 7 and higher prostate cancer volume (20,46). # Justification for Recommendation 5 -Gleason score is a widely used disease classification measure and biopsy is the gold standard for measuring the status of disease.Thus Gleason 7 (4+3 pattern or 3+4 with Gleason pattern 4 pathology accounting for >10% total tumour) is the recommended indicator for disease reclassification to higher risk in prostate cancer.-The most commonly reported active treatments received by patients on AS who were reclassified to higher risk were RP and RT (5)(6)(7)(9)(10)(11)(12)(13)21,45).-Although clear biopsy criteria for defining progression of high volume Gleason 6 disease have not been established, it is the consensus of the Expert Panel members that increasing volume of Gleason 6 tumour is an indicator of disease progression and of the need to consider active treatment.It is the consensus of the members of the Expert Panel that patients on AS with Gleason 7 disease on repeat biopsy can be considered for continued AS provided that Gleason pattern 4 accounts for ≤10% of total tumour.-Prospective intradepartmental consultation should be encouraged as an important quality assurance activity for Gleason score interpretation (27). Qualifying Statements for Recommendation 5 -An RCT comparing RP to WW found that RP reduced the risk of distant metastases and reduced prostate cancer mortality rates (46).-In six studies, 17% to 31% of patients undergoing AS were reclassified to a higher risk group over time (8)(9)(10)(11)(12)(13)(14)(15)45). -In 11 studies, 14% to 42% of patients undergoing AS received active treatment because of disease reclassification to higher risk, anxiety, patient choice, or another reason (5)(6)(7)(8)(9)(10)(11)(12)(13)19,45).-Since evidence to predict disease reclassification in prostate cancer was conflicting for PSA level and lacking for DRE and prostate cancer antigen3 (PCA3) level these were not included in the recommendation.This recommendation is based on a consensus of opinion of the Expert Panel members. - # FURTHER QUALIFYING STATEMENTS Currently, there is insufficient evidence to make recommendations with regard to the personnel who should be responsible for the management of AS protocols.However, patients should have access to a multidisciplinary consultative approach when a change to active treatment is considered. # FUTURE RESEARCH Although a National Cancer Institute trial has previously shown that RCTs comparing AS with immediate active treatments for prostate cancer are difficult to conduct because of insufficient patient accrual (ClinicalTrials.gov registration number: NCT00499174), RCTs would still provide the best evidence on which to base clinical recommendations.Should RCTs become available in the future, these Guideline Recommendations may change.Every few years, the PEBC conducts a review and assessment of its guidelines to update the evidence and any new relevant studies identified will be taken into consideration to evaluate whether these Guideline Recommendations are still valid.
For information about this document, please contact Dr. Eric Winquist, the lead author, through the PEBC via: Phone: 905-527-4322 ext.42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext.42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca # PUBLICATIONS RELATED TO THIS REPORT The evidence review has been published as a Supplement Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario.Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.
Questions 1.What treatment provides the optimum disease control and survival in older patients (at least 60 years of age) with newly diagnosed, advanced-stage, aggressive histology lymphoma?2.What are the toxicities associated with these treatments?3.What are the roles of granulocyte-colony stimulating factor or granulocyte macrophage-colony stimulating factor in combination with chemotherapy in these patients?These recommendations apply to patients older than age 60 who have newly diagnosed, advanced-stage, aggressive histology non-Hodgkin's lymphoma, an Eastern Cooperative Oncology Group (ECOG) performance status of less than 4 and no significant comorbid illnesses.Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is recommended for patients with no apparent cardiac disease or significant comorbidity.Dose and schedule should be the same as that used in younger patients. The addition of rituximab to CHOP is recommended for patients with diffuse large B-cell lymphoma. There is insufficient evidence to support the routine use of granulocyte-colony stimulating factor as primary therapy. While use of granulocyte-colony stimulating factor shortens the duration of neutropenia and decreases the infection rate in these patients, no differences in disease control or survival have been detected. The primary use of granulocyte-colony stimulating factor is recommended for older patients who are at a particularly high risk of experiencing neutropenic fever.These patients are best identified as those with a poor performance status (ECOG 2 or greater), neutropenia prior to therapy, or an ongoing infection; there are insufficient data to recommend the primary use of granulocyte-colony stimulating factor for patients whose sole risk factor is bone marrow involvement with lymphoma. The use of granulocyte-colony stimulating factor as secondary prophylaxis is recommended for patients who have previously experienced an episode of neutropenic fever or a treatment delay resulting from persisting neutropenia.Qualifying Statements Treatment decisions in older patients with aggressive histology lymphoma are complex and may be influenced by comorbidity, patient preferences, quality of life issues, and the goals of the treatment program.These factors may alter recommendations for individual patients and require discussion between health care providers, patients, and their families. Radiation therapy is not considered in this guideline and may be an important part of the treatment plan for these patients.# - In a randomized trial comparing CHOP with a regimen considered to be less toxic (etoposide, mitoxantrone and prednimustine, progression-free and overall survival were superior in the group receiving CHOP. In a randomized trial comparing a CHOP-like regimen, in which pirarubicin is substituted for doxorubicin and teniposide is substituted for vincristine (CTVP), with a regimen considered to be less toxic (cyclophosphamide, teniposide and prednisone, progression-free and overall survival were superior in the group receiving CTVP. In a randomized trial comparing CHOP with a fractionated schedule of weekly CHOP, overall survival was superior in the group receiving standard CHOP. In two randomized trials comparing CHOP with a regimen in which mitoxantrone was substituted for doxorubicin (CNOP), progression-free and overall survival were superior in the groups receiving CHOP.In a third randomized trial in which a weekly doxorubicin-containing regimen was compared with a regimen in which mitoxantrone was substituted for doxorubicin, response rate and overall survival were superior in the group receiving the mitoxantrone-containing regimen.The investigators of this study are currently conducting a randomized trial in which the weekly mitoxantrone-containing regimen is compared with CHOP. In a randomized trial comparing CHOP to a combined regimen of rituximab and CHOP, event-free and overall survival were superior in the group receiving CHOP plus rituximab. In three randomized trials evaluating the primary use of granulocyte-colony stimulating factor, no differences between the randomized groups were detected in disease control or overall survival. Less severe granulocytopenia and fewer infections and days of antibiotic use were observed in patients receiving granulocyte-colony stimulating factor. # Related Guidelines # PREAMBLE: About our Practice Guideline Reports The Practice Guidelines Initiative (PGI) is a project supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term Care, as part of the Program in Evidence-based Care (PEBC).The purpose of the Program is to improve outcomes for cancer patients, to assist practitioners to apply the best available research evidence to clinical decisions, and to promote responsible use of health care resources.The core activity of the Program is the development of practice guidelines by multidisciplinary Disease Site Groups of the PGI using the methodology of the Practice Guidelines Development Cycle.1 The resulting practice guideline reports are convenient and up-to-date sources of the best available evidence on clinical topics, developed through systematic reviews, evidence synthesis and input from a broad community of practitioners.They are intended to promote evidence-based practice. This practice guideline report has been formally approved by the Practice Guidelines Coordinating Committee (PGCC), whose membership includes oncologists, other health providers, patient representatives, and Cancer Care Ontario executives.Formal approval of a practice guideline by the Coordinating Committee does not necessarily mean that the practice guideline has been adopted as a practice policy of CCO.The decision to adopt a practice guideline as a practice policy rests with each regional cancer network that is expected to consult with relevant stakeholders, including CCO. # Glossary of Chemotherapy Regimens # II.CHOICE OF TOPIC AND RATIONALE The numbers of elderly persons are increasing and are soon expected to make up 20% of the population in North America (24).One-half of patients with aggressive histology lymphoma are older than 65 years (25).Age is known to be a powerful prognostic factor for overall survival for patients with aggressive histology lymphoma (26).Until recently, patients older than 65 have been underrepresented in clinical trials, and most conclusions about the best chemotherapy for these patients have not been based on direct evidence.Outcomes of older patients with lymphoma may differ from those of younger patients due to alterations in disease biology and poorer tolerance of standard chemotherapeutic regimens.Biological age plays a more important role than chronological age, and compromises in response and survival may occur if suboptimal chemotherapy is given to patients with chemosensitive lymphoma (27)(28)(29)(30). The members of the Hematology Cancer Disease Site Group (Hematology DSG) suspected that the selection of chemotherapy for this group of patients varied across Ontario.The availability of recent evidence, the perceived variability in practice patterns, and the potential for this variation to influence the outcomes of older patients led to the development of this topic as a practice guideline.The few published guidelines for patients with lymphoma (31)(32)(33) have either not specifically focused on the treatment of older patients (32) or have not used systematic review methodology in their data collection (31;33).Two published guidelines (34)(35)(36) and one expert panel review (37) for the use of colony stimulating factors in patients with malignancy have made recommendations in patients receiving myelosuppressive chemotherapy but do not address the older population specifically.The Hematology DSG felt it appropriate to appraise studies on the use of colony stimulating factors in older patients to see whether suggestions should differ from those already published.This guideline will, therefore, address both the optimum choice of primary therapy and the role of granulocyte-(or granulocytemacrophage) colony stimulating factor when treating older patients with aggressive histology lymphoma.The role of radiation therapy may also be an important part of the overall treatment plan for these patients but will not be addressed in this document. A previous version of this guideline report was circulated for practitioner feedback in August 2000.Based on the practitioner feedback and the availability of new data, the document was revised and recirculated for practitioner feedback.Portions of this guideline have been published as a systematic review of full paper publications of chemotherapy trials for older patients with aggressive histology lymphoma (38). # III.METHODS Guideline Development This practice guideline report was developed by the Practice Guidelines Initiative (PGI) of Cancer Care Ontario's Program in Evidence-based Care (PEBC), using methods of the Practice Guidelines Development Cycle (39).Evidence was selected and reviewed by four members of the PGI's Hematology DSG and methodologists.Members of the Hematology DSG disclosed potential conflict of interest information. The practice guideline report is a convenient and up-to-date source of the best available evidence on chemotherapy and growth factors in older patients with newly diagnosed aggressive histology lymphoma, developed through systematic reviews, evidence synthesis, and input from practitioners in Ontario.The body of evidence in this report is primarily comprised of mature randomized controlled trial data; therefore, recommendations by the DSG are offered The report is intended to promote evidence-based practice.The Practice Guidelines Initiative is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. External review by Ontario practitioners was obtained through a mailed survey consisting of items that address the quality of the draft practice guideline report and recommendations and whether the recommendations should serve as a practice guideline.Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee (PGCC). The PGI has a formal standardized process to ensure the currency of each guideline report.This consists of periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. # Literature Search Strategy Searches were performed without language restriction in the following databases (40)).The following terms were used for MEDLINE and CANCERLIT: "lymphoma, non-Hodgkin" (MESH, text word), "lymphoma" (text word) combined with "aged" (text word) or "older" (text word) combined with "chemo:" (text word).These terms were then combined with search terms for the following study designs: practice guidelines, systematic reviews, meta-analyses, and randomized controlled trials.The detailed search strategy has been described in Appendix I. Bibliographies of major textbooks, review articles, and primary studies were hand searched.Conference proceedings of the American Society of Hematology (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001), American Society of Clinical Oncology (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001), International (Lugano) Conference on Malignant Lymphoma (1996,1999), and the European Cancer Conference (ECCO 1995(ECCO 1997(ECCO 1998(ECCO 2001 were searched.A manual review of the table of contents was performed for the following journals from 1993 to 1998: American Journal of Hematology, Annals of Oncology, Blood, British Journal of Hematology, Cancer, European Journal of Cancer, European Journal of Hematology, Journal of Clinical Oncology, and the New England Journal of Medicine.The Physician's Data Query (PDQ, National Cancer Institute, USA) clinical trials database on the Internet (/) was searched for trials in progress using the terms "non-Hodgkin's lymphoma, adult" and "chemotherapy". A separate search for studies assessing risk factors predictive of fever and neutropenia in elderly lymphoma patients was undertaken to assist the Hematology DSG in evaluating the role of primary prophylaxis with growth factors.The following terms were searched in MEDLINE (1966through September 2001 and CANCERLIT (1984through September 2001: "lymphoma, non-Hodgkin" (MESH, textword), "lymphoma" (textword) combined with "neutropenia" (textword) and "risk factor" (textword).Abstract publications were not included.Specific parameters to assess the quality of these studies were not applied. # Inclusion Criteria Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized controlled trials (RCTs) involving newly diagnosed patients with aggressive histology lymphoma who were 60 years of age and older.The age threshold of 60 years was chosen in order to remain consistent with the findings of the International Prognostic Index (IPI) (26). - To assess the role of chemotherapy, RCTs must compare at least two chemotherapy regimens.2.To assess the role of colony stimulating factors, RCTs comparing the use of G-CSF or GM-CSF with a control group were sought.In the initial phase of this guideline, non-randomized studies utilizing colony stimulating factors that included at least ten patients (chosen arbitrarily) were also eligible.These trials were subsequently made ineligible in February 2001 when data from three randomized trials became available.3.Randomized studies assessing the use of monoclonal antibodies (e.g., rituximab) were eligible.4.Subgroup analyses based on age or histology were eligible. The outcome measures of interest included at least one of the following: overall survival (OS), disease-free (DFS) or failure-free survival (FFS), time-to-treatment failure (TTF), relapse-free survival (RFS), response rate, toxicity, or quality of life measures. # Exclusion Criteria Studies were excluded if: 1.Patients included had indolent lymphoma, refractory or relapsed lymphoma, human immunodeficiency virus (HIV) related lymphoma, Hodgkin's disease, multiple myeloma, or other hematological malignancies; 2.Transplantation, maintenance chemotherapy, or interferon were used as interventions; or 3.Radiation therapy was used unevenly in experimental and control groups. Studies assessing the role of chemotherapy were excluded if they incorporated growth factors as part of the primary therapy in all randomized groups.Also, letters and editorials were not considered. # Risk Factors for Fever and Neutropenia Responses obtained in the first external review by Ontario practitioners of the initial draft version of the evidence-based recommendations supported a need to review and clarify recommendations regarding the use of hematopoietic growth factors for primary prophylaxis to prevent fever with neutropenia.Subsequently, new data assessing the use of growth factors became available.To better evaluate the potential role of primary prophylaxis, the DSG determined that a separate analysis limited to elderly lymphoma patients assessing risk factors that predict for fever with neutropenia and treatment-related mortality would be helpful. # Article Selection Citations were blinded for authors, journal name, institution, and results by one author.An assessment was made by two independent observers who scored each blinded citation as: "yes" (inclusion criteria were met, no exclusion criteria were met); "no" (one or more exclusion criteria were met); or "maybe" (unclear from citation if article meets any criteria).The full-length article was retrieved if the citation scored "yes" or "maybe" by at least one observer.Inclusion and exclusion criteria were applied again to the full article if necessary.Interobserver kappa coefficients (quadratic weighted) were calculated using PCAgree © (42) for the MEDLINE, CANCERLIT, and EMBASE databases, and an intraobserver coefficient was calculated from a random sample (random numbers table) of twenty MEDLINE citations for the citations assessing the role of chemotherapy.Acceptable kappa coefficients were 0.60 or greater (43).The citation lists for subsequent search updates were reviewed by one author using the same inclusion/exclusion criteria outlined previously. # Study Quality Assessment Methodological assessment was performed using the published validated quality assessment tool of Jadad et al.for randomized controlled trials (44), but the score was not used to explicitly weight study results or to exclude studies from the analysis.This scale assigns one point if the study is randomized, one point if it is double-blinded, and another point if there is a complete description of withdrawals.An additional point each may be awarded if the randomization and the blinding were done appropriately.Studies may therefore score from zero to five points.It has been shown that studies scoring 2 points or less on this scale are more likely to produce treatment effects that are on average 35% larger than those produced by trials scoring 3 points or more (45).Randomized trials were also assessed based on whether the study population was explicitly defined, how baseline characteristics of the randomized groups compared, whether primary and secondary outcome measures and minimum important differences were stated, how the target sample size was projected (46), whether an intentionto-treat analysis was performed (47), whether randomization was concealed, whether co-interventions and endpoints were explicitly stated, and whether appropriate statistics were used. Fully published articles are generally required in order to be most confident that the methodological assessment has identified the strengths and weaknesses of the trials.Most abstracts provide information of a more preliminary nature that may result in a lesser degree of confidence in making treatment recommendations.Subset analyses, while providing information of a hypothesisgenerating nature, may be potentially misleading (48) and thus provide limited information for devising treatment recommendations.Therefore, conclusions about the use of chemotherapy and growth factors are most influenced by the full paper publications of primary studies. # Synthesizing the Evidence Pooling trial results for both the chemotherapy and colony stimulating factor trials was considered but was not feasible.The nature of the chemotherapy regimens tested was very heterogeneous, making meaningful results from pooling impossible.Pooling of outcomes for studies assessing G-CSF was also considered but was not feasible because of the differences in outcome measurement assessed and the timing of assessment.Where p values were missing in individual studies, the appropriate statistical test was done using the Statistical Package for the Social Sciences (version 8.0, SPSS Inc., Chicago, IL) (49). # IV.RESULTS # Literature Search Results Two hundred and eighty-nine publications were initially identified from MEDLINE, 106 publications from CANCERLIT, 376 from EMBASE and 52 from Current Contents for the chemotherapy question, up to 1999.No additional appropriate publications were found by searching the thesis database, Best Evidence, or the Cochrane Library.Six abstracts were found by hand searching.After removing duplicate citations and those dealing exclusively with Hodgkin's disease, myeloma, leukemia, or younger patients, a total of 385 blinded citations were assessed by two independent reviewers.This search was updated in 2001 and 2002.Including the updated searches, 23 publications (13 full papers, 10 abstracts) met the eligibility criteria for chemotherapy trials and were included.Two systematic reviews were also found (38;50), one of which represents a portion of this document published as a systematic review (38). From the initial search for studies assessing the role of growth factors, 246 citations were found in EMBASE, 421 in MEDLINE, 130 citations in CANCERLIT, and 25 in Current Contents.No additional relevant publications were found by searching the thesis database, Best Evidence, or the Cochrane Library.Three abstracts were found by hand searching.Two independent reviewers assessed a total of 293 blinded citations.This search was also updated in 2001 and 2002.In the updated searches, five articles were reviewed for this section: two practice guidelines, one full-length paper, and two abstracts.Table 1 summarizes the reasons that publications were excluded based on the original searches.The search for risk factors for febrile neutropenia and treatment-related mortality resulted in 955 citations that were reviewed by one author.
# Agreement Statistics The interobserver weighted kappa was 0.74 for the chemotherapy citations.The intraobserver weighted kappas for the random sample of 20 MEDLINE chemotherapy citations were 0.60 (reviewer 1) and 0.80 (reviewer 2).The interobserver weighted kappa was 0.82 for the colony stimulating factor citations.These represent adequate agreement coefficients (43). # Quality Assessment Scores Of the 23 studies assessing the role of chemotherapy (Table 2), three scored 3 on the Jadad quality scale (11;22;51), ten scored 2 (4;5;7;12;16;18;52-55) and ten scored 1 (1;2;6;10;15;20;21;56-58).The studies assessing the use of colony stimulating factors scored 2 points (23) and 1 point (57;59).One study assessing the role of rituximab scored 2 points (9). A total of 23 publications (1-7;10-12;15;16;18;20-22;51-55;57;58) and two systematic reviews (38;50) were identified that addressed the chemotherapy guideline question.One systematic review (50) contained a section on elderly patients with lymphoma; however, it was not explicit about the individual studies included, and the majority of studies present in this practice guideline report were not identified or discussed.The other systematic review was the published chemotherapy review portion of this practice guideline report (38), which only included full paper publications of randomized trials and not abstract reports. The studies testing various chemotherapy regimens fell into one of three general categories: (a) those comparing regimens that differed only in the type of anthracycline used; (b) those comparing different chemotherapy schedules; and (c) those comparing chemotherapy regimens that differed by other parameters (Table 2). (a) Comparison of regimens that differ only in the anthracycline This category consists of eight studies: five full papers (4;5;11;16;52) and three abstracts (2;21;57).None of the studies were blinded, only one described the randomization method (11), and none made any comments with respect to concealment.The full papers had complete descriptions of subject withdrawals, but the abstracts did not.The studies are summarized in Tables 3 and 4. Mainwaring et al. (16) randomized 473 patients 60 years of age and older to a doxorubicin-(35 mg/m 2 or a mitoxantrone-containing (7 mg/m 2 weekly combination regimen (PAdriCEBO v. PMitCEBO).Up to 40 percent of patients had stage I or II disease, and 66 percent had a World Health Organization (WHO) performance status of less than 2.The overall response rate was superior in patients receiving the mitoxantrone-containing regimen (Table 4).Although no difference in RFS was detected, four-year OS was superior in patients randomized to the mitoxantrone-containing regimen (Table 4).A multivariate analysis of prognostic factors in this trial identified the chemotherapy regimen, age greater than 70, advanced stage, and poor performance status as significant factors for survival. Björkholm et al. (57) reported on 455 patients aged 60 years of age and older randomized to CHOP or CNOP as part of a factorial design also involving G-CSF.Patients receiving CHOP had improved OS compared with those receiving CNOP (Table 4), but groups did not differ for complete response (CR) (Table 4). Aoki et al. (52) randomized 37 patients to low doses of CHOP or to one of two pirarubicin-based regimens (THP-COP or THP-COPE).Seven patients (19%) were subsequently withdrawn due to ineligibility and protocol violations, and the analysis was based on the remaining 30 patients.The overall response rate was similar among patients receiving low dose CHOP, THP-COP, and THP-COPE (Table 4).There was no significant difference in two-year OS (Table 4; p value not stated). Avilés et al. (5) randomized 169 patients to receive either CEOP-Bleo (epirubicin-based) or CIOP-Bleo (idarubicin-based) with escalating doses of the anthracycline.The group receiving the epirubicin-containing regimen had a superior CR rate (Table 4) and three-year OS (Table 4).There is a potential concern regarding patients who were excluded from the analysis if they experienced more than a two-week delay in chemotherapy administration.In addition, the study recorded no treatmentrelated mortality. Sonneveld et al. (11) tested whether the substitution of doxorubicin in CHOP for mitoxantrone (CNOP) improved outcomes in 148 patients 60 years of age and older.Almost half of the patients were less than 70 years, and in contrast to other studies, some degree of cardiac dysfunction (left ventricular ejection fraction at least 40%) was permitted.Patients receiving CHOP had a higher CR rate (Table 4), a superior median OS (Table 4), and a superior three-year OS (Table 4).At three years, 17% of CHOP and 13% of CNOP patients were alive and disease-free (p=0.12).Patients receiving CHOP experienced significantly more alopecia (p<0.001), nausea (p=0.02), and vomiting (p=0.02). The remaining studies (2;4;21) are summarized in Tables 3 and 4.Conclusions from these studies are limited due to lack of details reported in the papers. # Interpretive summary for this category This category contains studies with varied results.All studies included patients who were free of important comorbid illness.Two large studies (11;57) showed a survival benefit of doxorubicin compared with mitoxantrone when given in CHOP. When doxorubicin was compared with mitoxantrone in a non-CHOP-like, multi-agent chemotherapy regimen that was administered on a weekly basis, there was a survival benefit for patients receiving the mitoxantrone-based regimen (16).This study contained a higher proportion of patients with limited stage (I and II) disease.The remaining studies examining epirubicin, pirarubicin and idarubicin-based regimens were limited due to: concerns about the reporting of patient withdrawals and the lack of treatment-related mortality data (5); small numbers of patients; lack of an intention-to-treat analysis; use of less than standard doses of CHOP (52); lack of survival data (4); and reporting of subgroup analyses (2). # (b) Comparison of regimens with different schedules This category contains three studies: one full paper (53) and two abstracts (7;10).The studies were not blinded and did not mention the method of randomization or concealment.The studies are summarized in Tables 5 and 6. Pfreundschuh et al. (10) reported results of a four-arm randomized trial evaluating patients 61 to 75 years of age with aggressive histology lymphoma and comparing CHOP administered either every 21 days or 14 days and CHOP plus etoposide (CHOEP) also administered every 21 days or 14 days.Patients receiving either 14-day regimen (i.e., CHOP-14 or CHOEP-14) also received G-CSF.The trial was to be analyzed using a factorial design in order to assess the effect of compressing the treatment schedule and the addition of etoposide.Because of an interaction between the addition of etoposide and schedule compression, in which patients receiving CHOEP every 14 days experienced excessive toxicity, the trial was instead analyzed as a four-armed comparison using a Cox model.With respect to compressing the treatment schedule, a comparison of outcomes between the CHOP-21 and CHOP-14 groups detected that the CHOP-14 group had a superior 40-month TTF (Table 6) and OS (Table 6), with a trend for improved CR rate (Table 6). The randomized phase II study by Soubeyran et al. (7) published in abstract form, compared standard and fractionated schedules of CEVOP.No difference was detected in achievement of a CR.The group receiving the fractionated schedule of chemotherapy received therapy of reduced dose intensity, had a higher frequency of treatment interruptions due to toxicity, and reported lower quality of life scores.Specific data were not provided. A randomized phase II study by Meyer et al. (53) compared the conventional CHOP schedule with one-third doses administered weekly (chop) for the same intended dose-intensity.There were no differences in received dose intensities (primary outcome) when calculated by two different methods (53;60) or in the CR rate between CHOP and chop (Table 6).Although two-year progression-free survival (PFS) was similar between CHOP and chop (Table 6), the two-year OS was of borderline significance in favour of CHOP (Table 6).Apart from more leukopenia in patients randomized to CHOP, there were no statistically significant differences in important toxicities. # Interpretive summary for this category No benefits from fractionating the treatment schedule have been detected; the potential for outcomes to be inferior is suggested.In a preliminary abstract publication reporting results of compressing the schedule of CHOP from 21 days to 14 days, improvements in disease control and survival are indicated (10).However, the interpretation of this study is limited by the complex statistical analysis and requires a full report in article form for complete assessment. # (c) Comparison of other chemotherapy regimens This (3;6;12;15;18), and one study compared different doses of the same regimen, with dose determined by age stratification (20).These studies are highlighted in Tables 7 and 8. Of the seven trials comparing CHOP with another regimen, one (22) has been published in article form, three as subgroup analyses (51;55;58), and three in abstract form (1;10;54).A European Organization for the Research and Treatment of Cancer (EORTC) trial ( 22) randomized 120 patients 70 years of age and older to CHOP or VMP.Patients with a performance status of 2 or 3 were started at 75 percent of the standard chemotherapy dose.Patients who received CHOP had a higher overall response rate (Table 8), a borderline higher CR rate (Table 8), a longer median PFS (Table 8), a longer median OS (Table 8), and an improved four-year OS (Table 8).There was a trend toward more cardiovascular toxicity in patients receiving CHOP; they also experienced more alopecia and gastrointestinal and neurological toxicity. None of the other publications in this category have reported a survival advantage for patients receiving a treatment that was compared with CHOP.A Group d'Etude des Lymphomes de l'Adulte trial (GELA) (1) randomized 708 patients aged 61-69 years to ACVBP or CHOP.No differences were detected in CR rate or three-year OS.There was an improvement in three-year event-free (Table 8) and disease-free survival (Table 8) in patients randomized to ACVBP.These benefits appear to be offset by an increased treatment-related mortality in patients receiving ACVBP (13% v. 7%; p<0.01).A study published in abstract form compared CHOP with CHOP plus etoposide (10) in patients greater than 60 years old.No differences were detected in response rate, TTF, or OS, and the authors commented that the addition of etoposide was associated with significant toxicity.Four studies (51;54;55;58) compared CHOP with one or more "second or third generation" regimens.In each of these studies, no advantage favouring an experimental arm was detected in any outcome measure.Treatment with MACOP-B was associated with an inferior response rate in one study (51) and inferior OS in another (54). Five studies (6;12;15;18;56) compared regimens that did not include CHOP, and one study examined dose intensities of the same regimen in older patients of different ages (20); two reports are in article form (12;56).Bastion et al. (12) randomized 453 patients at least 70 years of age to CTVP or CVP.Treatment with CVTP was associated with a superior CR rate (Table 8), median TTF (Table 8), five-year TTF (Table 8), and five-year OS (Table 8) and a lower rate of progressive disease (Table 8).Patients receiving CTVP experienced more alopecia and mucositis and had more frequent and prolonged hospitalizations.The remaining studies (6;15;18;20;56) are summarized in Tables 7 and 8; all contain insufficient information to influence guideline development. # Interpretive summary for this category Except for one study (3), the studies in this category included patients who did not have any significant comorbid illnesses.In comparison with regimens presumed to be less toxic (e.g., VMP, CVP), anthracycline-containing regimens such as CHOP (22) or CTVP (12) were associated with improvements in OS in patients 70 years of age and older.Two studies (1;10) testing chemotherapy regimens that are more intensive than CHOP both detected an increase in toxicity with no survival benefit detected.Subset analyses comparing CHOP with "second and third generation" regimens (51;54;55;58) show that CHOP is at least as effective or less toxic than these other regimens.The remaining studies (6;15;18;20;56) in this category did not contribute additional information. # Monoclonal Antibodies One study by GELA (9) evaluated the combination of chemotherapy and monoclonal antibodies.This study scored 2 on the Jadad quality scale, contained adequate information about patient withdrawals, but was not blinded and did not provide the details of the randomization process or concealment.In this trial (9) 399 patients ages 60-80 years were randomized to receive CHOP with or without rituximab 375 mg/m 2 on day 1 of each treatment cycle.Patients randomized to CHOP plus rituximab experienced an improved CR rate (76% v. 63%; p=0.005) and 2-year event-free (57% v. 38%; p<0.001) and overall survival (70% v. 57%; p=0.007).No differences in standardly measured treatment-related toxicity were detected; nine percent of patients receiving rituximab experienced grade 3 or 4 infusion-related toxicities. # Interpretive summary for this category The administration of rituximab with CHOP improves the response rate and event-free and overall survival compared with CHOP alone and is well tolerated. # Colony Stimulating Factors Two practice guidelines (34;36) and three RCTs (23;57;59) were identified, which address the growth factors guideline question.One practice guideline (34) has been updated (35;61). # Practice guidelines Two practice guidelines (34-36;61) address the use of colony stimulating factors in patients receiving myelosuppressive chemotherapy.Based on the results of three randomized trials (62-64), the American Society of Clinical Oncology (ASCO) produced a guideline (34;35) suggesting that primary prophylaxis with colony stimulating factors may reduce the incidence of febrile neutropenia by 50 percent if the incidence of febrile neutropenia is greater than 40 percent in a control population (34).In conjunction with a decision analysis (65) that concludes that primary prophylaxis is cost-effective in this circumstance, the ASCO guideline recommends use of colony stimulating factors when the risk of febrile neutropenia is estimated to be greater than 40 percent.The decision analysis utilized data extracted from a randomized trial assessing primary prophylaxis in patients with small cell lung cancer (62) in which neutropenia was defined as a count of less than 1.0x10 9 /L and all patients with febrile neutropenia were treated with intravenous antibiotics in hospital; the perspective taken was that of the hospital-costs payer.The authors do not indicate whether the value of 40 percent applies to the risk to the patient over an entire treatment course or to an individual treatment cycle.The second guideline was published by the Cancer Care Ontario Systemic Treatment DSG (36) and suggests that G-CSF is a reasonable option if quality of life is expected to be improved by a reduction in the number or duration of febrile neutropenic episodes. # Randomized studies Three randomized studies have evaluated primary prophylaxis with G-CSF in older patients with aggressive histology lymphoma (23;57;59); these trials are detailed in Tables 9 and 10.Two trials scored 2 (23;59) and the third scored 1 (57) on the quality scale.A full paper publication (23) and one abstract (59) contain information on patient withdrawals but not about the method of randomization or concealment.The other abstract (57) lacks details about withdrawals, randomization and concealment. 10).The percentage of treatment cycles associated with a WHO grade II-IV infection was 14 (134/949) in patients receiving CHOP alone and 10 (95/926) in patients receiving CHOP plus G-CSF (J.K. Doorduijn, personal communication).While this difference reached statistical significance (p=0.011), the absolute risk reduction of 4 percent corresponds to a number needed to treat (NNT) of 25 cycles in order to prevent one WHO grade II-IV infection.No difference in the percentage of patients experiencing a WHO grade II-IV infection was detected (53% treated with CHOP v. 46% treated with CHOP plus G-CSF; p=0.20).Quality of life was evaluated in this study using the European Quality of Life Questionnaire (EuroQoL), EORTC Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30), and the Multidimensionele Vermoeidheids Index (MVI; a fatigue scale) questionnaires administered after the second, fourth and sixth cycle of treatment and at 3, 6, 10, and 18 months of follow-up (66).Out of the entire group, 162 patients were selected to participate in the quality of life analysis, and 132 agreed to do so, with a 90% questionnaire return rate.No differences in scores between randomized groups were detected. Using a factorial design, Björkholm et al. (57) randomized 455 patients at least 60 years of age to CHOP or CNOP with and without G-CSF.No differences in CR rate or five-year OS were detected between patients receiving or not receiving G-CSF.Patients receiving G-CSF experienced less WHO grade 4 neutropenia (Table 10) and fewer infections during granulocytopenia (Table 10).Using these data, the patient NNT to prevent one infection during granulocytopenia was six. Zinzani et al. (23) randomized 149 patients at least 60 years of age to VNCOP-B with or without G-CSF.No statistically significant differences were detected in CR rate (Table 10), partial response rate (Table 10), relapse-free survival (RFS) at 30 months (Table 10), or OS at 30 months (Table 10).Patients randomized to G-CSF experienced less neutropenia (less than 0.5 x 10 9 /L; Table 10) and fewer clinically relevant infections (Table 10).Using these data, the patient NNT to prevent one clinically relevant infection was six.One-third of the patients in the control group who experienced an infection required parenteral antibiotics or hospitalization compared with none in the G-CSF group.The report does not comment on the rate of febrile neutropenia in the control group. # Risk factors for toxicity The trials testing the role of growth factors failed to detect differences in disease control or survival but did show a reduction in the risk of infections.The Hematology DSG therefore concluded that the ability to make a recommendation regarding the role of primary prophylaxis with growth factors in older patients with aggressive histology lymphoma might be assisted by an evaluation of literature addressing factors that predict for an increased susceptibility to the toxic effects of therapy, including the risk of infection.An evaluation of these prognostic factors is complicated by the inclusion in some studies of an evaluation of factors that predict for other outcome measures, such as OS.Specific multivariable toxicity analyses from two randomized trials (11;12) were reviewed along with an additional six retrospective studies (67-72) dealing with risk factors for toxicity.
Two randomized trials evaluated factors associated with an inferior OS (11;12).In the trial comparing CHOP with CNOP (11), the early toxic death rate was 10 percent for patients receiving CHOP; a multivariate analysis of prognostic factors detected that treatment with CNOP, high lactate dehydrogenase (LDH), bulky disease, and poor performance status (ECOG greater than 1) were associated with a higher risk of death.In the trial comparing CTVP with CVP (12), the group receiving CVTP had a toxic death rate of 15 percent and 13 percent experienced a major infection following the first cycle of therapy; a multivariate analysis detected that advanced stage, performance status, LDH, and albumin were predictive for shorter survival. Six studies (67-72) have retrospectively evaluated (70;71) factors that predict for treatment toxicity in patients with lymphoma.Only one of these reports was limited to older patients and included a multivariate analysis (67).Gomez et al. (67) evaluated 267 patients 60 years of age and older who received CHOP without growth factors; 53 percent of patients were older than 70 years, 52 percent had stage III or IV disease and 28 percent fell within the high-intermediate or high IPI risk groups.A toxic death was defined as a death occurring within six months of commencing treatment; 13 percent of patients suffered a toxic death with 83 percent of these secondary to infection.Sixty-five percent of the infection-related deaths were associated with neutropenia.A multivariate analysis detected that the only factor that independently predicted for a toxic death was an ECOG performance status of 2 or greater (relative risk 3.5; p=0.000001).Other factors assessed included age, histology, Ann Arbor stage, presence of extranodal disease or B symptoms, disease bulk, IPI risk category, LDH, and doxorubicin dose intensity. # Interpretive summary for this category Three randomized trials (23;57;59) assessing primary prophylaxis with G-CSF have failed to detect a difference between groups in OS or any measure of treatment efficacy, such as initial response rate or duration of disease control.All three trials, however, did show a reduction in the frequency of severe neutropenia and in the risk of infection.Two studies (23;57) detected that the patient NNT to avoid having one patient experience an infection was six; another study (59) detected that the number of cycles needed to treat to avoid an episode of infection was 25.One study (66) reported quality of life outcomes and failed to detect a difference between randomized groups.Baseline ECOG performance status is the most powerful factor predicting for treatment-related toxicity that results in a toxic death. ONGOING TRIALS The Hematology DSG is aware of the following ongoing trials: # VI.DISEASE SITE GROUP CONSENSUS PROCESS The Hematology DSG considered the management of older patients with aggressive histology lymphoma to be an important topic for guideline development because of its incidence, the availability of evidence, and a perception that practice patterns varied outside a range suggested by this evidence.The Hematology DSG concluded that treatment of these patients is complex, with the decision-making process requiring knowledge of available evidence and with application of this evidence to each patient after evaluating their specific circumstances, including their preferences.Based on the results of randomized trials that have tested many chemotherapy regimens founded on different principles, the Hematology DSG concluded that it is possible to provide specific treatment recommendations for older patients who have no significant comorbid health problems or specific preferences that would reduce the priority of providing therapy that offers the best opportunity of durable disease control. The first topic dealt with the optimum base chemotherapy regimen.The Hematology DSG concluded that CHOP should remain as standard therapy for these patients, just as it currently is for younger patients.The Hematology DSG concluded that age alone should not be the prime determinant for selecting the base chemotherapy regimen but that alternatives to CHOP should be reserved for patients of any age who have significant comorbid conditions or specific preferences.Physicians should be cautioned that many older patients might have significant comorbid illnesses or preferences that would make the use of CHOP inappropriate (75). The second topic considered dealt with the addition of rituximab to CHOP.The GELA trial testing this agent ( 9) included patients ages 60 to 80 years with stage II-IV diffuse large B-cell lymphoma, an ECOG performance status of less than 2 and no contraindications to doxorubicin.The Hematology DSG concluded that the reported data were sufficiently strong enough to justify a recommendation stating that these patients should receive rituximab in combination with CHOP.The Hematology DSG also discussed whether this recommendation should be generalized to other patients such as those older than 80 years, with limited stage disease, receiving chemotherapy other than CHOP or receiving subsequent-line chemotherapy.The Hematology DSG concluded that patients older than 80 years who otherwise satisfy criteria for treatment with CHOP do not represent a specific prognostic entity and should, therefore, receive similar treatment to patients aged 60 to 80 years of age.The Hematology DSG concluded that current data are insufficient to support a recommendation to add rituximab to chemotherapy for patients with limited-stage or relapsed disease or for patients receiving chemotherapy other than CHOP. The third topic considered dealt with the use of growth factors as part of primary therapy in combination with chemotherapy and rituximab.The Hematology DSG initially concluded that in the absence of trials detecting superior disease control, survival, or quality of life, current data were insufficient to support a recommendation to use growth factors as part of primary therapy.The Hematology DSG did conclude that secondary prophylaxis with G-CSF was appropriate and recommended for patients who have experienced a previous episode of neutropenic fever or a treatment delay resulting from prolonged neutropenia.This initial recommendation concerning primary therapy did not achieve unanimous approval from the Hematology DSG-some members regarded a reduction in the risk of infection as a sufficient outcome to justify using G-CSF as primary therapy for all patients.A minority of practitioners from across Ontario who reviewed the initial guideline (August 2000) also supported this position.With the availability of results from three randomized trials indicating that the absolute reduction in infections may be less than initially anticipated (55) and with a review of data that assists in predicting which patients are at greatest risk of life-threatening infections, the Hematology DSG reached consensus for a modified recommendation.The Hematology DSG now concludes that there are insufficient data to support a recommendation to routinely use growth factors as part of primary therapy but does support the primary use of growth factors for patients at high risk of developing life-threatening infections.These patients are best identified as those with a poor (ECOG greater than 1) performance status.The Hematology DSG also concluded that this recommendation should be expanded to include those patients who present with neutropenia or who have an active infection at the time that therapy is commenced.The recommendation for using growth factors as part of secondary prophylaxis was not altered. # VII.EXTERNAL REVIEW OF THE PRACTICE GUIDELINE REPORT Draft Recommendations Based on the evidence described above, the Hematology DSG drafted the following recommendations: # Target Population These recommendations apply to patients older than age 60 who have newly diagnosed, advanced-stage, aggressive histology non-Hodgkin's lymphoma, an ECOG performance status of less than 4 and no significant comorbid illnesses. # Draft Recommendations Key Recommendations Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is recommended for patients with no apparent cardiac disease or significant comorbidity.Dose and schedule should be the same as that used in younger patients. The addition of rituximab to CHOP is recommended for patients with diffuse large B-cell lymphoma. There is insufficient evidence to support the routine use of granulocyte-colony stimulating factor as primary therapy. While use of granulocyte-colony stimulating factor shortens the duration of neutropenia and decreases the infection rate in these patients, no differences in disease control or survival have been detected. The primary use of granulocyte-colony stimulating factor is recommended for older patients who are at a particularly high risk of experiencing neutropenic fever.These patients are best identified as those with a poor performance status (ECOG 2 or greater), neutropenia prior to therapy or an ongoing infection; there are insufficient data to recommend the primary use of granulocyte-colony stimulating factor for patients whose sole risk factor is bone marrow involvement with lymphoma. The use of granulocyte-colony stimulating factor as secondary prophylaxis is recommended for patients who have previously experienced an episode of neutropenic fever or a treatment delay resulting from persisting neutropenia. Qualifying Statements Treatment decisions in older patients with aggressive histology lymphoma are complex and may be influenced by comorbidity, patient preferences, quality of life issues and the goals of the treatment program.These factors may alter recommendations for individual patients and require discussion between health care providers, patients and their families. Radiation therapy is not considered in this guideline and may be an important part of the treatment plan for these patients. # Related Guidelines Practice Guidelines Initiative's Practice Guideline Report #12-2: Use of Granulocyte Colony-Stimulating Factor (G-CSF) in Patients Receiving Myelosuppressive Chemotherapy for the Treatment of Cancer and Evidence Summary Report #6-8: Rituximab in Lymphoma. # Practitioner Feedback Based on the evidence and the draft recommendations presented above, feedback was sought from Ontario clinicians. Practitioner feedback was obtained through a mailed survey of 110 practitioners in Ontario (49 medical oncologists, 30 hematologists, 21 pharmacists and 10 resident hematologists).The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations above should be approved as a practice guideline.Written comments were invited.The practitioner feedback was mailed out on August 6, 2002 or October 28, 2002 for staff clinicians and October 10, 2002 for resident hematologists.Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again).The Hematology DSG reviewed the results of the survey. Sixty-four responses (three residents and 61 staff clinicians) were received out of the 110 surveys sent (58% response rate).Responses include returned completed surveys as well as phone, fax, and email responses.Of the practitioners who responded, 53 (three residents and 50 staff clinicians) indicated that the report was relevant to their clinical practice and completed the survey.Key results of the practitioner feedback survey are summarized in Table 11. # Summary of Written Comments Eighteen respondents (34%) provided written comments.The main points contained in the written comments were: - Three respondents felt that the conclusions about CHOP plus rituximab (CHOP-rituximab) were premature and required confirmation.One of these respondents felt that the use of CHOPrituximab should be permissive rather than prescriptive since there are resource utilization issues with CHOP-rituximab. - One respondent asked why rituximab use with CHOP was limited to those 60 years of age and older. - One respondent felt that the data from the German trial (CHOP-14/21±etoposide) (10) were compelling and that the results were unlikely to change upon publication.The respondent felt that either these results should be incorporated into the conclusions of the guideline or that the guideline's conclusions should be delayed until full paper publication of this study. - One respondent commented on the poor quality of the data used to better define the risk factors for toxicity. - One respondent requested more guidance on the management of those patients with comorbid illness. Modifications/Actions 1.The DSG felt that the survival advantage reported with CHOP-rituximab was statistically significant and clinically important, despite the short follow-up.Based on these results, the DSG felt that rituximab should be added to CHOP in this patient population.No changes were made to the recommendations. - The DSG has summarized this aspect in the DSG consensus section based on: the lower age limit in the randomized trial, the extension of the treatment principles of those aged 60 to 80 years to those above the age of 80, and the lack of evidence for benefit of CHOP-rituximab, thus far, in younger patients.No changes were made to the recommendations. - The DSG concluded that recommendations could be made regarding the use of CHOP-rituximab based on the results of one randomized trial (9) as this trial has been published in full article form and used an intention-to-treat analysis that included all patients.This analysis detected superior overall survival in the group randomized to receive CHOP-rituximab.In contrast, the German study (10) has been published only in abstract form and used a factorial design to assess two questions; the eventual analysis was performed using different methodology.Given this complexity, the DSG concluded that recommendations should not be made until results are published in article form.When published, the results will be incorporated into the guideline.No changes were made to the recommendations. - The DSG acknowledges the limited quality of the data available for the assessment of risk factors for toxicity in older patients with lymphoma.However, the DSG felt that the most reasonable interpretation of available evidence, in conjunction with clinical experience, was to recommend that "pre-existing infection" and "neutropenia at the time of commencing chemotherapy" should be included as two risk factors leading to a recommendation to use granulocyte-colony stimulating factor as primary prophylaxis.No changes were made to the recommendations. No evidence exists to better guide therapy for those patients with comorbid illness. # Practice Guidelines Coordinating Committee Approval Process The practice guideline report was circulated to members of the Practice Guidelines Coordinating Committee (PGCC) for review and approval at the May 2003 teleconference meeting.Twelve of 16 members of the PGCC attended the meeting, and all 12 approved the practice guideline report as written. The PGCC felt that the guideline covered a lot of questions and the Hematology DSG did a great job handling the questions.One member questioned whether the level of detail was shortchanged given the number of questions and volume of evidence.Other comments included that the guideline was well written overall, the Interpretive Summary was succinct, and 90% practitioner feedback approval indicated great recommendations. # VIII.PRACTICE GUIDELINE This practice guideline reflects the integration of the draft recommendations with feedback obtained from the external review process.It has been approved by the Hematology DSG and the Practice Guidelines Coordinating Committee. # Target Population These recommendations apply to patients older than age 60 who have newly diagnosed, advanced-stage, aggressive histology non-Hodgkin's lymphoma, an ECOG performance status of less than 4, and no significant comorbid illnesses. - Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is recommended for patients with no apparent cardiac disease or significant comorbidity.Dose and schedule should be the same as that used in younger patients. The addition of rituximab to CHOP is recommended for patients with diffuse large B-cell lymphoma. There is insufficient evidence to support the routine use of granulocyte-colony stimulating factor as primary therapy.  While use of granulocyte-colony stimulating factor shortens the duration of neutropenia and decreases the infection rate in these patients, no differences in disease control or survival have been detected. The primary use of granulocyte-colony stimulating factor is recommended for older patients who are at a particularly high risk of experiencing neutropenic fever.These patients are best identified as those with a poor performance status (ECOG 2 or greater), neutropenia prior to therapy, or an ongoing infection; there are insufficient data to recommend the primary use of granulocyte-colony stimulating factor for patients whose sole risk factor is bone marrow involvement with lymphoma. The use of granulocyte-colony stimulating factor as secondary prophylaxis is recommended for patients who have previously experienced an episode of neutropenic fever or a treatment delay resulting from persisting neutropenia. Qualifying Statements Treatment decisions in older patients with aggressive histology lymphoma are complex and may be influenced by comorbidity, patient preferences, quality of life issues, and the goals of the treatment program.These factors may alter recommendations for individual patients and require discussion between health care providers, patients and their families. Radiation therapy is not considered in this guideline and may be an important part of the treatment plan for these patients. CANCERLIT (1983to February 1999, EMBASE (1980 to January 1999), Current Contents (1993 to May 1999), the Cochrane Library (Issue 2, 1999), and Best Evidence (1991 to August 1999) databases were searched without language restriction.This search was updated in April 2000.The following terms were used for MEDLINE and CANCERLIT: "lymphoma, non-Hodgkin" (MESH, text word), "lymphoma" (text word) combined with "aged" (text word) or "older" (text word) combined with "chemo:" (text word).These terms were then combined with search terms: "practice guidelines" (MESH, text word) or "practice guideline?" (text word) or "guideline?" (text word); "meta-analysis" (MESH, text word) or "meta analy:" (text word) or "metaanaly:" (text word) or "systematic review?" (text word) or "systematic overview?" (text word); "random:" (text word) or "random allocation" (MESH, text word).The CANCERLIT search was limited to non-MEDLINE entries.The following headings were used for EMBASE: "lymphoma" or "non-hodgkin lymphoma"; "age" or "old" or "older"; "chemo"; "practice guideline?"or "guideline"; "meta-analysis" or "metaanaly" or "meta analy" or "systematic review?"or "systematic overview?"; "random" or "random allocation?".The Cochrane Library, Current Contents, and Best Evidence were searched using the following terms: "lymphoma" and "older" and "chemotherapy". # Related Guidelines The search strategy for the growth factors question used the following terms for MEDLINE and CANCERLIT (limited to non-MEDLINE entries): "lymphoma" (MESH, text word) or "lymphoma, nonhodgkin" (MESH, text word) and "age?" (text word) or "elder:" (text word) or "old:".These terms were then combined with the following terms: "growth factor?" (text word) or "granulocyte-macrophage colony-stimulating factor" (MESH) or "granulocyte colony-stimulating factor" (MESH) and "review?"or "overview" or "guide:".The following terms were used for EMBASE: "lymphoma" and "older" or "aged" and "granulocyte colony stimulating factor" or "granulocyte macrophage colony stimulating factor".Searches of the Cochrane Library, Current Contents, and Best Evidence were performed using the following terms: "lymphoma" and "older" and "colony stimulating factor".
The paucity of randomized trials assessing the role of colony stimulating factors in the elderly led to a broadening of the inclusion criteria to include non-randomized studies. # Study Section Criteria: The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial over-all survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. The baseline characteristics of the pegfilgrastim and filgrastim groups were imbalanced with increased bone-marrow involvement and prior therapy in the former. When the treatment groups were balanced for these risk factors, duration of grade 4 neutropenia was comparable with 2.0 and 3.0 vs. 0.6 and 0.5 days for pegfilgrastim 100 microg/kg and filgrastim patients with and without these risk factors, respectively. The incidence of febrile neutropenia (defined as ANC 38.2degrees C) was low (10% of patients). The Hematology Disease Site Group would like to thank Drs C.T. Kouroukis, G. Browman, K. Imrie, and R. Meyer and Ms. R. Esmail, Ms. J. Makarski, and Ms. A. Stevens for taking the lead in drafting and revising this practice guideline report. For a complete list of the Hematology Disease Site Group members and the Practice Guidelines Coordinating Committee members, please visit our web site at /. # DOCUMENT ASSESSMENT AND REVIEW RESULTS # Question Considered - What are the roles of granulocyte-colony stimulating factor or granulocyte macrophage-colony stimulating factor in combination with chemotherapy in these patients? # Literature Search and New Evidence The new search from October 2001 to January 2013 yielded 19 references representing 17 RCTs (2 RCTs had 2 publications each), evaluating the use of chemotherapy and growth factors in older patients with newly diagnosed, advanced-stage, aggressive histology non-Hodgkin's lymphoma. Sixteen of these references had full text publications and 3 were in abstract form.There were 3 ongoing studies identified from clinicaltrials.gov.Brief results of these searches are shown in the Document Review Tool. # Impact on Guidelines and Its Recommendations # OUTCOMES DEFINITION - ARCHIVED -An archived document is a document that will no longer be tracked or updated but may still be useful for academic or other informational purposes.The document is moved to a separate section of our website, each page is watermarked with the phrase "Archived document, not for use in clinical decision making," - ENDORSED -An endorsed document is a document that has been reviewed by the DSG/GDG for currency and relevance, and determined to be still useful as guidance for clinical decision making.A document may be endorsed because the DSG/GDG feels the current recommendations and evidence are sufficient, or it may be endorsed after a literature search uncovers no evidence that would alter the recommendations in any important way. # DELAY - A Delay means that there is reason to believe new, important evidence will be released within the next year that should be considered before taking further action. # UPDATE -An Update means that the DSG/GDG recognizes that there is new evidence that makes changes to the existing recommendations in the guideline necessary but these changes are more involved and significant than can be accomplished through the Document Assessment and Review process.The DSG/GDG will rewrite the guideline at the earliest opportunity to reflect this new evidence.Until that time, the document will still be available as its existing recommendations are still of some use in clinical decision making.
To provide an updated guideline on the use of rituximab in lymphoma and chronic lymphocytic leukemia (CLL).# For information about this document, please contact Dr. Tom Kouroukis or Dr. Matthew Cheung through the PEBC via: Phone: 905-527-4322 ext.42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca: For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext.42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca # INTENDED USERS Intended users of this updated guideline include hematologists and oncologists treating patients with lymphoma or CLL. # RECOMMENDATIONS Recommendation 1 Aggressive histology B-cell lymphomas, including Burkitt lymphoma: first-line, secondline and maintenance treatment and patients with human immunodeficiency virus (HIV)-associated lymphomas. Previously Untreated Patients a. Previously untreated patients with aggressive histology CD20-positive B-cell lymphomas who are candidates for treatment with curative intent and will receive combination chemotherapy with curative intent (including cyclophosphamide, doxorubicin, vincristine, and prednisone CHOP-like, or similar dose-intense regimens) should receive this therapy in combination with rituximab. Patients with Relapsed/Refractory Disease b. For previously treated patients with aggressive histology CD20-positive B-cell lymphomas: There is insufficient evidence at this time to support treatment with a rituximabcontaining chemotherapy regimen in patients who have been previously treated with a rituximab-containing chemotherapy regimen.ii. If patients have not previously received rituximab as part of their treatment regimen, the addition of rituximab to chemotherapy is reasonable. Rituxmab Maintenance Treatment c. There is insufficient evidence at this time to support the use of maintenance rituximab in aggressive histology B-cell lymphomas. Patients with HIV-Associated Lymphomas d. Previously untreated patients with HIV-related lymphoma with a CD4 count ≥50/mm 3 who are candidates for treatment with curative intent and will receive combination chemotherapy with curative intent (including CHOP, CHOP-like, or similar dose-intense regimens), should receive this therapy in combination with rituximab.The addition of rituximab to chemotherapy in patients with CD4 <50/mm 3 is not recommended. # Recommendation 2 Indolent histology B-cell lymphomas: first-line, second-line, and maintenance treatment and patients with asymptomatic CD20-positive B-cell lymphomas Previously Untreated Patients a. Previously untreated patients with indolent histology CD20-positive B-cell lymphomas, excluding small lymphocytic lymphoma (SLL), who are appropriate candidates for chemotherapy, should receive their chemotherapy in combination with rituximab.b. For patients with indolent histology CD20-positive B-cell-histology lymphomas, excluding SLL, who are candidates for therapy, but not combination chemotherapy, rituximab monotherapy is a reasonable option. Patients with Relapsed/Refractory Disease c. For previously treated patients with indolent histology CD20-positive B-cell lymphomas, excluding SLL: i. Patients who have not previously received rituximab and who are appropriate candidates for chemotherapy should receive this chemotherapy in combination with rituximab or as rituximab monotherapy.ii.Patients who have previously received rituximab (including combination rituximab chemotherapy, rituximab monotherapy, or maintenance rituximab) and who have achieved a response of at least one year's duration from the last rituximab administration and who are appropriate candidates for therapy should receive this therapy in combination with rituximab or as rituximab monotherapy. Rituxmab Maintenance Treatment d. For patients with indolent histology CD20-positive B-cell lymphomas, excluding SLL, who respond to treatment with combination chemotherapy and/or rituximab, this treatment should be followed by the use of maintenance rituximab. # Patients with Asymptomatic CD20-Positive B-Cell Lymphomas e. There is insufficient evidence at this time to support or refute upfront treatment with rituximab monotherapy for asymptomatic indolent histology CD20-positive B-cell lymphomas. # Recommendation 4 Hepatitis B virus reactivation in all patients treated with rituximab The Hematology Disease Site Group recommends that all patients be screened for surface antigen for hepatitis B (HBsAg) and for hepatitis B core antibody (HBcAb) prior to treatment with rituximab.Consultation with an expert in hepatitis B virus (HBV) should be considered for all patients who test positively for HBV.Patients who are HBsAg positive should receive prophylactic antiviral therapy during and after rituximab.Patients who are HbsAg negative/HBcAb positive should be considered for either prophylactic antiviral therapy, close monitoring for viral reactivation, and/or should be followed by an expert in HBV.In the absence of active hepatitis (elevated transaminases), it is not usually necessary to delay rituximab.In most cases, HBV screening and management can occur in parallel with non-Hodgkin lymphoma/CLL treatment.
Version 2 IN REVIEW.This means that it is undergoing a review for currency and relevance.It is still appropriate for this document to be available while this updating process unfolds.The PEBC has a formal and standardized process to ensure the currency of each document.#Guideline Report History # Target Population These recommendations apply to adult patients with relapsed SCLC. - The evidence for the clinical benefit of second-line chemotherapy in the treatment of patients with relapsed SCLC is limited.The selection of patients for treatment with second-line therapy should be dependent on the treatment-free interval, the extent of response to first-line therapy, residual toxicity from first-line therapy, and the performance status of the patient. -There is insufficient evidence to recommend a specific chemotherapy regimen.However, in the opinion of the Lung Cancer Disease Site Group, patients who relapse three or more months following the completion of first-line chemotherapy may benefit from retreatment with the same regimen that induced their initial response.This would generally mean retreatment with etoposide-cisplatin.Alternative regimens may include cyclophosphamide, doxorubicin, and vincristine (CAV) or carboplatin and etoposide. -Oral topotecan is a possible alternative for patients who initially responded to chemotherapy and had a response duration of 45 days or longer. -There is insufficient evidence to determine whether one mode of administration of topotecan is superior to any other mode of administration.Oral administration is more convenient and may be a treatment option for patients not suitable for intravenous therapy.Oral administration is associated with a higher incidence of grade 3/4 diarrhea, whereas intravenous administration may result in a higher frequency of grade 3/4 neutropenia. -There is currently no standard second-line chemotherapy regimen for patients who fail to respond to or who relapse shortly after first-line therapy.Clinical trials are needed to determine the optimal treatment regimen. # Key Evidence - One randomized phase III trial compared chemotherapy to best supportive care, three randomized trials (one phase II and two phase III) compared different secondline chemotherapy regimens, and two randomized trials (one phase II and one phase III) compared different forms of administration of second-line single-agent chemotherapy. -One recent randomized phase II trial showed that chemotherapy consisting of oral topotecan and best supportive care (BSC) extended survival when compared with BSC alone and improved the quality of life for patients who had relapsed, resistant SCLC.The response rate for patients treated with oral topotecan and BSC was only 7%. -One randomized phase II trial comparing cisplatin and etoposide to carboplatin, cisplatin, and etoposide found no significant differences in response rate (p=0.20) or survival (p=0.11). -One randomized phase III trial that treated patients with CAV or topotecan alone reported no significant differences in response rate (p=0.285) or survival (p=0.795). -One phase III trial randomized patients to either bis-chloro-ethylnitrosourea , thiotepa, vincristine, cyclophosphamide (BTOC) or etoposide and cisplatin; no significant differences in response rate (p=0.91) or survival (p=0.15) were found. -Two randomized trials (phase II and phase III) compared oral to intravenous (IV) administration of topotecan.Response rates were 18.3% and 23.1% for oral administration and 14.8% and 21.9% for IV administration.Survival was not significantly different between the modes of administration (HR, 0.98; 95% CI, 0.77-1.25; and risk ratio, 0.84; 95% CI, 0.53-1.32). # Related Guidelines - # 7-13-1: The Role of Combination Chemotherapy in the Initial Management of Limited-Stage Small-Cell Lung Cancer; - # 7-13-2: Prophylactic Cranial Irradiation in Small Cell Lung Cancer; - # 7-13-3: The Role of Thoracic Radiotherapy as an Adjunct to Standard Chemotherapy in Limited-Stage Small Cell Lung Cancer. The PEBC is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term Care.All work produced by the PEBC is editorially independent from its funding agencies. Copyright This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario.Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.
The 2014 guideline recommendations have been ENDORSED, which means that the recommendations are still current and relevant for decision making.Please see Section 4: Document Assessment and Review for a summary of updated evidence published between 2013 and 2022, and for details on how this guideline was ENDORSED. What is the impact of intermittent strategies of administering systemic therapy on length and quality of survival in patients with untreated, unresectable metastatic colorectal cancer? # TARGET POPULATION These recommendations apply to adult patients (≥18 years old) with inoperable, advanced (Stage IV) colorectal cancer. # INTENDED USERS This guideline is intended for use by clinicians and healthcare providers involved in the management of patients with advanced colorectal cancer. # RECOMMENDATIONS AND KEY EVIDENCE Ten trials (1-10) were identified, and seven (1,2,5-9) had published overall survival hazard ratios (HRs) that could be used for the meta-analysis.Meta-analysis demonstrates no clinically significant survival difference between the continuous and intermittent Intermittent strategies of administering first-line systemic therapies to patients with unresectable metastatic colorectal cancer (mCRC) do not result in a statistically significant reduction in overall survival and either improve or maintain quality of life compared to continuous administration of therapy.Patients who want a break from treatment can be reassured that intermittent strategies of administering first-line therapy are a reasonable alternative to continuous administration.Intermittent systemic treatment strategies should be part of an informed discussion of treatment options for this group of patients.chemotherapy strategies (HR, 1.02; 95%CI, 0.95-1.10, p=0.62).No subgroup of trials based on the type of induction or maintenance therapy in the intermittent arm demonstrates a significant difference in overall survival between the two chemotherapy strategies (Figures 2, 3, and 6).Toxicity assessments revealed differential toxicity patterns for the two strategies.However, these toxicity assessments reflect maximal levels of toxicity experienced during exposure to the treatment on that arm of the trial.These measures are important, but for patients on intermittent treatment, duration of exposure to toxicity, or ability of patients to recover from the toxicities after induction treatment, are also important and are likely better captured in quality-of-life (QOL) assessments.Of the two trials that measured quality of life, the Maughan et al. (1) trial demonstrated no difference in QOL, and several benefits were demonstrated for the intermittent chemotherapy arm at 24 weeks in the COIN (6) trial.Specifically, there were statistically significant benefits with respect to role functioning (OR, 0.82; 95%CI, 0.70-0.96, p=0.015) and social functioning (OR, 0.82; 95%CI, 0.70-0.96, p=0.016) as well as for several symptom scales including fatigue, nausea and vomiting, appetite loss, constipation, diarrhea, dry or sore mouth, eating or drinking problems, problems handling small objects, and treatment interfering with activities of daily living (all p<0.04). # QUALIFYING STATEMENTS - Given that the trials included in this systematic review included a variety of maintenance strategies, a definitive recommendation regarding an optimal maintenance strategy is not possible.However, our analyses of strategies that did not use any maintenance systemic therapy did not demonstrate any statistically significant detriment in overall survival.Therefore, this approach may be preferred by patients, as it offers them a complete break from treatment. -All but one of the intermittent strategies offered 12 to 18 weeks of induction treatment and were monitored with imaging at least every 8 to 12 weeks during the intermittent phase of treatment, with reintroduction of the induction chemotherapy at disease progression.These represent reasonable guidelines to consider when using an intermittent strategy, but adaptation of a strategy to individual circumstances should always be considered.A longer induction period or closer clinical monitoring of patients on maintenance therapy or chemotherapy-free interval might be appropriate for patients with very bulky or symptomatic disease.For some patients like this, an intermittent strategy may not be appropriate. -Five of the seven trials that contributed to the meta-analyses were based on treatments with FOLFOX chemotherapy, one of the commonly used first-line chemotherapy regimens for mCRC in Ontario.The other two trials included in the meta-analyses used fluoropyrimidine monotherapy or FOLFIRI as induction chemotherapy regimens.Given the acceptability of fluoropyrimidine monotherapy as one of the options for first-line therapy (see EBS #2-5) and the accepted equivalence of FOLFIRI and FOLFOX as first-line therapies (11,12), extrapolation of our conclusions to all commonly used induction chemotherapy regimens is reasonable. -During maintenance therapy or a chemotherapy-free interval, best supportive care should be continued for patients. # FUTURE RESEARCH Future research should include a population study to evaluate the impact of intermittent strategies of administering first-line therapy for mCRC on outcomes in routine practice. # RELATED GUIDELINES - PEBC Evidence-based Series #2-5: Strategies of Sequential Therapies in Unresectable, Metastatic Colorectal Cancer Treated with Palliative Intent (currently under development) The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care.All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario.Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.
The Ontario Cervical Screening Program (OCSP) is currently being relaunched to incorporate an organized call and recall component.This relaunch has necessitated a review of evidence related to the research questions listed above and an update of the relevant portions of the Program in Evidence-based Care (PEBC) May 2005 guideline Cervical Screening (1).The updated guideline will help the OCSP to realize its long-term goals of reducing the incidence of and mortality from cervical cancer through an organized screening program and improving the capacity of providers to engage in organized cervical screening.It will also address the 2011-2014 Ontario Cancer Plan (2) goal of creating evidence-based guidelines for cervical cancer screening. Evidence clearly indicates that there is a role for HPV testing in primary screening, and, thus, the primary recommendations presented in Part 1 of this guideline are for HPVbased testing for women 30 years of age and over.The proposed algorithm (Figure 1) assumes the existence of an organized province-wide screening program. There is lesser quality evidence at this time for the appropriate screening algorithm for women under 30.For this reason, and because HPV testing is not currently funded in the province and the components of an organized screening program are in the process of being put in place, a set of interim recommendations (Section 1, Part 2) are also provided that include the younger age group and acknowledge the current standard of cytology-based testing.The goal of the interim recommendations is to provide a bridge to the time when HPV testing for primary screening is funded in Ontario.Because screening for cervical cancer is a quickly evolving field, the HPV testing-based algorithm, the optimal age for screening initiation, and a method of screening for women younger than 30 years should be reviewed prior to implementation.A comparison of recommendations contained in this guideline and in the previous version published in 2005 is presented in Table 1.A table of screening test results terminology and a glossary of terms are provided in Appendices 1 and 2, respectively.For more information on HPV and the development of cervical cancer, details of the systematic review, and discussion of the impact of adoption of HPV testing for primary screening, please see Section 2 of this report. # RECOMMENDATION Primary Screening Test HPV DNA testing of cells collected from the cervix is recommended for primary cervical screening.Cytology screening, which was recommended for primary screening in the previous version of this guideline, is now recommended only in the event of a positive HPV DNA test result (see HPV screening algorithm, Figure 1).Interim recommendations are provided in Section 1, Part 2 (Interim Recommendations), because HPV testing is not funded at this time for primary screening in Ontario. # KEY EVIDENCE HPV testing Seven randomized controlled trials (RCTs) (3)(4)(5)(6)(7)(8) have been conducted to assess the performance of HPV testing in primary screening.The trials assessed the rates of cervical intraepithelial neoplasia grade 2 or grade 3 (CIN2 or CIN3), either at a baseline screening round or over two screening rounds.CIN2 is a useful indicator because it is often the threshold for clinical management.CIN3 is less likely than lower grades of CIN to regress or resolve without treatment and so is a useful predictor of the risk for cervical cancer.The results showed that: - HPV testing consistently detected significantly more CIN2 and CIN3 in the baseline screening round than did cytology-based testing.HPV testing detected fewer CIN2 or more severe (CIN2+) cases in the subsequent screening round, indicating a lead time gain with HPV testing. The one trial that had sufficient sample size to report incidence and mortality due to cervical cancer found a significant reduction with HPV testing but not with cytology testing, compared to standard care (9). There was no significant difference in the number of invasive cancers detected in the baseline screening round in the New Technologies in Cervical Cancer trial (8) comparing HPV testing and cytology testing.In the subsequent screening round, no cases of cancer were found in the HPV-testing group, while nine cases were found in the cytology-testing group.A high number of the cancers detected in the second round in the cytology group were adenocarcinomas (10).This is consistent with previous reports that cytology is less effective in preventing adenocarcinomas than squamous cell carcinomas (approximately 20% of cervical cancers in Ontario are adenocarcinomas) (11). # Cytology Triage of HPV Positive Results - Due to the higher sensitivity of HPV testing compared to conventional cytology, the rate of colposcopy referral with HPV testing alone is higher than the rate with conventional cytology.For example, in the Canadian Cervical Cancer Screening Trial (CCCaST) RCT, the rate of referral to colposcopy after a positive HPV test alone was 6.1%, compared to a referral rate of 2.6% for conventional cytology results of atypical squamous cells of undetermined significance (ASCUS) (3). A triage test can reduce the number of colposcopy referrals and increase the specificity of the screening algorithm.In CCCaST, HPV with Pap triage resulted in a 1.1% rate of referral based on ASCUS (3).The Finnish Public Health Trial found the frequency of colposcopy referrals was 1.2% in both the conventional cytology arm at a threshold of low-grade squamous intraepithelial lesions (LSIL) and the HPV with cytology triage arm of their trial (12). # QUALIFYING STATEMENT - The recommendation for HPV testing is applicable only in the context of an organized screening program with an adequate database infrastructure that allows for an invitation to screening at recommended intervals, and a follow-up of women with abnormal test results. HPV testing has been shown to be more effective for women 30 years of age and older (see Age of Screening Initiation below). Women who have never been sexually active 1 do not require cervical screening. # RECOMMENDATION Age of Screening Initiation It is the opinion of the Cervical Screening Guideline Working Group (the Working Group) that there is insufficient evidence at this time to make a recommendation for the age at which to begin cervical screening using HPV testing as the primary screen.HPV testing performs better for women 30 and over compared to younger women because the rate of transient infections is higher in the younger age group; therefore, the screening algorithm in the following recommendation is presented for women 30-65 years of age. # RECOMMENDATION Screening Interval (Women 30-65) Screening interval recommendations are according to the algorithm presented in Figure 1.For women aged 30-65, HPV DNA testing is to occur at five-year intervals after an initial negative result, which is a change from the recommendation for repeat cytology testing every two to three years contained in the 2005 version of this guideline.HPV-positive tests should be assessed with cytology testing and not referred directly to colposcopy.Repeat HPV testing for results of HPV positive/cytology negative should be conducted after one year. # KEY EVIDENCE The proposed HPV testing algorithm is based on a combination of evidence from cohort studies, the natural history of HPV infections, and the consensus of the Working Group. # Five-Year Interval after HPV Negative Results - Six years after a negative HPV test, pooled cohort data found a cumulative incidence rate for CIN3+ of 0.27% (95% CI, 0.12 to 0.45), which was lower than the rate after three years with a negative cytology test (0.51%; 95% CI, 0.23 to 0.77) (14).This indicates that retesting at five-year intervals would entail a low level of risk. The risk of CIN3+ after a negative HPV test is low: in a Danish cohort study the 12-year absolute risk of CIN3+ after a negative HPV DNA test in women with normal cytology was 3.0% (95% CI, 2.5 to 3.5%) (15). # One-Year Interval with HPV Positive/Cytology Negative Results The short-term persistence of HPV infection for at least one year is an important predictor of CIN2+ (16).In women who tested HPV positive at enrolment and negative after about one year (nine-21 months), the cumulative incidence of CIN2+ after three years was 1.2% (95% CI, -0.2 to 2.5).The three-year cumulative incidence of CIN2+ in women who tested positive for carcinogenic HPV at study enrolment and again after approximately one year was 17.0% (95% CI, 12.1 to 22.0) (16).Consequently, referral to colposcopy after two consecutive positive HPV tests occurring a year apart is recommended, even in the event of initially negative cytology results. # QUALIFYING STATEMENTS The screening algorithm (Figure 1) should be reviewed for currency prior to implementation. A variation on this algorithm includes genotyping for HPV 16 and/or HPV 18 immediately after a positive HPV test and cytology results of normal, ASCUS or LSIL, based on the rationale that HPV 16 has been shown to be more persistent and more often associated with high-grade lesions, and HPV 18 is more often associated with difficult to detect lesions in the endocervical canal (13).Positivity for either of these types may require immediate colposcopy. # RECOMMENDATION Age of Screening Cessation Screening may be discontinued after the age of 65 provided there is an adequate negative screening history in the previous 10 years (i.e., two or more negative tests) and a final negative HPV test at age 65.Women who do not meet these requirements should continue with screening at recommended intervals.This is a change from the previous recommendation of cessation at age 70 (1). # KEY EVIDENCE This recommendation is the consensus of the authors, taking into account the low rate of cervical cancer in this age group among women who have previously been adequately screened, the potential discomfort of the procedure, and difficulties with visualization of the squamocolumnar junction in older women. # PART 2: INTERIM RECOMMENDATIONS (TO BE FOLLOWED UNTIL HPV TESTING IS FUNDED) INTERIM RECOMMENDATION Primary Screening Test On an interim basis, the authors endorse the recommendation contained in the 2005 version of this guideline: primary screening with cytology testing (1). # KEY EVIDENCE This recommendation is the opinion of the authors based on the systematic review conducted for the previous version of this guideline (1). # QUALIFYING STATEMENTS - Women with Pap tests that lack transformation zone components (i.e., endocervical and/or metaplastic cells) may continue screening at the regular intervals recommended by the guideline.Repeated samples lacking transformation zone may require further investigation. The above statement does not include women with test results of "unsatisfactory", who should undergo repeat screening in three months.This qualifying statement is the opinion of the Working Group based on the clinical experience that a shorter waiting period may result in the detection of reactive changes as a result of the first screening test. The Working Group maintains the recommendations for screening of special populations contained in the 2005 guideline:  Immunocompromised women (e.g., those currently taking long-term immunosuppressants, those who are HIV positive) should receive annual screening. Screening can be discontinued in women who have undergone a total hysterectomy for benign causes with no history of cervical dysplasia or HPV.Women who have undergone subtotal hysterectomy (with an intact cervix) should continue screening according to the guidelines. Indications for screening frequency for pregnant women should be the same as for women who are not pregnant.Manufacturers' recommendations for the use of individual screening tools in pregnancy should be considered. Women who have sex with women should follow the same cervical screening regimen as women who have sex with men. # INTERIM RECOMMENDATION Age of Screening Initiation Cytology testing should commence at 21 years of age for sexually active women. # KEY EVIDENCE Lower quality evidence was available for the questions regarding the age of initiation of cervical screening.Three case-control studies were found that addressed the questions of initiation (17)(18)(19).The results of these studies were mixed, with a trend towards higher efficacy of screening for older women.There were no studies found that directly assessed the optimal age of initiation of cervical screening with HPV testing as the primary screen. - After weighing the available evidence, the authors of this guideline have concluded that the harms of screening women under 21 years of age significantly outweigh the benefits. In the opinion of the authors, the potential for adverse reproductive outcomes with treatment, anxiety related to the testing procedure, and the anxiety and potential stigma associated with positive test results considerably outweigh the benefits of screening in women younger than 21 years of age (20)(21)(22)(23), given the relatively high rate of HPV infection (24), rarity of cervical cancer in women under 25 years, and the up to decadeslong time period of progression from HPV infection to cervical cancer (25). In the opinion of the Working Group, evidence regarding the necessity, utility, and/or effectiveness of screening in women 21 to 24 years is not as clear; the authors of this guideline are not convinced that the harms outweigh the benefits of screening for these women.Therefore, the consensus is that lesions in these women should be detected and treated where appropriate in order to minimize the potential for their progression to cervical cancer. The guideline authors do recognize that there is also a potential for harm with screening.The potential harms related to treatment of CIN are adverse reproductive outcomes, including premature rupture of membranes, low birth weight, and preterm delivery (22).The early detection and treatment of CIN3 in young women, however, might prevent some cancers developing to a stage where treatment could result in compromised fertility.Based on the information available at this time, the authors of this guideline consider that the benefit of eliminating potential cases of invasive cervical cancer in women 21-24 years of age outweighs the reproduction-related harms, as well as the potential anxiety, fear, and uncertainty related to abnormal screening tests, intensified screening, colposcopy, biopsy, and treatment for CIN. # QUALIFYING STATEMENTS - Women who are not sexually active 3 by age 21 may delay cervical screening. Women who have never been sexually active do not require cervical screening. The interim recommendation to begin screening at 21 years of age should be reviewed within 24 months of the publication of this guideline. As HPV-vaccinated women reach the age of screening initiation, there may be impact on the screening recommendations. # KEY EVIDENCE The key evidence for this recommendation is presented in Section 2 (systematic review section) of the 2005 PEBC guideline Cervical Screening (1). # INTERIM RECOMMENDATION Screening Interval Women should be screened every three years. # KEY EVIDENCE The previous guideline recommended three annual negative screens before lengthening the screening interval to two to three years.Evidence presented in the previous version of this guideline showed that the excess risk with screening every three years compared to annually was approximately three additional cases of cervical cancer per 100,000 women (26). A modelling study conducted in Australia found that increasing the recommended screening interval from two years to three years with cytology-based testing would result in no substantial change to incidence and mortality due to cervical cancer (27). # INTERIM RECOMMENDATION Age of Screening Cessation The authors endorse the age of cessation of cytology-based testing presented in the 2005 version of this guideline: Screening may be discontinued after the age of 70 if there is an adequate negative cytology screening history in the previous 10 years (i.e., three to four negative cytology tests). # KEY EVIDENCE Key evidence for this recommendation is presented in Section 2 (systematic review section) of the 2005 PEBC guideline Cervical Screening (1). # Recommended Management for Women with Abnormal Cytology Management recommendations were not included in the scope of the current guideline.The algorithm for the management of abnormal results from the previous version of this guideline has been appended, however, as its recommendations still apply to the interim cytology-based guidelines provided here.Please see Appendix 3 (Section 1, page 19).If the evidence base for these recommendations is required, please email ccopgi@mcmaster.ca. # FUTURE RESEARCH Results from further screening rounds of several of the RCTs included in the evidence base for this guideline are anticipated (Table 2).These results should further inform the optimal screening algorithm for women 30 years of age and older and the optimal age for commencing cervical screening.An international agreement has been reached to conduct future meta-analyses of the HPV screening trials and to synthesize evidence on new methods for cervical cancer prevention (28). # NTCC (ISRTCN81678807) February 2002 December 2004 Yes; A cost-benefit analysis is underway (10).Also, the group is updating the follow-up of a third screening round (personal communication, Guglielmo Ronco, May 2011). # ARTISTIC (ISRCTN25417821) June 2001 November 2009 Yes; the ARTISTIC trial is continuing to follow women while maintaining the randomised concealment of HPV testing results for a further three-year round of screening (29).The HPV FOCAL study (Trial Registration No.ISRCTN79347302) is being conducted by the BC (British Columbia) Cancer Agency, in collaboration with the BC Centre for Disease Control, the University of British Columbia, McGill University, and healthcare providers in Metro Vancouver and Greater Victoria.In a Canadian context, this study aims to establish the efficacy of human HPV testing as a stand-alone screening test with cytology triage of HPV positive women, establish an appropriate screening interval for HPV negative women, and determine cost-effectiveness of HPV testing as a primary screening test. Other HPV testing strategies under study are based on molecular markers and include viral load, genotyping, testing for the RNA of the viral oncogenes E6 and E7, and testing for the overexpression of the p16-INK4A protein (31). As research continues into the risk factors for cervical cancers and the different typespecific and other tests evolve, screening algorithms will become increasingly more complex.In response to this, a group is developing a tool to predict the risk for a woman of having or developing cervical precancer.These risk estimates could be used to make referral and screening interval decisions (32) and may be considered for implementation in future update of this guideline.
Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario.Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. # RELATED GUIDELINES
2b.In female patients with locally advanced breast cancer does locoregional irradiation result in higher survival and lower recurrence rates compared with breast/chest wall irradiation alone?2c.In female patients with locally advanced breast cancer and pathologically complete response to neoadjuvant therapy is radiotherapy indicated? - In female patients with locally advanced breast cancer who receive neoadjuvant chemotherapy is sentinel lymph node biopsy (SLNB) or axillary dissection the most appropriate axillary staging procedure?Is SLNB indicated before neoadjuvant chemotherapy rather than at the time of surgery?4.How should female patients with locally advanced breast cancer who do not respond to initial neoadjuvant therapy be treated? # TARGET POPULATION This guideline is pertinent to female patients with locally advanced breast cancer (LABC).For purposes of this guideline, LABC includes Stages IIB and IIIABC and inflammatory cancer, as defined in the AJCC Cancer Staging Manual, 6 th edition (1).Most studies in the evidentiary base (see Section 2) included heterogeneous populations spanning Stages IIB -IIIC and sometimes included inflammatory breast cancer.Very few studies dealt only with Stage III or specific subgroups such as patients with T3N0 cancer.As most of the major studies did not report results separately for patients with Stage IIB and Stage III cancers, the evidence did not support recommendations based on a narrower definition of LABC or subdivided by stage.Although some people do not consider Stage IIB to be locally advanced, there is an increasing trend to treat less bulky disease (Stage IIB) in a similar manner, including neoadjuvant therapy; therefore, the recommendations may also be applicable to this group. # INTENDED USERS The intended users are surgeons and medical and radiation oncologists specializing in breast cancer. This guideline addresses several questions related LABC as defined previously.In early breast cancer, breast-conserving surgery (BCS) with adjuvant radiotherapy (RT) has been found equivalent to mastectomy (in patients meeting BCS selection criteria) for long-term outcomes and it is preferred by many patients for cosmetic and psychological reasons.The applicability of BCS to LABC and the use and extent of RT after mastectomy is still a matter of debate. Historically, LABC has had poor outcomes.Although neoadjuvant (preoperative, induction) therapy was first introduced in an attempt to improve tumour resectability and overall survival (OS) rate with early adjuvant treatment, improved OS was not realized (2-6).However, other clinically important outcomes were observed, including disease downstaging and feasibility of breast conservation in select cases, which form the basis for continued use of this approach.Furthermore, neoadjuvant chemotherapy (NACT) 3 may also allow an in vivo assessment of chemosensitivity, potentially allowing a regimen change that would not otherwise be made with traditional postoperative adjuvant treatment.Finally, NACT provides a platform for important biomarker and correlative studies to enhance our understanding of this disease. Although BCS becomes technically feasible in some patients with LABC with good response to NACT, there is uncertainty as to whether mastectomy or BCS is most appropriate.Conversely, optimal treatment when LABC does not respond to initial NACT is unclear.Sentinel lymph node biopsy (SLNB) is used in early breast cancer as an alternative to full axillary lymph node dissection (ALND).The role of SLNB compared with ALND in patients with LABC receiving NACT has not been established. NACT has expanded beyond classically unresectable LABC and it is being used more frequently for some smaller tumours, especially certain clinical subtypes (e.g., triple negative, HER2+.Although this document does not evaluate effectiveness of NACT, its expanded use means that clinical trials often cover a heterogeneous patient population (see Target Population). Communication between oncologists, surgeons, radiologists, and pathologists is essential.A multidisciplinary case conference is the recommended forum for discussion of cases. Any prior use of neoadjuvant therapy should be indicated when specimens are submitted for pathologic examination. Clinical details often affect the pathologic examination and interpretation, whereas details of pathology reports will determine appropriate treatment.Prior therapy (including neoadjuvant therapy) can change the nature of the specimen and what should be reported.The experience of the authors is that use of neoadjuvant treatment is frequently not indicated when submitting specimens. It is recommended that surgical clips marking the original (pretreatment) tumour location be inserted before administration of neoadjuvant therapy.Neoadjuvant therapy may result in a change in the extent or distribution of tumour, including complete disappearance (clinically or pathologically complete response).The consensus reached at the Canadian Consortium for Locally Advanced Breast Cancer (COLAB) in 2011 (7) was that clips should be inserted at the time of diagnosis to mark tumour location and that this should be considered the standard of care.Use of clips allows for more accurate identification of the original tumour site (especially if there is complete response), resection of all (previously) cancerous tissue with adequate margins, pathologic interpretation of the most appropriate area of specimens, and greater accuracy of molecular analyses. # Question 1.In female patients with locally advanced breast cancer (LABC) with good response to neoadjuvant therapy, what is the role of breast-conserving surgery (BCS) compared with mastectomy? # Recommendation 1 For most patients with LABC, mastectomy should be considered to be the standard of care. BCS may be considered for some patients with non-inflammatory LABC on a case-by-case basis when the surgeon deems the disease can be fully resected and there is strong patient preference for breast preservation. # Key Evidence (go to Results in Section 2) - No randomized controlled trials (RCTs) that directly compared BCS with mastectomy in patients with LABC were found in the literature review (see Section 2). -Evidence in early breast cancer is that BCS plus radiation is equivalent to mastectomy alone (8,9).There is a continuum in breast cancer stage, as opposed to a sharp cut-off between early and locally advanced (see Target Population).The Cancer Care Ontario/Program in Evidence-Based Care (CCO/PEBC) guideline (9) included all of Stage I and II, although the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) defined early as "breast cancer in which all clinically apparent disease can be removed surgically" (10).Therefore, at least some cancers defined as LABC in the current guideline (e.g., Stage IIB) are covered in the recommendations of these other guidelines. # Qualifying Statements - Patients should be informed that for LABC as a whole the data are insufficient to recommend BCS as a rule; however, there may be some exceptions that can be considered on a case-by-case basis. -The extent of surgery, including BCS, should be determined after full discussion between the patient and the treating oncologist, taking into consideration the patient's values and the lack of direct evidence regarding the relative benefit of BCS vs mastectomy in this particular situation.Treatment of the axilla is discussed in Recommendations 2 and 3. -When considering between mastectomy and BCS (for those meeting selection criteria), benefits and harms must be weighed.BCS is considered to have generally better cosmetic effects, and for some female patients may have less impact on body image, self-esteem and sexuality than complete breast removal by mastectomy.With BCS there is usually no need for additional reconstructive surgery and the operation may be less complex.In some cases of BCS, there may be positive margins requiring re-excision.In cases of recurrence after BCS, further surgical procedure may be needed, and some patients may wish to reduce this possibility by having mastectomy as initial treatment. -Wide excision of the remaining tumour in the region of the original pre-neoadjuvant treatment tumour bed plus RT is recommended for patients with LABC who strongly desire BCS.The volume of tissue to excise will be decreased if there is response to neoadjuvant therapy.Surgical clips marking the original (pretreatment) tumour location should be inserted before administration of neoadjuvant therapy (see Preamble). -BCS is not advised in inflammatory breast cancer because the extent of tumour involvement cannot be reliably ascertained. -There is continuing evolution in the type of surgical procedures offered (e.g., skin-sparing mastectomy with immediate reconstruction), but these are beyond the scope of this guideline. # Question 2a.In female patients with locally advanced breast cancer who have had a mastectomy is radiotherapy indicated? # Recommendation 2a Radiotherapy following mastectomy is recommended for patients with LABC. # Key Evidence (go to Results in Section 2) - The EBCTCG meta-analyses (15,16) (see Section 2 Table 1) found postmastectomy radiotherapy (PMRT) significantly reduced 5-year and 10-year recurrence risk in patients with positive nodes (including subgroups with 1-3 positive nodes or with ≥4 positive nodes) or who received systemic therapy (primarily cyclophosphamide + methotrexate + fluorouracil and/or tamoxifen; >85% of patients with positive nodes received systemic therapy).This recurrence risk reduction applied to patients who had mastectomy plus ALND, mastectomy plus axillary sampling, or mastectomy only. - In the EBCTCG meta-analyses PMRT significantly improved 20-year breast cancer mortality (including all subgroups).PMRT also significantly improved 20-year overall mortality for node positive patients with ALND (overall or with ≥4 positive nodes) or with axillary sampling. -The benefit of RT in reducing breast cancer recurrence and mortality rates appears to be offset by adverse effects in older trials (primarily cardiovascular and lung adverse effects) especially in female patients with lower risk of recurrence.The ratio of breast cancer mortality rate to other mortality rates was strongly affected by nodal status, age, and decade of follow-up.The absolute benefit still favoured RT overall, but not necessarily in subgroups with particularly low risk of recurrence.More recent reviews found that the effectiveness of RT is increased and cardiopulmonary adverse effects are greatly reduced with modern RT planning and technique; therefore, the non-cancer mortality rate data in the EBCTCG meta-analyses may not be relevant to current practice. # Qualifying Statements - The use of three-dimensional (3D) treatment planning is important to minimize the dose to the lung and heart to ensure improvements in breast-cancer-specific survival rates are not offset by non-breast cancer mortality rates.Treatments provided should conform to accepted standards with respect to tissue coverage and dose.Techniques such as gated RT or active breath-hold are used in some centres to reduce cardiotoxicity, although these were not evaluated in this guideline series. -Radiotherapy after BCS was not part of this review, however guidelines for early breast cancer recommend radiation following BCS (8,9) and this is the current standard of care. In the absence of RCTs to the contrary, it is logical that radiation be used following BCS for LABC as well.Radiotherapy following BCS for LABC is the current standard of care. -The EBCTCG meta-analyses found RT improved recurrence and survival rates in the subgroup of patients with systemic treatment.Several of the studies used older regimens such as CMF.Whelan et al (17) also found RT reduced mortality in patients with nodepositive breast cancer who received systemic treatment.Figure 1 of Section 2 indicates RT significantly improved the local recurrence rate in patients receiving anthracyclinebased chemotherapy but there was no effect on survival rate.No studies were included in the systematic review (Section 2) using taxane-based chemotherapy.Newer chemotherapies and targeted therapies may reduce the absolute benefit of RT for some patients, although in the absence of RCTs, RT is still recommended. - Patients should be informed that improvements in recurrence and disease-specific survival rates have not necessarily translated into advantages in OS, possibly related to radiationinduced adverse effects in older studies.This applies especially in patients at lower risk of recurrence; however, most LABC patients who receive NACT would not be considered at low risk.Of patients with LABC, those with T3N0 confirmed by SLNB as N0 prior to chemotherapy are of lower risk than N+ patients.RT reduced the recurrence rates in all groups reported, but the absolute benefit in patients with very low risk of recurrence due to disease characteristics and systemic therapy may be small, and some may consider the incremental benefit of RT, although statistically significant, to be clinically unimportant. -Lymphedema is more likely when surgical procedures include ALND or/and when RT includes the nodal areas (see Section 2).Decreased shoulder mobility, decreased strength, arm weakness, and paresthesia/hypesthesia have also been reported.The German Breast-Cancer Study Group trial (also referred to as the Bundesministerium für Forschung und Technologie 03 study) (18) found that 25% of RT patients had acute skin reactions, and 28% had long-term skin alterations (1-2 years after RT).Radiation pneumonitis in the MA.20 trial was reported in 1.3% of patients receiving RT and 0.2% without.In some older RT regimens there was a significant increase in contralateral breast cancer and non-cancer mortality rates, primarily from heart disease and lung cancer (15,19).Careful treatment planning is likely to reduce (but not eliminate) risks other than lymphedema and skin effects. -The benefit of PMRT in patients with node-negative LABC (T3-4N0) is less clear because they have not been reported separately from smaller (T2N0) cancers.Additionally, in patients clinically T3N0 the rate of pathological node positivity exceeds 50% and these patients may be considered T3Nx unless deemed N0 by SLNB before NACT or by ALND. The EBCTCG fifth cycle analysis (16) found that patients with node-negative cancer (primarily early cancer) treated with mastectomy + ALND + RT had no difference in recurrence risk (3.0% RT vs 1.6%, p>0.1)due to RT but significantly higher overall mortality rate (47.6% vs 41.6%, p=0.03).Control patients (no RT) with node negative cancer in studies using mastectomy + axillary sampling had higher recurrence than in studies with ALND (17.8% vs 1.6%); RT in patients treated with axillary sampling resulted in significantly lower recurrence risk (3.7% vs 17.8%) and no difference in 20-year mortality (46.1% vs 49.9%, RR=1.0, p>0.1). Patients with T3N0 cancer remain a group with limited data and should be discussed individually with regards to risks and benefits. # Question 2b.In female patients with locally advanced breast cancer does locoregional irradiation result in higher survival and lower recurrence rates compared with breast/chest wall irradiation alone? # Recommendation 2b It is recommended that patients with LABC receive locoregional radiation encompassing the breast/chest wall and local node-bearing areas following breast-conserving surgery or mastectomy. # Key Evidence (go to Results in Section 2) - The recommendation for breast/chest wall irradiation is based on several RCTs as summarized in the EBCTCG meta-analyses (10,15,20-23) and is discussed in Question 2a. -A prospective nonrandomized study (24) in high-risk patients with Stage II-III breast cancer found improved disease-free survival (DFS) rates at median 77 months follow-up (73% with internal mammary (IM) node RT vs 52% without, p=0.02), whereas OS was 78% vs 64%, p=0.08.Subgroups at higher risk of recurrence may have greater benefit, as has been reported for patients with positive nodes. -A meta-analysis of the role of RT to regional nodes included three trials (two abstracts and one full publication) in patients with early/LABC (25) and concluded that regional RT to IM and medial supraclavicular (MS) nodes improves DFS, OS, and distant metastasis-free survival (DMFS) in Stage I-III breast cancer.This analysis did not meet our inclusion criteria because only approximately 36% of patients had LABC; therefore, the results need to be confirmed when the trials are fully published including subgroup data. -The recommendation to include local node-bearing areas is consistent with current practice and other clinical practice guidelines.The NCCN guideline (12) recommends that if IM lymph nodes are clinically or pathologically positive, RT should be administered to the IM nodes; otherwise, treatment to the IM nodes should be strongly considered in patients with node-positive and T3N0 cancer.NCCN also states that RT to the infraclavicular region and supraclavicular area is recommended for patients with ≥4 positive nodes and should be strongly considered if 1-3 nodes are positive, and considered for patients with T3N0 cancer (especially if inadequate axillary evaluation or extensive lymphovascular invasion). -The ACR (26) recommends PMRT for T1-2N2+ and T3-4N+, usually including ipsilateral supraclavicular fossa for patients with positive nodes.There is more variation for IM nodes, but IM RT is considered for patients at risk of IM involvement such as those with medial or centrally located tumours and positive axillary lymph nodes.PMRT treatment of T1-2N1 and T3NO is controversial and should be individualized. # Qualifying Statements - Locoregional treatment (compared with breast/chest wall alone) increases the risk for cardiovascular/pulmonary adverse effects.The additional fields are more technically complex to administer.The use of 3D treatment planning is important to minimize the dose to the lung and heart to ensure improvements in breast-cancer-specific survival are not offset by non-breast cancer mortality. -The risk of long-term adverse effects from locoregional radiation should be weighed against the potential benefits in patients with lower-risk disease, particularly those with left-sided tumours.Ideally, such patients should be discussed in a multidisciplinary setting. -In light of incomplete data, any recommendations regarding the role of regional radiation to specific nodal groups (e.g., IMC, MS, apical axilla, full axilla) in LABC are significantly limited.Although some studies attempted to isolate the role of irradiation to the IM nodes (27,28), others included additional radiation to the MS nodes (29-31) or all locoregional nodes (32,33). -The additional benefit of regional nodal RT is small, but significant for the overall patient groups studied in RCTs (early cancers plus LABC combined). -The incidence and/or severity of lymphedema is higher with locoregional RT.Especially in patients with lower-risk disease, the risk of long-term adverse effects from locoregional radiation should be weighed against the potential benefit of reduced recurrence rates and increased survival rates. -Patients with T3N0 cancer (verified to be node negative pre-and post-neoadjuvant therapy) remain a heterogeneous group with limited data and should be discussed individually with regards to risks and benefits.In patients clinically T3N0 the rate of pathological node positivity exceeds 50% and these patients may be considered T3Nx unless deemed N0 by SLNB before NACT or by ALND.In the latter case, they may be similar to T2N0 patients and less RT to the chest wall may be considered. # Question 2c.
In female patients with locally advanced breast cancer and pathologically complete response to neoadjuvant therapy is radiotherapy indicated? # Recommendation 2c It is recommended that postoperative radiotherapy remains the standard of care for patients with LABC who have pathologically complete response to neoadjuvant therapy. # Qualifying Statements (go to Results in Section 2) - No prospective randomized studies were found in the literature review (see Section 2) that compared treatment with vs without RT in female patients with pathologically complete response (pCR) to neoadjuvant therapy.The consensus of the authors is that postoperative RT should therefore remain the standard of care. -When examining the evidence, it is important for the clinician to be aware of the various definitions for pCR that have been used in clinical studies.These range from no microscopic evidence of viable tumour cells, only residual necrotic or nonviable tumour cells, or only residual intraductal tumour cells in the resected specimen.The MD Anderson Cancer Center requires the added disappearance of axillary lymph node metastasis for a pCR. - Randomized trials such as those planned by the Athena Breast Cancer Network (34,35) and the NSABP B51/RTOG 1304 trial may provide data to re-evaluate the recommendation for specific subgroups in the future. # Key Evidence (go to Results in Section 2) - The median sentinel lymph node (SLN) identification rates (SLN ID rates) for the trials in Section 2 were 88% overall, 93% in patients with cN0 cancer and 85% in patients with clinically positive nodes.SLN ID rates depend on the experience of surgeons and the techniques used (see Section 2 for details). -The ACOSOG Z1071 trial (36,37) conducted with patients with positive nodes (>85% LABC) is one of the largest and most recent studies.It found a 93% SLN ID rate for cN1 cancer and 89% for cN2 cancer.This study found detection with radiolabeled colloid much better than blue dye alone (94% colloid + dye, 91% colloid, 79% dye). -For the studies in Section 2, median false negative (FN) rates were 10% overall, 7% cN0, and 13% clinically node positive.The SN FNAC study (38,39) found the FN rate decreased with the number of sentinel nodes removed (FN rate 19% for 1 SN, 7% for 2+ SN) and is consistent with the SENTINA trial findings.Using radiolabelled tracer plus blue dye and removing at least 2-3 SLNs, the best teams achieved FN rates of 5-7%.The FN rate is not dissimilar to the FN rates of 5-10% for early breast cancer surgery (40-42). - Although the studies indicate that SLNB is technically feasible in both early and locally advanced breast cancer, a small percentage of patients will be understaged using SLNB alone.This risk needs to be weighed against the increased adverse effects of ALND. -This recommendation is based on the authors' valuing potentially increased survival rates with use of ALND over increased postoperative complications.Given the results of the Z0011 and EBCTCG studies for early or operable cancers, some patients may decide that for less advanced LABC (e.g, Stages 2b-3a) the adverse effects of ALND are greater than the benefits. # Qualifying Statements - Although the SLNB technique in patients (mostly with LABC) receiving NACT is comparable to that in early breast cancer, the clinical implications of a FN SLNB is not known in these patients (see Discussion in Section 2). -The benefit of ALND is that more nodes are removed and examined, giving more accurate staging for some patients.Provided that locoregional RT is to be administered in all patients, as recommended in Questions 2a and 2b, the staging may have no impact on treatment.However, some patients may value the additional prognostic information.If a patient is not going to receive locoregional RT, then ALND is recommended.Trials in patients with LABC are ongoing. -More than 80% of female patients undergoing ALND have at least one postoperative complication in the arm and psychological distress is common (43).In the Z0011 trial (44,45) ALND added to SLNB resulted in more wound infections, axillary seromas, paresthesias, and subjective reports of lymphedema than SLNB alone. -The NCCN guideline (12) (not specifically on NACT) indicates "in the absence of definitive data demonstrating superior survival the performance of ALND may be considered optional in patients who have particularly favourable tumours, patients for whom the selection of adjuvant systemic therapy is unlikely to be affected, for the elderly, or those with serious comorbid conditions".They recommend that cN0 plus SLN negative (including T3N0) need no further ALND.However, the authors of the current guideline note that most patients with LABC are pathologically node positive before neoadjuvant therapy, even those considered clinically negative; therefore, a high portion may still be pathologically node positive after neoadjuvant therapy. -None of the studies included inflammatory breast cancer; therefore, these findings cannot be extrapolated to that cohort of patients. # Recommendation 3-2 Although SLNB before or after NACT is technically feasible, there is insufficient data to make any recommendation regarding the optimal timing of SLNB with respect to NACT.Limited data suggests higher SLN ID rates and lower FN rates when SLNB is conducted before NACT; however, this must be balanced against the requirement for two operations if SLNB is not performed at the time of resection of the main tumour. # Key Evidence (go to Results in Section 2) - Only three of the studies in Table 6 of the evidence summary (46-48) compared timing of SLNB (before or after NACT) and one additional study (abstract only) performed SLNB before neoadjuvant therapy (49).The rest of the studies performed SLNB and ALND after completion of NACT.Before NACT the SLN ID rate was 98-99%, whereas after NACT it was a median of 93% in patients with clinically node-negative cancer and 88% overall.The studies also suggest FN rates are lower when SLNB is conducted before NACT. -The SENTINA study (46) did not conduct ALND if the SLNB before NACT was negative so FN rates could not be determined for this subgroup.Arm B of the SENTINA trial included patients initially cN0 with a positive SLN (pN1SN) before NACT and conducted a second SLNB plus ALND after NACT.SLN ID rate was 76% in the second SLNB and the FN rate based on the second SLNB was 61% compared with a SLN ID rate of 99% in patients with cN0 cancer when SLNB was performed before NACT.This suggests that SLNB should not be performed both before and after NACT. # Qualifying Statements - It is often considered that adjuvant treatment should be based on the initial stage as determined before any treatment, although the extent of surgery depends on the size/extent of the tumour immediately before the surgical procedure (i.e., after any neoadjuvant treatment).Some studies suggest NACT often eliminates cancer from the SLN but not all the other nodes.For these reasons, there is theoretical justification for performing SLN biopsy before NACT.The very limited data would support this, but is considered insufficient at this time to make a strong recommendation due to the trade-off required in risk and inconvenience of needing to perform two separate operations (one for SLNB and one to remove the main tumour) compared with the normal procedure of removing the tumour and SLN (or ALND) in one operation. # Question 4.How should female patients with locally advanced breast cancer who do not respond to initial neoadjuvant therapy be treated?Recommendation 4-1 It is recommended that patients receiving neoadjuvant anthracycline-taxane-based therapy (or other sequential regimens) whose tumours do not respond to the initial agent(s) or where there is disease progression be expedited to the next agent(s) of the regimen. # Recommendation 4-2 For patients who, in the opinion of the treating physician, fail to respond or who progress on first-line NACT, there are several therapeutic options to consider including second-line chemotherapy, hormonal therapy (if appropriate), radiotherapy, or immediate surgery (if technically feasible). Treatment should be individualized through discussion at a multidisciplinary case conference, considering tumour characteristics, patient factors and preferences, and risk of adverse effects. # Key Evidence (Recommendations 4-1 and 4-2) (go to Results in Section 2) - Anthracycline-taxane is a standard therapy, with the taxane administered either concurrently or consecutively.The NSABP B-27 trial (50-52) found AC followed by docetaxel gave significantly improved clinical and pathological response and lower rates of local recurrence compared with neoadjuvant AC alone.Because most patients were not LABC and patients were not randomized based on response, the trial is not included in the evidence review of Section 2. - The GeparTrio study (53) and a trial by Qi et al (54) evaluated early switching to second-line chemotherapy after nonresponse to two cycles of first-line chemotherapy and demonstrated conflicting findings: the GeparTrio demonstrated no improved response to treatment but better tolerability and DFS; the other trial demonstrated some improved response but worse adverse effects and treatment delays.There is therefore insufficient evidence to switch chemotherapy mid-treatment. -The recommendations are based on current practice and are consistent with the guidelines by NCCN (12), Health Canada (55), and the Consensus Panel for Neoadjuvant Chemotherapy (13). # Qualifying Statements (Recommendation 4-2) - There is a body of literature including patients with locally advanced and metastatic disease (mostly single-arm case series, small pilot studies, or retrospective studies) that supports a variety of second-line single agent and multi-agent NACT and/or RT regimens to improve response (including pCR) and, thus, operability or survival.Although the data are limited and not within the rigorous inclusion criteria of the literature review, Table 8 of Section 2 lists some of these studies as examples of regimens in the medical literature that have been tried in this clinical scenario.These data are not systematically reviewed nor of quality sufficient to make a recommendation as to preferred regimens.It is advised that oncologists individualize the choice of therapy based on the patient and risk of adverse effects. # FUTURE RESEARCH There is a need for prospective randomized clinical trials designed for patients with LABC who fail to respond to NACT so that more definitive treatment recommendations can be developed. # RELATED GUIDELINES The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care.All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol.
Recommendation Report SCT-6: Section 1 # Stem Cell Transplantation in the Treatment of Acute Lymphoblastic Leukemia: Recommendations OBJECTIVES 1.To establish the indications for allogeneic stem cell transplantation (allo-SCT) in the management of acute lymphoblastic leukemia (ALL) in adults 2.To identify the role of reduced-intensity conditioning (RIC) regimens for SCT in the management of ALL of adult patients 3.To identify the role of tyrosine-kinase inhibitors (TKIs) for patients undergoing allo-SCT for Philadelphia chromosome-positive ALL (Ph+ ALL) 4.To identify the role of alternative donor transplantation (haploidentical, cord blood) in the management of adult patients with ALL who lack a suitable related or unrelated donor. # TARGET POPULATION All adult ALL patients considered for treatment that involves SCT.Outcomes of interest are relapse, disease-free survival, relapse-free survival, progression-free survival, overall survival, and non-relapse mortality. # INTENDED USERS This recommendation report is targeted for: 1.Healthcare physicians performing SCT in Ontario. - Healthcare institutions and system leaders responsible for providing resources for SCT. # RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE Recommendation 1 Allogeneic stem cell transplantation (allo-SCT) is an option for adult patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1).Allo-SCT is recommended in CR2 or greater (refractory or relapsed). # Key Evidence for Recommendation 1 The studies involved patients with Philadelphia chromosome-negative ALL in first complete remission (CR1) and beyond (refractory or relapsed ALL).All patients were treated with total body irradiation (TBI)-based myeloablative conditioning, and sibling donor transplantation. - One evidence-based review with recommendations (1), and two systematic reviews with meta-analysis (2, 3) showed that allo-SCT offers superior overall survival and disease-free survival in patients with chromosome-negative ALL in CR1. -The recommendation surrounding allo-SCT in CR2 or beyond (refractory or relapsed) for adults with ALL represent the consensus of the Working Group members based on guidance provided by the 2012 American Society for Blood and Marrow Transplantation (ASBMT) guideline from USA (1). # Qualifying Statement for Recommendation 1 The studies looking at outcomes of allo-SCT in CR1 were older and many used less intensive regimens that may be currently used in adults with ALL, in particular regarding Lasparaginase.Thus, modern ALL therapy based on pediatric protocols may provide for better outcomes without the need to undergo allo-SCT in CR1. # Interpretation of Evidence for Recommendation 1 The primary outcomes considered to inform this recommendation include relapse, non-relapse mortality, disease-free survival and overall mortality/survival. The certainty of the evidence on the efficacy of allo-SCT compared with other postremission therapy (chemotherapy) is reasonable but with the caveat that current ALL chemotherapy protocols are more intensive than those used in the studies.This recommendation is generalizable to all adult patients with ALL in remission who are eligible for allo-SCT. # Recommendation 2 A myeloablative conditioning is the conventional regimen for most patients with leukemia; however, reduced-intensity conditioning (RIC) is an option for patients with acute lymphoblastic leukemia (ALL) in remission when they are deemed unsuitable for the standard myeloablative conditioning (MAC) regimen. # Key Evidence for Recommendation 2 This recommendation is supported by evidence obtained from the 2012 American Society for Blood and Marrow Transplantation (ASBMT) evidence-based review (1) and a systematic review with meta-analysis (4). - The 2012 ASBMT review (1) recommended RIC regimens only for patients with ALL in remission who are unsuitable for MAC regimens, as it was shown that RIC may produce similar outcomes to MAC regimens.The systematic review (4) stated that RIC may be a potential therapeutic option in patients with high risk of treatment-related mortality (TRM) associated with MAC regimens, as there was a lack of overall survival benefit of MAC over RIC regimens. -One retrospective cohort study (5) detected an improved overall survival for patients undergoing RIC when compared with MAC as conditioning for allo-SCT in ALL. # Qualifying Statement for Recommendation 2 Reduced-intensity conditioning may produce similar outcomes to myeloablative regimens, but available data are limited.Based on the evidence, the members of the Working Group have determined that RIC could be an effective therapeutic option for patients with ALL who are ineligible for MAC allo-SCT.There are important clinical differences in those patients undergoing the two types of conditioning that could affect outcomes.More prospective studies are required to better define the value of reduced versus MAC regimens. # Interpretation of Evidence for Recommendation 2 The primary outcomes considered to inform this recommendation include relapse, disease-free survival, non-relapse mortality, progression-free survival, and overall survival. The certainty of the evidence on the efficacy of RIC in adults with ALL in remission is non-relapse mortality, progression-free survival, and overall survival. The certainty of the evidence on the efficacy of haplo-SCT for patients in remission is low and therefore this recommendation cannot be generalized to all patients with ALL.This recommendation is generalizable only to patients with ALL who lack a suitable related or unrelated donor. # IMPLEMENTATION CONSIDERATIONS Should an increase in SCT for ALL result from this recommendation report, there may be issues related to capacity and timeliness of transplant in Ontario centres.Also, the use of haploidentical donors and RIC could increase the number of patients with ALL who may become eligible for a SCT.Due to the nature of the evidence showing improved outcomes in terms of survival and disease control, SCT for ALL would align with patient and provider values. # RELATED GUIDELINES moderate.This recommendation is generalizable to patients with ALL in remission who are not suitable for MAC regimens. # Recommendation 3 Post-transplant use of a BCR-ABL tyrosine-kinase inhibitor (TKI) in patients with Philadelphia chromosome-positive ALL (Ph+ ALL) is a reasonable option. # Key Evidence for Recommendation 3 - One evidence-based review with recommendations (1) and one prospective study ( 6) addressed this question.The consensus is that TKI therapy is useful pre and/or posttransplant.However, the evidence is not as strong as the 2012 ASBMT evidence-based review included one trial that evaluated the use of imatinib (TKI) in only five patients with Ph+ ALL (1). -One prospective, comparative cohort study ( 6) evaluated the administration of imatinib in 62 patients based on BCR-ABL transcript levels after allo-SCT, and it showed a lower relapse rate, lower non-relapse mortality and a survival advantage in favour of imatinib. # Qualifying Statement for Recommendation 3 The standard of care is to administer TKIs in combination with chemotherapy for ALL and before SCT.Demonstrating benefits of TKIs post SCT may therefore be difficult, as most patients will have received TKIs pre-transplant. # Interpretation of Evidence for Recommendation 3 The primary outcomes considered to inform this recommendation include relapse, non-relapse mortality, progression-free survival, and overall survival. The certainty of the evidence on the efficacy of TKIs post SCT is low.However, due to the poor prognosis for patients with Ph+ ALL, the members of the Working Group have determined that the use of TKI post SCT should be an option for this population. # Recommendation 4 Haploidentical hematopoietic Stem Cell Transplantation (haplo-SCT) for patients with ALL in CR1 or later who lack a suitable related or unrelated donor is a reasonable option. # Key Evidence for Recommendation 4 Two retrospective cohort studies compared the efficacy of haplo-SCT with chemotherapy alone when used as post-remission treatment in patients with ALL.Both studies showed improvement in relapse rate, disease control and overall survival in favour of the haplo-SCT patients.Non-relapse mortality was at acceptable levels.Patients in these studies had both standard and high-risk ALL. # Qualifying Statement for Recommendation 4 Haplo-SCT appears to be feasible in patients with ALL and it seems to provide an advantage over chemotherapy.As the evidence is somewhat limited, more prospective comparisons are required. # Interpretation of Evidence for Recommendation 4 The primary outcomes considered to inform this recommendation include relapse,
# GUIDELINE OBJECTIVES - To provide clinical guidance with respect to suitability for breast reconstruction, timing of reconstruction, and optimal reconstruction techniques. -To make recommendations that will inform decisions at the policy and administration level aimed at improving the quality of life of women with breast cancer in Ontario. # TARGET POPULATION - Women who have been diagnosed with breast cancer who have chosen or been recommended for therapeutic mastectomy. -Women who are at high risk for breast cancer who have chosen or been recommended for prophylactic mastectomy. # INTENDED USERS General surgeons practicing breast cancer surgery, plastic surgeons, oncologists, administrators, other referring physicians, and oncology healthcare professionals (e.g., those involved in patient education or psychosocial programs). # RECOMMENDATIONS Recommendation 1: Patient education and preoperative evaluation For women who have chosen or been recommended for therapeutic mastectomy: - The discussion of immediate or delayed breast reconstruction should be initiated at the time that mastectomy is offered by the general surgeon. - For women seeking immediate breast reconstruction for ductal carcinoma in situ (DCIS), preoperative evaluation with a general surgeon and a plastic surgeon should be performed. - For women seeking immediate breast reconstruction for early stage breast cancer who will potentially require adjuvant chemotherapy or radiotherapy (RT), a medical oncologist and/or radiation oncologist should be included in preoperative evaluation, either through a formal consultation or by a multidisciplinary cancer conference. - For women seeking immediate reconstruction, there should be adequate preoperative imaging of the breasts, aligning with existing guideline recommendations. # Qualifying Statement - Please see Cancer Care Ontario guidelines regarding recommendations about the use of mastectomy versus breast-conserving therapy (BCT) in early stage breast cancer (www.cancercare.on.ca). -Advance age is not a contraindication to breast reconstruction.There is no evidence that indicated a specific age cut-off as a contraindication; however, the number of people who received reconstruction after 70 years of age was limited. # Qualifying Statements - If morbid obesity and smoking status have been resolved, then women may be appropriate candidates for breast reconstruction. - None of the two characteristics listed above are absolute contraindications to reconstruction. - There is insufficient evidence to indicate whether diabetes is a contraindication to reconstruction. - Patients with increased (>BMI 30 kg/m 2 are at higher risk for complications and are encouraged to lose weight if undergoing delayed reconstruction.o Small invasive cancers with extensive microcalcifications or atypia that would preclude BCT and there is a low likelihood of nodal disease. - Positive margins following breast-conserving surgery opting for completion mastectomy o Recurrent disease following failed initial BCT and not deemed to be at high risk for metastatic disease - Provisional Recommendation October 2021: In patients expected to require radiotherapy, the timing of breast reconstruction should be determined after multidisciplinary discussion including the general surgeon or surgical oncologist, medical oncologist, radiation oncologist, and plastic surgeon and with full consideration of the values and preferences of the patient. # Qualifying Statement - Provisional Qualifying Statement October 2021: Women who will receive RT and are considering immediate breast reconstruction should be informed of the possibility of increased risk of complications, compromised esthetic outcome, and the potential for increased need for future revisional surgeries.The risk of these may vary depending on type and timing of RT, type of reconstruction, and patient characteristics. Recommendation 4: Skin-sparing, nipple-sparing, and areola-sparing mastectomy - Skin-sparing mastectomy (SSM), nipple-sparing mastectomy (NSM) and areola-sparing mastectomy (ASM) are incisions utilized simultaneously with immediate breast reconstruction - SSM or NSM with immediate breast reconstruction can be offered to women at high risk for breast cancer (>25% lifetime risk) undergoing prophylactic mastectomy and women with known DCIS. - SSM or NSM with immediate breast reconstruction is a reasonable option for women with early breast cancer who are believed to be likely lymph node negative. - SSM, NSM, and ASM are not recommended for women intending to receive postoperative radiation with: - early breast cancer who are lymph node positive, inflammatory breast cancer or locally advanced breast cancer who will require postoperative RT. - any clinical skin or nipple-areolar complex (NAC) involvement by invasive tumour - NSM and ASM are not recommended for women with Paget disease of the breast or women with a retroareolar tumour. - NSM or ASM with immediate reconstruction is reserved for patients with minimal ptosis and do not require skin reducing incisions - Women with multicentric DCIS or early invasive cancer within 2 cm of the NAC) who are contemplating NSM may consider a sampling taken from the base of the nipple for pathological assessment.Women found to have tumour involvement in the NAC either intraoperatively or postoperatively should have the nipple resected. # Qualifying Statements - SSM, NSM, and ASM are oncologically safe when the tumour is resected with clear margins. - Women considering NSM should be made aware that they will experience nipple anesthesia and that there is a risk of nipple necrosis. - Likelihood of lymph node positivity should be determined by consultation with a breast surgeon with oncology expertise or by a multidisciplinary tumour board discussion.When required, for women with invasive breast cancer and clinically negative nodes, a standalone sentinel lymph node biopsy may evaluate lymph node status prior to definitive mastectomy. # Recommendation 5: Delayed breast reconstruction - Delayed reconstruction should be offered as an option for any woman undergoing mastectomy who desires reconstruction, has completed any recommended adjuvant chemotherapy and/or RT, and does not have contraindications to breast reconstruction. # Qualifying Statements - For women who have received RT, it is the opinion of the Expert Panel that reconstruction should not occur sooner than one year after mastectomy. - For women with advanced disease (T4, or N2 or N3), it is the opinion of the Expert Panel that it may be optimal to wait two or three years before undergoing reconstruction when the risk of recurrence is lowered. # Recommendation 6: Autologous tissue versus implant-based reconstruction - Women treated by mastectomy should be made aware that autologous tissue reconstruction and implant-based reconstruction are options for immediate or delayed reconstruction. - Reconstruction methods should be selected based on patient and surgeon factors, because overall patient satisfaction and willingness to recommend reconstruction to others appear to be similar between autologous tissue and tissue-expander implant (TE/I)-based reconstructions.However, if women are candidates for either reconstruction, then they should be informed that TE/I reconstruction may be accompanied by a higher risk of reconstructive failure or soft tissue infection and that there is a trend toward decreased esthetic satisfaction with TE/I reconstruction over time.In patients who have received textured implants, they should be informed of the risk for a rare type of lymphoma called anaplastic large cell lymphoma (ALCL) that is associated with textured implants. - Latissimus dorsi flap with or without implants is another option to TE/I or abdominal autologous tissue reconstruction. # Radiation setting: - For women who have received prior RT to their breast as part of BCT, mastectomy with immediate autologous tissue reconstruction is the recommended option.Current evidence suggests that reconstruction using TE/I alone may be associated with an increased risk of complications. # Qualifying Statement - Women desiring reconstruction in a previously radiated breast should be informed of the increased risk of complications compared with no radiation. # Recommendation 7: Types of autologous tissue reconstruction - In patients who will undergo unilateral autologous tissue reconstruction, pedicled transverse rectus abdominis myocutaneous (TRAM), free TRAM, or deep inferior epigastric perforator (DIEP) flaps are all recommended options that are supported by positive patient-reported outcomes. - In patients who will undergo bilateral autologous tissue reconstruction, DIEP flap is preferred over free or pedicled TRAM flap due to less functional disruption to the abdominal wall following surgery. - Alternative autologous tissue donor types (e.g., gluteal flaps, thigh flaps) are suitable for selected patients in whom abdominal tissue is not available; however, the evidence on these types of reconstructions is very limited. - All patients should be told of the risk of fat necrosis that can present as a nodule or mass after autologous tissue reconstruction, a benign condition that can mimic breast cancer recurrence.The risk of fat necrosis is likely to be greater following DIEP flaps compared with TRAM flaps. -It is the opinion of the Expert Panel that direct-to-implant reconstruction in a single stage using ADM may be used as an adjunct to implant-based breast reconstruction to improve esthetic outcomes in selected women who have smaller and non-ptotic breasts. - Patient selection and surgical technique are critical to good outcomes. - Other than improved esthetic outcomes, ADM has not been shown to have any other benefit for two-staged TE/I reconstruction. - Esthetic outcomes, especially the inframammary fold, are potentially improved with the use of ADM in implant reconstruction. # Recommendation 9: Autologous fat grafting - With the shortage of high-quality studies on the use fat grafting, no recommendation can be made for or against the use of autologous fat grafting as an adjunct to improve esthetic outcomes in breast reconstruction. # Qualifying Statement - Autologous fat grafting is a potential adjunct to improve esthetic outcomes in breast reconstruction following mastectomy; however, more high-quality evidence on the efficacy and safety of this procedure is necessary before its widespread implementation. Recommendation 10: Routine screening for breast cancer recurrence following postmastectomy breast reconstruction - There is insufficient evidence to support the use of postmastectomy surveillance mammography in the reconstructed breast. - Women should be followed with clinical examination of the chest wall and reconstructed breast as per the regular breast cancer follow-up regimen. - Diagnostic mammography, ultrasound, and magnetic resonance imaging may be helpful in the evaluation of symptomatic women with a reconstructed breast (e.g., lumps, skin changes).
# INTENDED PURPOSE To summarize the available evidence regarding provider tools for ACP or GoCD. # INTENDED USERS Healthcare providers who engage in ACP or GoCD with their patients or should engage in ACP or GoCD with their patients and administrators who wish to provide ACP or GoCD training to providers within their institution. This evidence summary was developed by a Working Group, consisting of three family physicians that have an interest in palliative care and who hold palliative care positions within their communities, one family physician who practices comprehensive family medicine, one family physician with clinical focus areas in both emergency and hospitalist medicine, one clinician engagement lead, and one health research methodologist, at the request of CCO"s former Palliative Care Program. The Working Group was responsible for reviewing the identified evidence and drafting the summary.Conflict of interest declarations for all authors are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy. This evidence review was conducted in two planned stages, including a search for systematic reviews followed by a search for primary literature.These stages are described in subsequent sections. # Search for Existing Guidelines and Systematic Reviews A search was conducted for existing guidelines and systematic reviews from 2010 onwards.The MEDLINE (2010 to June 2015) and EMBASE (2010 to week 26,2015) databases were searched using the literature search strategy found in Appendices 2 and 3.Guidelines and systematic reviews were included if they were published in English, were directly related to one or more of the guideline questions, and reported at least one outcome of interest. Identified systematic reviews were evaluated based on their clinical content and relevance.Relevant systematic reviews were assessed using the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) tool to determine whether or not existing systematic reviews met a minimum threshold for methodological quality and could be considered for inclusion in the evidence base. # Search for Primary Literature A search strategy was developed and implemented that captured the primary literature in the following databases: MEDLINE, EMBASE, and American Society for Clinical Oncology (ASCO) Palliative Care Symposium meeting abstracts. # Literature Search Strategy The MEDLINE (1998 to September 2015) and EMBASE (1998 to week 37, 2015) databases were searched using the literature search strategies found in Appendix 4.In addition, ASCO Palliative Care Symposium for 2014 and 2015 were also searched using the following terms: advance care planning or ACP, goals of care or GoC, advance directives or AD, terminal care, and patient care planning.Reference lists of included studies were also searched. # Study Selection Criteria and Process Inclusion Criteria - English language Patients living with chronic illnesses and/or their substitute decision makers OR simulated patients Healthcare provider tools (as opposed to patient tools) Includes at least one outcome of interest (see Appendix 5) Comparative data (randomized trials, cohort, case-controlled, historically controlled trials, etc.)if available Non-comparative data Minimum study size of 30 patients # Exclusion Criteria - Case studies, commentaries, editorials A review of the titles and abstracts that resulted from the search was conducted independently by one reviewer (RC).For items that warranted full-text review, one reviewer (RC) reviewed each item independently.However, if there was any uncertainty regarding a particular paper, the Working Group was consulted. # Data Extraction and Assessment of Study Quality and Potential for Bias Data from the included studies were extracted by one member of the Working Group (RC).All extracted data and information were audited by an independent auditor. Randomized controlled trials (RCTs) were assessed using the Cochrane Risk of Bias tool (chapter 8.5) (/) and all non-RCTs were assessed using the Cochrane Risk Of Bias In Non-Randomized Studies -of Interventions (ROBINS-I) tool (/). # Synthesizing the Evidence Meta-analysis was not planned as the studies included in this systematic review were quite varied and included some non-comparative data. # Search for Existing Guidelines and Systematic Reviews A search for guidelines uncovered 1701 documents.Of these, 82 papers (73 adult and nine pediatric) underwent full-text review.No adult guidelines were retained and one pediatric guideline was retained. A search for systematic reviews yielded 824 documents.Of these, 55 papers (47 adult and eight pediatric) underwent full-text review.No adult systematic reviews were retained and one pediatric systematic review was retained. # Search for Primary Literature A search for primary literature was conducted for all guideline questions. # Literature Search Results A search for primary studies yielded 31,105 documents.Of these, 353 (313 adult and 40 pediatric) underwent full text-review.From this, 34 adult studies represented by 36 papers and three pediatric primary studies represented by four papers were retained.In addition, the abstracts from the 2014 and 2015 ASCO Palliative Care in Oncology symposia were searched, resulting in the retention of one abstract of adult ACP.A search of the reference lists of included studies led to the inclusion of a further seven adult studies.For a summary of the full literature search results (including guidelines and systematic reviews), please refer to Figure 1, which is a flow diagram depicting the inclusion and exclusion of all studies for this evidence document.A summary of all included studies can be found in Table 1. Of the 42 included adult primary studies, 10 were RCTs, seven were pre/post designs and four were controlled trials.There were three studies each of the following types of designs: repeated measures, qualitative, chart reviews, and non-comparative studies.There was one or two each of various other study types including one systematic review, which was identified from the search for primary studies and not the search for systematic reviews.Of the three included pediatric primary studies, one was a RCT, one was a survey, and one was a chart review. # ADULT STUDIES Boettcher 2015 Respecting Choices Repeated Measures Davis 2015 Conversation Project Qualitative Evaluation Hickman 2015 POLST Systematic Review Kadlec 2015 Practice Support Program -EOL Module Repeated Measures Detering 2014 Next Steps Pre/Post Study Paladino 2014 abstract Serious Illness Conversation Guide Cluster RCT Pecanac 2014 Respecting Choices Chart Review Slort 2014a ACA Controlled Trial Slort 2014b ACA Controlled Trial Wheeler 2014 Foundation in EOL/Palliative Care Pre/Post Study Wilson 2014 HCM Non-comparative Abel 2013 Planning Ahead Retrospective Cohort Levi 2013 MYWK Qualitative Evaluation Millington-Sanders 2013 Coordinate My Care Non-comparative Slort 2013 ACA Controlled Trial Wilson 2013 EpicCare HER Chart Review Au 2012 NA Cluster-RCT Clayton 2012 PREPARED Pre/Post Study Colville 2012 NA Descriptive Qualitative Study Green 2011 MYWK RCT Resnick 2011 NA Survey Detering 2010 Respecting Choices RCT Hammes 2010 Respecting Choices Chart Review Kirchhoff 2010/2012 PC-ACP RCT Szmuilowicz 2010 NA RCT Newton 2009 Preferred # Study Design and Quality Various study designs are included in this guidance document.All systematic reviews were assessed using AMSTAR (see Table 2).Randomized controlled trials were assessed using the Cochrane Risk of Bias tool (chapter 8.5) (/) (see Table 3) and all non-RCTs were assessed using Risk Of Bias In Non-Randomized Studies -of Interventions (ROBINS-I) tool (/) (see Table 4). No suitable guideline was identified. # Systematic Reviews All systematic reviews used in this guidance document were assessed using the AMSTAR tool.Both systematic reviews provided an a priori design, conducted duplicate study selection and data extraction, performed a comprehensive literature search, provided the characteristics of each included study, combined the findings of the included studies appropriately (e.g., by not combining), and provided conflict of interest statements. (Table 2). # Randomized Controlled Trials Eleven RCTs reported in 14 papers 39,40,44,47,48,50,51] were included in this guidance document and were assessed using Cochrane"s Risk of Bias tool (chapter 8.5) (/) (Table 3).Paladino et al. was only available in abstract form; therefore, risk of bias was unclear because the needed information was not available in the abstract.Six other trials had overall high risks of bias owing to several items being rated as either high risk of bias or unclear risk of bias.Unclear risk of bias may only be a reporting issue; however, it is impossible to know.This tool assesses each trial on seven domains of bias (Table 4) as well as an overall assessment of risk of bias.Almost all of the studies 24,25,27,32,45,46,49,53] had a moderate risk of bias, three studies had low risk of bias and five studies had a serious risk of bias. # Initiating and Facilitating ACP or GoCD Adult Studies No clear distinction has been made between clinical tools that either introduce or facilitate both ACP and GoCDs and, as such, these two search criteria were combined. The ACP provider tool most often encountered in the literature is Respecting Choices® or tools based on the Respecting Choices® program (e.g., patient-centred ACP, Honoring Choices Minnesota) (see Table 5).A key feature of this program is the use of trained facilitators for the ACP process.All studies addressing the Respecting Choices® program describe various patient outcomes.In general, exposure to a Respecting Choices® type of intervention, compared with controls, can result in: increased AD completion ; increased appointment of a surrogate ; more involvement in EOL decisions ; increased consistency between patient wishes and medical interventions undertaken at EOL ; increased patient and surrogate satisfaction with care received ; increased ACP knowledge ; fewer symptoms of anxiety and depression in family members of decedents ; decreased decisional conflict ; and increased consistency between wishes of patients and their surrogates.Only one study described provider outcomes.This study reported that case managers trained and certified by Respecting Choices® demonstrated increased motivation, confidence, preparedness, and skill in facilitating ACP discussions at three months post-training compared with immediately after training.However, no p-values are reported. Although there are different views on its relationship with GoCD, a commonly used provider tool is the Physician Orders for Life Sustaining Treatment (POLST) form.POLST is a standardized form containing medical orders that reflect a patient"s treatment preferences.One recent systematic review of this tool that included 23 studies was identified.It may be prepared by a non-physician facilitator and then reviewed and signed by a physician.Healthcare providers report that POLST expresses patient preferences reliably, guides care, improves communication, and helps in initiating EOL care discussions.POLST has challenges as well including the following difficulties: explaining the form, obtaining physician signatures, and transferring the form between settings, as well as issues regarding the time needed to complete the form.Overall, it has been reported that there is high consistency between code status and treatment received by patients as well as between antibiotic use and wishes of patients.There is general consistency between artificial nutrition use and patient wishes.There are mixed results in terms of the consistency between the level of medical intervention requested and received by patients. Three studies of the Availability, Current Issues and Anticipation (ACA) tool were identified.ACA training is an eight-step program that takes approximately six hours to complete over a six-month time period.Briefly, it is an iterative process of roleplaying and simulated patient interviews, followed by feedback and revision of learning goals.When tested in simulated and real palliative care patients, there were no significant differences between intervention and control groups on any of the outcomes measured (Table 5). Two studies of the Making Your Wishes Known (MYWK) tools were identified.MYWK is an interactive, online decision aid to help adults complete an AD.Providers use the decision aid to facilitate ACP with older patients.Green et al. compared the effectiveness of the MYWK tool with a standard ACP planning package in medical students learning to facilitate ACP discussion with patients.Each student helped an adult aged ≥50 years old engage in ACP discussions.Compared with controls, students in the MYWK intervention group had significantly higher confidence in engaging in ACP and intervention patient-participants were significantly more satisfied with their ACP planning method (Table 5). There were also many one-off-type tools identified, some of which were named and others not.They all measured different and varied outcomes.In general, these various tools resulted in positive patient and provider outcomes (see Table 5 for more detail) including achieving preferred place of death when an ACP document is available. # Pediatric Studies Only a few pediatric ACP (pACP) studies were identified (Table 5).Lyon et al. compared the Family-Centered Advance Care Planning (FACE) intervention with a control group that received current standard of care in teens with cancer and their surrogates.This RCT included 17 intervention and 13 control dyads.FACE consists of three sessions: a survey that assesses the values, beliefs, and experiences with EOL care in patients and their surrogates; a Respecting Choices® interview customized for adolescents; and completion of Five Wishes document (an AD document) customized for adolescents with a trained facilitator.Quality of communication was not different between groups.However, treatment preference congruence between control dyads was low for all scenarios tested whereas treatment preference congruence between intervention dyads was statistically significant for five of the six scenarios.Intervention adolescents thought they were significantly better informed regarding EOL decisions than did control adolescents (p=0.007).Moreover, intervention families all rated the three FACE sessions as worthwhile.Intervention adolescents had significantly lower depression scores at baseline and at the three-month follow-up compared with controls (p=0.0268).There were not significant differences in quality of life between intervention and control adolescents.More intervention than control adolescents completed ADs (100% vs. 0%). A systematic review by Lotz et al. uncovered only three pACP programs: FACE, Footprints, and Respecting Choices®.A review of these interventions revealed that many people are supportive of ADs for children although parents report discomfort of emergency personnel with ADs for children.Parents and adolescents find pACP interventions helpful for ensuring good care, providing time for decision making, facilitating communication among caregivers, and in providing peace of mind.They also found that fears about increasing distress in patients undertaking pACP are unfounded.However, some families do have difficulties thinking about a dismal future (Table 5). A survey conducted by Mitchell et al. found that 58% of pediatric intensive care units (PICUs) in the United Kingdom use a pACP document.All such documents were developed locally. Finally, Walter et al. evaluated prognostic, goals-of-care conversations (PGOCC) in a review of 645 charts of children in the top decile for risk of mortality upon admission to the PICU in a children"s hospital in Michigan.A documented PGOCC was found in 200 (31%) of charts.Patient characteristics significantly associated with a documented PGOCC were length of stay (p<0.001) and cancer diagnosis (p<0.001) (Table 5). o No significant differences between the groups with respect to the mean number of ACA issues (current or anticipated) discussed.o Significant differences between the groups with respect to only 3 types of affective utterances.No other significant differences with respect to quality of communication Computer generated reminders 2x2 factorial RCT Comparison of computer-generated reminders to discuss one or both types of ADs vs. no reminders to increase AD discussions and completion in outpatients # Documenting ACP or GoCD Adult Studies Evidence regarding the documentation of ACP or GoCD is sparse.Overall, storage of ACP documents is varied and inconsistent and the documents can be quite difficult to find even when they exist (Table 6).Wilson et al. conducted a chart review to identify the location of ACP in the electronic health record (EHR) of patients at least 65 years old who were known to have an ACP document in their EHR.Most ACP, POLST, and ADs were not scanned into the EHR.Of those that were, they could be scanned, scanned and in progress notes, scanned and in the problem list, or all three.Patients had a mean of four scanned documents per year but the maximum was 231.Therefore, it was often extremely difficult to locate the ACP documents among them. Colville et al.in a qualitative evaluation, demonstrate the need to document ACP plans such that all providers of care for a given patient have access to them.Resnick et al. surveyed a sample of home, health, and hospice agencies in the USA and found that AD storage varied.Most ADs were stored with the patient"s record at the agency (94.4%), many were stored at the patient"s residence (48.8%), and a few were stored in a special AD file at the agency (3.3%). Bricker et al. describe the development of an AD documentation process within an electronic medical record (EMR).They cite three options for creating an electronic AD: scanning the existing AD into the EMR; dictating an AD note using the existing telephone transcription service; and typing the AD note directly into the EMR.In all cases, the AD note was then highlighted within the list of EMR documents for ease of access.Moreover, singlepage AD forms were developed for ease of completion and ease of scanning into the EMR.All personnel, from healthcare providers to transcriptionists, were made aware of this new system.The result was an increase in the number of completed electronic AD notes.A further benefit was that the patient preferences were accessible throughout the healthcare system. Finally, Pauls et al. describe a model for transferring ADs from a long-term care (LTC) facility to an emergency department (ED).The model consists of three parts: the form, completing the form, and using the form.The form itself is only one or two pages employing simple language and providing a choice of three or four levels of care from which to choose.In terms of form completion, LTC residents and their families were given education sessions regarding ACP and ADs as soon as they entered LTC.The forms are reviewed annually or when there have been changes in a patient"s health.The completion of the forms involves various healthcare providers and they are remunerated.With respect to using the forms, they are kept in an accessible and consistent location and are printed on coloured paper for ease of transferability to the ED via paramedics. # Pediatric Studies No pediatric studies regarding the documentation of ACP or GoCD were identified.
# Ongoing, Unpublished, or Incomplete Studies None.NA Descriptive Development of an AD documentation process within one healthcare system Specifically developed an electronic AD note within the EMR Developed short instructional video to increase patient understanding of the importance of ADs 3 options for creating electronic AD o Scan the existing AD document into the EMR o Dictate AD note using existing telephone transcription service o Type AD note directly into EMR The AD note was then highlighted within the list of EMR documents for easy access Single page forms developed for ease of completion of AD and for ease of scanning into EMR Everyone in the system from healthcare providers to transcriptionists had to be aware of the new system Number of completed electronic AD notes increased and continues to increase Informal polling of healthcare providers indicates that they like that patient preferences are available throughout this healthcare system Recently, considerable attention has been given to the important role for ACP conversations and GoCD in decision making for patients not only in the setting of serious illness, but also when there is no illness.Currently, no consensus exists as to the tools or processes clinicians should use to inform or guide ACP and GoCD.The purpose of this evidence summary was to identify existing tools that could be used for each of these clinical encounters.The specific questions that shaped this review were intended to reflect the elements clinicians find particularly challenging, i.e., introducing, facilitating, and documenting both ACP and GoCD.Although a number of studies reported positive findings, there is a lack of consistent patient outcomes evidence to support any one clinical tool for use in either ACP or GoCD.However, despite this, the evidence points to important elements for clinicians to consider when reflecting on their practice around ACP and GoCD.Also, certain evidence emerged that is important for healthcare leaders and system planners to consider.Of note, no clear distinction has been made between clinical tools that either introduce or facilitate both ACP and GoCDs and, as such, these two search criteria were combined. There are common challenges providers encounter in clinical practice relating to ACP and GoCD.There continues to be a lack of widespread agreement on the definitions of ACP and GoCD, their critical elements, and desired outcomes.For example, in some studies and in practice, ACP has been equated with determining a person"s resuscitation status, whereas others define it differently.This is problematic on several levels.However, for the purpose of this review, the lack of standard definitions prevents a unified approach to studying ACP and GoCD and contributes to great difficulty interpreting and comparing the findings among different studies.Improving a shared understanding of these concepts as described in this review is an essential step to establishing evidence for best practice.Similarly, consensus on outcomes are needed.The ideal ACP outcomes may include adequate understanding of the person"s health status by the patient and their SDM, and the SDM understanding the patient"s values, beliefs, and wishes as they relate to the patient"s healthcare.The ideal GoCD outcome would be that current healthcare decisions are informed by the person"s goals and values.This can occur at any point along the illness journey, but will always occur in relation to current, not future, healthcare decisions.Addressing these discrepancies will be beneficial for clinicians, for the development of tools and to guide evidence-informed best practices. A second challenge in attempting to identify tools for clinicians is clarifying what might be considered appropriate tools for the contexts of introducing and facilitating these conversations.Additionally, different tools may be more or less effective for clinicians with varying expertise and competency in advanced communication skills, EOL communication skills, and values-based conversations.Finally, development and evaluation of tools must take into account the relationship of ACP and GoCD with regional laws on capacity, consent, and substituted decision making.It is important to note that tools structured for use by patients or caregivers without immediate clinical support were excluded from this review. Finally, synthesizing evidence for ACP and GoCD is challenging owing to the nature of these two clinical encounters as each has inherent limitations to standardization.ACP is considered to be a process over time, which can lead to a lack of clarity and inconsistent practices around what could or what should be documented for any given clinical encounter.For GoCDs, there are different understandings of the expected outcomes or products of the clinical encounter and one standard approach has yet to be proposed or studied. The majority of studies that met inclusion criteria address ACP-related processes (rather than GoCD), such as the occurrence of any kind of EOL conversation and documentation.Differences in the interpretations of the essential components of ACP are evident, with a key difference being the perceived importance of addressing specific treatments in the conversations.However, it is worth pointing out that the tool with the largest evidence base is Respecting Choices®, which moves away from preferences for specific treatments and shifts toward a greater emphasis on patient values.Although this shift makes the desired outcome of the clinical interaction more challenging to capture, the evidence suggests values-based information is more likely to be help future SDMs than treatment-based or treatment-focused ACP conversations.Considering these emerging themes from the evidence suggests that tool development should focus on enabling healthcare providers to facilitate values-based discussions.Future studies with corresponding valuesbased outcome measures are needed to evaluate the impact on patient care. Irrespective of how ACP effectiveness might be defined, the evidence suggests it is critical to think beyond singular ACP elements in order to meaningfully impact patient care.The evidence related to the Respecting Choices® model outlines the high likelihood that a comprehensive, systematic approach to ACP is necessary.Ideal patient outcomes are unlikely to be achieved in the absence of broad systemic commitments to integrate and deliver ACP as part of routine care.A comprehensive approach to ACP includes community engagement, professional education, development of standard practices, monitoring of these practices through Quality Improvement initiatives, supporting policies and practices, and a technology infrastructures.This approach must be applied across public health and healthcare sectors to support the exchange of clinical information and will involve system-level coordination and planning.Addressing only one, or a few, of these elements creates the risks of leaving critical gaps that could prevent positive impacts on quality patient care. The development of materials, clinical processes, and professional development experiences that improve communication skills, designed to enable clinicians to facilitate a discussion of a person"s values, must be embedded in a system-wide approach to ACP.Evidence from studies addressing the ACA tool serve as important examples of this.The associated education components of the intervention (i.e., simulation and direct feedback) are known to be highly effective from the perspectives of educational design and adult learning theory.However, high-quality education, although essential, on its own is unlikely to improve care or the patient experience in the absence of supporting systemic changes. Important findings for the pediatric population mirror many of the early reports that address ACP in adults.The evidence outlines that, in general, children and their parents are supportive of ACP and find these discussions helpful to ensure good care, to facilitate communication among caregivers, and to provide peace of mind.Concerns that ACP discussions will cause distress in children and parents are not supported by the evidence.However, parents are aware of discomfort among clinicians attempting to navigate ACP discussions.This is an important area for further exploration and discovery. Very few studies specifically address GoCDs and in large part this is likely due to GoCDs having been added to the healthcare lexicon relatively recently.There is a resultant lack of patient outcome evidence and many problematic elements in the research findings.These include a lack of widespread agreement on the expected outcomes, general approach, and components of GoCD.Detailed information regarding the specific clinical interaction was notably absent from studies involving the GoCD.Exploring the elements of GoCD that could be amenable to standardization would uncover important clinician tool-related information. One specific element of the GoCD on which practices differ among clinicians is the perceived relationship with decision making.This ranges from considering GoCD to be separate and distinct from decision-making discussions to considering the two to be one and the same.These differing perspectives may parallel differences in how the POLST is viewed in relation to the GoCD.Some clinicians would likely view the POLST as a tool for use during the GoCD whereas others would not.For the purpose of this evidence review, we include POLST studies with the caveat that this not be considered endorsement for its use as a GoCD or ACP tool.We have chosen to include the POLST to highlight this challenge and enable further discussion. It should be highlighted that the Ontario legal context should preclude the widespread use of tools like the POLST for ACP conversations.Regional variation exists with regard to the completion of orders sets in advance of receiving healthcare.Practitioners should be familiar with their regional laws surrounding consent, capacity, and healthcare decision making.In Ontario, direction and decision making for a person"s current care must come from a capable person (either the patient or their SDM if the patient is not capable), not a previously completed order set.In cases where the patient has been found incapable for a current decision, the SDM will rely on applicable previously expressed wishes or the person"s values.This underscores the importance of ACP conversations as preparation of the SDM for many eventualities of future decision making. The involvement of interprofessional healthcare providers was identified as an important element of the ACP process in a number of positive studies.The shift toward emphasizing patient values in the ACP context has expanded the facilitation of such discussions to include non-physician providers.The Respecting Choices® model demonstrates how the training of interested and willing clinicians, regardless of profession, may be a critical strategy for impacting patient outcomes.An example for GoCDs is the role of clinical nurse specialists and the communication skills they bring to the patient experience.Implementation of ACP as an interprofessional practice is an important consideration in addressing the concern of many physicians about not having adequate time for these discussions. - Outcome evidence for ACP suggests the greatest impact is likely to be made by a system-wide approach to integrating ACP into practice, one that maximizes clinical skills of all interprofessional team members. What is likely to be of greatest value for the GoCD context is to achieve widespread agreement on the specific outcomes that should be expected? The most important patient-related outcome of any future planning or current care decision-making process is a patient receives the care that is wished for or desired. Inconsistencies in definitions and desired outcomes for both ACP and GoCD need to be addressed to enable better understanding of effective healthcare provider tools. # INTERNAL REVIEW The evidence summary was reviewed by the Director of the PEBC.The Working Group is responsible for ensuring the necessary changes are made. The Palliative Care Program and the Working Group would like to thank the following individuals for their assistance in developing this report: - Melissa Brouwers, Sheila McNair, Hans Messersmith, for providing feedback on draft versions. Ruth Chau for conducting a data audit. Sara Miller for copy editing.
# GUIDELINE OBJECTIVES To recommend systemic therapy options for women with recurrent epithelial ovarian cancer including fallopian tube and primary peritoneal cancers. # TARGET POPULATION The target population comprises women with recurrent epithelial ovarian cancer who have previously received platinum-based chemotherapy.Specific subgroups of interest are identified based on response to therapy. # INTENDED USERS The intended users of this guideline are gynecologic oncologists or medical oncologists in the province of Ontario. # BACKGROUND INFORMATION This guideline was based on an updated systematic review of the 2011 evidence base.New evidence has led to new recommendations in some areas. Recommendations 1, 2, and 3 are endorsements of those found in the 2011 version of this guideline; the original recommendations continue to be valid and have not changed. Recommendations 4 and 5 are new in this current version of the guideline. # Recommendation 1 Systemic therapy for recurrent ovarian cancer is not curative.As such, it is recognized that, to determine the optimal therapy, each patient needs to be assessed individually in terms of recurrence, sensitivity to platinum, toxicity, ease of administration, and patient preference. # Recommendation 2 All patients should be offered the opportunity to participate in clinical trials, if appropriate. # Recommendation 3 Chemotherapy for patients with platinum-sensitive recurrent ovarian cancer: - - If a single platinum agent is not being considered (e.g., because of toxicity or allergy), then monotherapy with paclitaxel, topotecan, or pegylated liposomal doxorubicin is a reasonable treatment option. # Recommendation 4 For patients with platinum-sensitive recurrent ovarian cancer: - Women with platinum-sensitive recurrent ovarian cancer should be offered chemotherapy with biologics after a discussion concerning the safety profile Targeted agents: - Bevacizumab combined with combination chemotherapy and as maintenance therapy can be considered. - Cediranib administered during the chemotherapy and maintenance therapy can be considered. - PolyADP-ribose polymerase (PARP) inhibitors are recommended for patients with known BRCA 1 or 2 mutation (somatic and germline) as maintenance treatment post platinum-based chemotherapy for recurrent disease. - Niraparib can be considered for patients who are BRCA wild-type as maintenance post-platinum-based chemotherapy for recurrent disease. # Qualifying Statements for Recommendation 4 - With the increase in evidence supporting the use of PARP inhibitors in patients with homologous recombination deficiency mutations, consideration should be given to testing the BRCA status of all women with ovarian cancer at initial diagnosis. -PARP inhibitors have demonstrated an increase in progression-free survival in patients with BRCA mutations without a significant improvement in overall survival - Women with wild-type BRCA also showed a minor improvement in progression-free survival # Recommendation 5 For patients with platinum-refractory or platinum-resistant recurrent ovarian cancer: - Lower levels of response to treatment are expected for this group; therefore, the goals of treatment should be to improve patient's quality of life by extending the symptom-free interval, reducing symptom intensity, increasing progression-free interval, or if possible, prolonging life. -Monotherapy with a non-platinum agent should be considered since there does not appear to be an advantage in the use of non-platinum-containing combination chemotherapy in this group of patients.Single-agent paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine have demonstrated activity in this patient population and are reasonable treatment options. -There is no evidence to support or refute the use of more than one line of chemotherapy in patients with platinum-refractory or platinum-resistant recurrences. There are many treatment options that have shown modest response rates but their benefit over best supportive care has not been studied in clinical trials. -Bevacizumab combined with chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan) can be considered for women who meet the eligibility criteria of the Avastin Use in Platinum-Resistant Ovarian Cancer (AURELIA) phase III randomized controlled trial: confirmed epithelial ovarian, fallopian tube, or primary peritoneal cancer that had progressed within six months of completing ≥4 cycles of platinum-based therapy, age ≥18 years, Eastern Cooperative Oncology Group performance status ≤2, and adequate liver, renal, and bone marrow function.Ineligible patients include those who have received >2 prior anticancer regimens or who had refractory disease, patients with a history of bowel obstruction (including subocclusive disease) related to underlying disease, a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess, or evidence of rectosigmoid involvement by pelvic examination, bowel involvement on computed tomography, or clinical symptoms of bowel obstruction. # Qualifying Statements for Recommendation 5 - At the time of the writing of this guideline there are numerous targeted agents in addition to vascular endothelial growth factor inhibitors, programmed death-1 and programmed death ligand-1 inhibitors, as well as other immunotherapies that are under investigation and that show promise in early trials.It is likely that one or some of these will become part of the lexicon of treatment protocols in the near future, either independently or in combination with conventional chemotherapy.
Guideline Questions 1.What are the chemotherapeutic and hormonal therapy options for women with advanced or recurrent endometrial cancer (excluding sarcomas and squamous cell carcinomas)?2.What are the chemotherapeutic options for women with advanced or recurrent uterine papillary serous carcinoma? # Target Population This practice guideline applies to adult patients diagnosed with advanced stage or recurrent endometrial cancer (excluding sarcomas and squamous cell carcinomas) or uterine papillary serous carcinoma. For women with advanced or recurrent endometrial cancer: - Combination chemotherapy is favoured over single agent chemotherapy because of higher response rates. Paclitaxel in combination with cisplatin/doxorubicin chemotherapy improves both response rate and median survival; however, the use of this three-drug combination is associated with increased toxicity. Hormonal therapy may be a therapeutic option for those patients with minimal symptoms or non-life threatening advanced or recurrent endometrial cancer. For women with uterine papillary serous carcinoma: - Evidence supporting or refuting various chemotherapy regimens for uterine papillary serous carcinoma is limited. Patients should be encouraged to participate in randomized trials. # Qualifying Statements: - The decision to use the three-drug combination, consisting of cisplatin/doxorubicin/paclitaxel, should be made with consideration of both the greater toxicity and the three-month increase in median survival time in comparison with the two-drug doxorubicin/cisplatin regimen.However, recent data suggest no benefit to the three-drug combination in terms of recurrence-free survival and was associated with increased toxicity. For uterine papillary serous carcinoma treatment, the most studied regimen is a paclitaxel/platinum combination.The addition of paclitaxel in small, non-comparative studies is associated with improved response rates and survival compared to non-platinum containing regimens.Added to Endorsement in June 2017: As mentioned in the Qualifying Statements above, there are data suggesting that a taxaneplatinum drug combination has similar efficacy with better toxicity when compared with the three-drug paclitaxel/cisplatin/doxorubicin combination.The Expert Panel recognizes that this evidence comes from an abstract of an interim analysis of a phase III RCT with no full publication and does not meet the criteria for inclusion in this review.However, practice has changed in light of this evidence with preference for a taxane-platinum drug combination although the three-drug combination is still an option.Added to Endorsement in July 2019: - There has been one small randomized phase II study showing a benefit of adding trastuzumab to carboplatin/paclitaxel in patients with overexpression of Her2/Neu in advanced (stage III or IV) or recurrent uterine serous carcinoma.Please see Section 2 for further details. Entries to MEDLINE (1966to April 2004, CANCERLIT (1975to October 2002, and Cochrane Library (2004, Issue 1) databases and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology (1997 to 2003) were systematically searched for evidence relevant to this practice guideline report. Evidence was selected and reviewed by four members of the Practice Guidelines Initiative's Gynecology Cancer Disease Site Group and methodologists.This practice guideline report has been reviewed and approved by the Gynecology Cancer Disease Site Group, which comprises gynecologic oncologists, medical oncologists, radiation oncologists, an oncology nurse, a pathologist, and patient representatives. External review by Ontario practitioners is obtained for all practice guidelines through a mailed survey.Final approval of the practice guideline report is obtained from the Practice Guidelines Coordinating Committee. The Practice Guidelines Initiative has a formal standardized process to ensure the currency of each guideline report.This process consists of the periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. # Key Evidence Seventeen randomized trials (including six abstracts and four phase II randomized trials) provided the evidence for systemic therapy of advanced or recurrent endometrial cancer.There were no randomized trials identified that compared systemic therapy to a control group of patients who received no treatment. Limitations of the evidence include: heterogeneous patient populations with respect to histology; type of previous treatment (surgery, radiation, chemotherapy, or hormonal therapy); results that are still maturing; and non-comparable outcome measurements. Chemotherapeutic options studied for the treatment of advanced or recurrent carcinoma of the endometrium have included single-, double-, and triple-agent therapies.There is limited information available on quality of life and meaningful survival data. Single-agent chemotherapy has reported response rates as follows: doxorubicin 17-27% and platinum agents 21%. For double-agent chemotherapy, randomized trials of doxorubicin/cisplatin reported response rates ranging from 28-45%, other agents in combination with doxorubicin reported response rates of 30% (cyclophosphamide) and 43% (paclitaxel). A randomized trial reported a 57% response rate in the doxorubicin/paclitaxel/cisplatin arm compared to 34% in the doxorubicin/cisplatin arm (p <0.01). One randomized trial has compared doxorubicin/cisplatin to whole abdominal radiotherapy and preliminary reports indicate that doxorubicin/cisplatin is more beneficial than radiotherapy in patients with advanced endometrial cancer in terms of overall survival and progression-free survival (p<0.01).However, recurrence rates are still high (55%) in both treatment arms. Neuropathy, hematological, and gastrointestinal toxicities were the most common adverse effects reported; toxicity increased in incidence with the increase in the number of agents used. One randomized trial comparing two dosages of medroxyprogesterone acetate (hormonal therapy) for advanced or recurrent endometrial cancer detected that patients receiving a lower dosage of medroxyprogesterone acetate had significantly increased overall survival (p=0.026) and response rate (p<0.05) than patients receiving a higher dosage.Hormonal agents were well tolerated: adverse effects were reported at less than 5%. Four non-comparative trials (two retrospective and one abstract) provided the evidence for systemic therapy of advanced or recurrent uterine papillary serous carcinoma.Response rates in the four small non-comparative studies ranged from 50-89% # Future Research In terms of future studies, it is important to be able to control for prognostic factors that affect outcome in these patient populations.Patients should be properly stratified with respect to their disease status (advanced versus recurrent), the amount of previous treatment, type of previous treatment (radiation or chemotherapy), and disease recurrence either in or out of the radiated field.Patients with uterine papillary serous carcinoma should be analyzed separately.Results relating to systemic therapy should be first assessed and proven in those patients with measurable disease so that an accurate assessment of any prolongation in disease-free survival can be made with reasonable assurance that these improvements are due to treatment.Treatment-related toxicity must be studied very carefully in the future in this patient population in order to ensure that the treatment itself has acceptable morbidity in relation to the patient's quality of life, as median survival is generally limited and rarely more than a year in this patient population.Survival, response and toxicity should be studied with regard to impact on quality of life.Comparing tumour responses for both chemotherapy and hormonal agents, stratified by grade, would provide valuable data for making treatment decisions.Added to Endorsement in July 2019: Immunotherapy is an emerging treatment, particularly in patients with tumours with high microsatellite instability, and should be addressed in future guidelines as studies become available. For further information about this practice guideline report, please contact Dr. Michael Fung Kee Fung, the lead author, through the PEBC at: Phone: 905-527-4322 ext.42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca The Practice Guidelines Initiative is sponsored by: Cancer Care Ontario & the Ontario Ministry of Health and Long-term Care. For information about the PEBC and the most current version of all reports, please visit the CCO website at or contact the PEBC office at: Phone: 905-526-4322 ext.42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca
# GUIDELINE OBJECTIVES To provide guidance on the optimal systemic therapies for the treatment of advanced gastric and gastro-esophageal junction (GEJ) carcinoma.Optimal systemic therapies were defined as those that provided improved overall survival and improved quality of life. # TARGET POPULATION Adult patients (age ≥18 years) with advanced gastric carcinoma or advanced carcinoma of the GEJ.In this patient population, advanced disease is defined as non-resectable disease that is either locally advanced, recurrent, or metastatic. # INTENDED USERS This guideline is intended for use by clinicians and health care providers involved in the management or referral of the target population. # Recommendation 1a Medical oncologists should prescribe either a fluoropyrimidine-oxaliplatin doublet or a fluoropyrimidine-irinotecan doublet regimen in the first-line treatment of patients with locally advanced, recurrent, or metastatic gastric and GEJ carcinoma. # Qualifying Statements for Recommendation 1a - Based on improved efficacy with fluoropyrimidine-oxaliplatin-taxane when compared with monotherapy, this triplet regimen may be discussed with selected patients as an alternative to a doublet regimen. -Medical oncologists should individualize treatment based on the different toxicities associated with the preferred regimens, patient characteristics, and patient preferences when choosing the appropriate therapy. # Recommendation 1b In patients with metastatic gastric cancer or GEJ carcinoma not overexpressing human epidermal growth factor receptor 2 (HER2), medical oncologists should not prescribe a biological agent in addition to a first-line chemotherapy regimen # Recommendation 2 In patients with recurrent or metastatic gastric and GEJ carcinoma, medical oncologists should prescribe an immune checkpoint inhibitor (ICI) in addition to a fluoropyrimidine doublet chemotherapy regimen in the first-line setting. # Qualifying Statements for Recommendation 2 - A positive association was observed between programmed cell death ligand 1 (PD-L1) combined positive score (CPS) and the magnitude of treatment benefit.In Checkmate-649, the overall survival benefit of nivolumab was confined to patients with a CPS of ≥5.To aid clinicians in informed decision making and counseling, we recommend that the CPS score be obtained, and the recommendation for the use of nivolumab be restricted to those patients whose tumours have a CPS of ≥5. # Recommendation 3 In patients with HER2 overexpressing gastric or GEJ carcinoma, medical oncologists should prescribe the addition of trastuzumab to a fluoropyrimidine doublet chemotherapy regimen in the first-line setting. # Qualifying Statements for Recommendation 3 - Trastuzumab should be prescribed until disease progression or intolerance in HER2 overexpressing patients # Recommendation 4 In patients with gastric or GEJ adenocarcinoma being considered for second-line therapy, medical oncologists may prescribe paclitaxel plus ramucirumab. # Qualifying Statements for Recommendation 4 - Single agent irinotecan or taxane is a reasonable alternative for patients not eligible for paclitaxel plus ramucirumab # Recommendation 5 In patients with gastric or GEJ adenocarcinoma being considered for third-line therapy, medical oncologists may prescribe trifluride-tipiracil monotherapy. # Recommendation 6 In patients with gastric or GEJ carcinoma undergoing later lines of therapy, medical oncologists should not prescribe ICI in addition to standard of care. # IMPLEMENTATION CONSIDERATIONS Although testing for PD-L1 CPS is available in Ontario through local laboratories or the industry funded access programs, CPS is not routinely included on the tumor pathology report.Medical oncologists will need to request CPS testing from available resources.Until reporting of the CPS is routine, requesting the score may result in treatment decision delays.
The purpose of the memorandum is to exchange information and expertise in the area of occupational safety and health.One product of this agreement is the development of documents to provide the scientific basis for establishing recommended occupational exposure limits.These limits will be developed separately by the two countries according to their different national policies.This document on the health effects of occupational exposure to acrylamide is the fourth product of that agreement.The document was written by Vlasta Molak, Ph.D., D.A.B.T. (DSDTT/NIOSH), and was reviewed by the Criteria Group and by DSDTT/NIOSH.#BACKGROUND # CHEMICAL AND PHYSICAL PROPERTIES Acrylamide is an odorless, white, crystalline solid used as a monomer or as a raw material in the production of polyacrylamides and other compounds.Chemical and physical properties of acrylamide are given in Table 1.Because most of the aciylamide monomer is produced and used as an aqueous solution, the physical properties of a 50% aqueous solution of acrylamide are also given (Table 2). # PRODUCTION AND USE OF ACRYLAMIDE In 1985,140 million lb (63,600 metric tons) of acrylamide were produced in the United States, and predictions in 1988 indicated that 164 million lb (74,500 metric tons) of this chemical would be produced in 1989 .Total acrylamide production capacity in western Europe was 93.5 million lb (42,500 metric tons) in 1984, and the estimated production in Japan was 90 million lb (41,000 metric tons) in 1982 .Acrylamide is also used and produced in the Soviet Union and China, but production estimates have not been reported . The reactive acrylamide monomer is used in the production of other compounds (mostly polymers of acrylamide) and as a grouting agent in the construction or rehabilitation of dams, buildings, sewers, tunnels, and other structures. Acrylamide grouts are used predominantly as barriers against groundwater seepage into sewers.About 95% of the acrylamide produced in the United States is consumed in the production of other compounds and polyacrylamide products that are widely used as (1) flocculents in potable water and wastewater treatment, mineral ore processing, and sugar refining, (2) water flow control agents in oil well operations, and (3) adhesives in papermaking and construction .The remaining 5% is used as a monomer . # POTENTIAL FOR OCCUPATIONAL EXPOSURE Data on worldwide occupational exposures to acrylamide are unavailable.However, since exposure occurs during aciylamide production and use, the potential for occupational exposure exists in all countries that produce or import acrylamide.The National Institute for Occupational Safety and Health (NIOSH) estimates that more than 10,000 U.S. workers were potentially exposed to acrylamide monomer during the period 1981-83, either in acrylamide manufacturing and processing or in grouting operations (particularly in sewer grouting) .Other workers that are potentially exposed to variable and intermittent airborne concentrations and possible dermal contact with acrylamide are the researchers and technicians involved in the preparation of polyacrylamide estimates that 100,000 to 200,000 of these U.S. workers have the potential for exposure. Because acrylamide is produced by catalytic or sulfuric acid hydration of acrylonitrile (identified by the International Agency for Research on Cancer as a probable human carcinogen ), acrylamide production workers may also be exposed to acrylonitrile. Evaluation of exposure data from industrial settings indicates that in all four U.S. acrylamide production plants, airborne concentrations were generally below 0.3 mg/m3-the occupational exposure limit set by many countries (see the Appendix). Of the ninety 8-hr time-weighted average (TWA) personal samples collected in the four U.S. acrylamide production plants, only two samples from one of the plants were above 0.3 mg/m3 (0.38 and 0.39 mg/m3).However, many samples exceeded the current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 0.03 mg/m3 adopted in 1989 . # Hills and Greife # EXISTING STANDARDS AND RECOMMENDATIONS Many international standards for workplace exposures to acrylamide are 0.3 mg/m3 with a skin notation.The current American Conference of Governmental Hygienists (ACGIH) threshold limit value (TLV») and the current OSHA PEL are both 0.03 mg/m3.The current Swedish occupational exposure limit is 0.3 mg/m3 with a skin notation and a short-term exposure limit (STEL) of 0.9 mg/m3.See the Appendix for a list of the occupational exposure limits for airborne acrylamide in various countries and a discussion of the bases for recommendations that depart from the frequently cited limit of 0.3 mg/m3. # TOXICOLOGY # METABOLISM Acrylamide is a small organic molecule that is very soluble in water and can react at both its amide group and its double-bond vinyl group.This reactivity and ease of transport may account for the toxic effects of acrylamide.Studies show that the toxicokinetics and tissue distribution of acrylamide are not significantly dependent on the dose and route of exposure.The parent compound is rapidly eliminated from the tissues.The uptake, distribution, biotrans formation, and elimination, which are summarized below, have been discussed in detail by Dearfield et al. . # Uptake No studies were found on the absorption of acrylamide by inhalation.All animal studies involved either oral or dermal exposure, and intraperitoneal (i.p.)or intravenous (i.v.)dosing.The uptake of acrylamide through the gastrointestinal tract of rats was rapid and complete, as indicated by similar excretion profiles of the chemical whether it was administered by i.v.injection or by gavage .Dermal absorption in the rat is less than complete.By comparing blood concentrations after i.v.or dermal administration of acrylamide, Ramsey et al. calculated that 25% of the applied doses (2 or 50 mg/kg) of acrylamide were absorbed through the skin of rats during the first 24 hr.Frantz et al. reported that 26% of a 0.5% aqueous solution of acrylamide was absorbed through the skin of rats in 24 hr and that, after the skin was washed, an additional 35% remained in the skin.The data from in vitro experiments were similar .These researchers used excised skin preparations to show that 67% of the applied acrylamide was either absorbed or available for absorption (that is, 54% was absorbed and 13% remained in the skin after washing). # Distribution and Toxicokinetics After rats received various doses of acrylamide (0.5 to 100 mg/kg) by i. 1970].Miller et al. reported that high percentages of the wC-labeled chemical were found in muscle (48%), skin (15%), blood (12%), and liver (7%), whereas the neural tissues (brain, spinal cord, and sciatic nerve) contained less than 1%.However, when the data were expressed as micromoles (¿tmoles) of acrylamide/g of tissue, the concentrations of acrylamide in the tissues were similar.In the neural tissues of rats there appears to be no preferential bioconcentration of acrylamide and/or its metabolites that can account for its neurotoxic effects . Acrylamide has also been reported to distribute readily in the tissues of other animal species.For example, acrylamide was found in the blood, brain, heart, liver, kidneys, and lungs of miniature swine and beagle dogs, with the highest concentrations found in the liver and kidneys .Because the authors did not analyze skin, muscle, and other tissues, it is difficult to compare the results with those reported by Miller et al. .In addition, autoradiographic studies have demonstrated a similar distribution of acrylamide in male and pregnant female mice .Acrylamide was found to cross the placentas of rats, rabbits, dogs, pigs, and mice and to be uniformly distributed in those fetuses . Ramsey et al. have examined the effects of multiple oral doses on tissue distribution.When rats were given acrylamide at 0.05 or 30 mg/kg for 13 consecutive days, the ratio of the 14C-labeled chemical in the tissues at the two doses was proportional to the ratio of the doses administered (that is, 600) except in the red blood cells (304), blood plasma (1,089), and testes (934).These data demonstrate that multiple doses of acrylamide do not greatly alter its distribution except at those three sites. Miller et al. used rats in a detailed study of the pharmacokinetics and distribution of acrylamide, both as the parent compound and as the total "¿-labeled chemical after an i.v.dose of 10 mg/kg.The elimination of the parent acrylamide was represented by a single compartment model.In the blood, the parent compound had a half-life of 1.7 hr, and the clearance of the unmetabolized acrylamide from all other tissues but the testes was similar.The testes showed a delay in the time necessary to reach peak concentration-an event attributed to their fat content.After the peak was attained, the parent acrylamide was cleared from the testes in a manner similar to that for other tissues . # Biotransformation and Elimination The distribution and the elimination of the total 14C-labeled chemical (representing acrylamide and its metabolites) was slower than that of the parent compound and was best represented by a biphasic curve .In addition, four tissues (liver, kidney, fat, and testes) demonstrated absorptive phases for the total 14C-labeled chemical.Since no absorption phases were noted for the parent acrylamide in the liver and kidney, the increases in the 14C-labeled chemical in these two tissues were attributed to metabolite accumulation.The higher lipid content of the fat and testes and the polar nature of acrylamide were reported by Miller et al. to have delayed the absorption in these two tissues.The initial portion (half-life of 5 hr) of the biphasic curve was attributed to the metabolism of acrylamide and the binding of its metabolites to biological macromolecules, since only 2% of the total dose of administered acrylamide was excreted as the parent compound.The terminal portion (half-life of 8 days) of the biphasic curve was thought to be the result of the release of acrylamide metabolites from tissue depots and the degradation of acrylamide-protein adducts .Support for these suppositions was provided by Ramsey et al. ,who analyzed urine, plasma, and tissue samples in male Fisher 344 rats following either i.v.,gavage, or dermal administration of 14C-labeled acrylamide.Their data indicated that the initial phase was due to the loss of the parent compound and that the latter phase resulted from the clearance of acrylamide metabolites. Because acrylamide affects reproduction, the very slow release of acrylamide or its metabolites from the testes is of particular interest.Although the fat content of the testes may have decreased the uptake of the parent acrylamide, it would not appear to account for its slow excretion.It is possible that acrylamide is metabolized and binds to constituents of the testes.Marlowe et al. reported that radioactivity appeared in the testes 1 hr after administration and migrated to the seminiferous tubules and head of the epididymis after 9 hr.After 9 days, radioactivity remained only in the tail of the epididymis and in the epithelium of the penis.Marlow et al. correlated this movement with that of the spermatids. # Factors That Can Affect Metabolism Studies of the effects of altering microsomal mixed-function oxidase activity on the expression of acrylamide-induced neuropathy have given disparate results. Pretreatment of rats with phenobarbital (PB) or DDT Srivastava et al. found that pretreatment of rats with PB or DDT decreased the time necessary for onset of acrylamide-induced hind-limb paralysis.This disparity does not appear to be due to variations in experimental protocol, but it may be explained by differences in the animal strains. The results of using drug metabolism inhibitors are difficult to interpret.For example, SKF 525A (which inhibits microsomal oxidation) has been reported to prevent acrylamide-induced enhance ment of striatal dopamine receptor activity and to increase the acute toxicity of acrylamide in rats , whereas cobalt chloride has been shown to cause a significant delay in the development of hindlimb paralysis in rats .Presently, no correlation exists between the effects of modifying microsomal metabolism of acrylamide and expression of its toxic effects.Accordingly, identification of metabolic factors important in the toxic manifestations of acrylamide is not possible.Khanna et al. studied the role of protein deficiency on the neurobehavioral effects of acrylamide in rat pups exposed during pregnancy and early infancy.They demonstrated that acrylamide was more toxic in protein-deficient animals because it decreased the dopamine and benzodiazepam receptor binding and delayed the development of reflexes and other physical milestones in pups. # TOXICOLOGIC MECHANISMS Because the most noticeable and earliest detectable effects of acrylamide exposures are neurological effects, numerous studies have attempted to find the mechanism of its action in neural tissues. found that acrylamide inhibits succinic dehydrogenase (SDH) activity in mitochondrial preparations from rat brain and causes changes in levels of biogenic amines and activities of monoamine oxidase and acetylcholine esterase.Biochemical changes may be responsible for the functional changes observed in neural tissues-for example, changes in membrane capacitance and sodium permeability remains to be established.However, the fact that acrylamide has been shown to interact with genetic material may have implications for its genotoxic and carcinogenic effects. # TOXICITY IN HUMANS AND ANIMALS # Neurotoxic Effects The # Developmental and Reproductive Effects Data on developmental and reproductive effects in animals are summarized in Tables 3 and 4 # GENOTOXIC EFFECTS The major concern about the genotoxicity of acrylamide is its clastogenic activity (that is, chromosomal breakage and other chromosomal abnormalities).The clastogenic effect of acrylamide appears more pronounced in the germ cells compared with somatic cells.The interaction with germinal tissues suggests the possible heritabUity of acrylamide-induced DNA alterations. # Gene Mutation Assays # Chromosomal Assays Studies that have examined the chromosomal effects of acrylamide have confirmed its clastogenic potential.This effect appears to be more pronounced in the germ cells than in somatic cells.The suggestive reciprocal translocation results raise the possibility that acrylamide-induced alterations to DNA may be transmissible to future generations.A study of heritable translocation in mice demonstrated that acrylamide is an effective inducer of translocations in postmeiotic germ cells.This result demonstrates that acrylamide may be capable of affecting heritable germ cells in a mammalian system. # CARCINOGENIC EFFECTS # Epidemiologic Findings Collins et al. studied the mortality of workers in acrylamide production plants.This study was performed by scientists at major production plants.Mortality was tracked for a cohort of 8,854 males from 1925 to 1983.This cohort (2,293 of whom were exposed to acrylamide) consisted of four plant populations in the United States and the Netherlands.Followup was completed for 95% of the cohort.At the end of the study 2,148 individuals were deceased, and death certificates were obtained for 95%.The underlying cause of death was coded by a nosologist.Exposure estimates were developed for all jobs at each of the four plants using exposure data collected at each plant and information obtained from plant personnel who had knowledge of past jobs and processes.Exposure to acrylamide was defined as a cumulative exposure greater than 0.001 mg/m3-years, which is approximately equivalent to a 1-day exposure to an average concentration of 0.3 mg/m3.Data on smoking history were available for only a third of the cohort.Standardized mortality ratios (SMRs) and internally standardized rate ratios were employed to estimate the risk. According to the authors, a particular strength of their study was the ability to detect a 25% increase in total cancer, a 50% increase in respiratory cancer, and a threefold increase in brain and other central nervous system cancers based on a two-tailed, 5% significance level with a power of 80%. The SMRs for all causes for both exposed and unexposed groups were significantly less than expected, which may be the result of both initial selection and the ongoing benefits of employment (i.e., the healthy worker effect).An excess of total cancer deaths was not observed among the exposed workers.A slight increase in cancer of the respiratory system (30 observed versus 26.3 expected) was not statistically significant.Analyses of trends by cumulative exposure showed no increased risk of mortality with increasing exposure.Because smoking history was obtained for only a third of the cohort, it was impossible to determine whether smoking habits had confounded the results. # Sobel et al. examined mortality in a group of 371 workers assigned to acrylamide monomer or polyacrylamide operations.Exposure to acrylamide was categorized on the basis of a review of job classifications.Before 1957, personal TWA exposures to acrylamide in the monomer production areas were 0.1 to 1.0 mg/m3.The data from 1957 to 1970 indicated that exposures to acrylamide were 0.1 to 0.6 mg/m3.After 1970, personal exposures to acrylamide were <0.1 mg/m3 for all job classifications.Associated with the production of acrylamide monomer is the potential for exposure to acrylonitrile.The possible confounding effect of this exposure was not formally addressed in this study; but in a previous epidemiologic study , no effects could be directly related to acrylonitrile under the conditions of exposure.The total number of deaths from malignancies was slightly elevated (11 observed versus 7.9 expected ), but this result was apparently due to the excess in a subgroup that was also exposed to organic dyes .Overall, the results did not indicate an excess of cancers from exposures to acrylamide.However, these results may be due to the small cohort size, limited followup, and short duration of exposure (274 workers were exposed for less than 5 years).Given the size of the total cohort and the period of observation, the study had only an 80% likelihood (power) of detecting a twofold or greater increase in total cancer incidence. # Evidence of Carcinogenicity in Animals Studies in rats and mice indicate that acrylamide is an animal carcinogen .Acrylamide was tested for skin-tumor-initiating activity in Senear mice and for the ability to induce lung adenomas in A /J mice .In a mouse skin initiation-promotion assay, 6-to 8-week old female Senear mice were divided into groups of 40 and treated topically, by gavage, or by i.p.injection with acrylamide dissolved in water.Acrylamide was tested at doses of 12.5, 25, and 50 mg/kg for six applications by the three routes over a 2-week period, resulting in total doses of 75, 150, and 300 mg/kg.
Ethyl carbamate, a known initiator, was used for a comparison in doses of 30,100, and 300 mg/kg in one application administered topically, by gavage, or i.p.A tumor promotion regimen was started 2 weeks after the last of the tumor-initiating doses of acrylamide.One microgram of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), a known tumor promoter, was applied topically 3 times/week for 20 weeks.Tumor incidences were charted from weekly observation.Surviving animals were sacrificed at 52 weeks and histopathological evaluations were done on all gross lesions.A highly significant (p<0.01) dose-response relationship existed for time to first tumor and for the total number of tumors in treated animals.The effect was more pronounced with i.p.and gavage treatment than with topical application.However, without application of TPA promotion, no increase occurred in tumor yield, either with acrylamide or ethyl carbamate treatment.In this assay system, acrylamide was therefore confirmed as being a tumor initiator. In a bioassay for lung adenoma in mice, groups of 40 male and 40 female, 8-week-old A /J mice received doses of 6.25, 12.5, or 25 mg/kg of acrylamide by gavage in an aqueous solution three times/week for 8 weeks .Animals were sacrificed at 7 months of age.Acrylamide increased the yield of lung adenomas in both sexes in a dose-related manner; the average number of tumors per animal increased from 0.2 to 1.4.The dose-response relationship was statistically significant (p<0.01) when both the number of animals with tumors and the multiplicity of tumors in each dose group were tested using logit regression model analysis.In the same investigation, groups of 16 male and 16 female, 8-week-old A /J mice received i.p.injections of 1, 3, 10, 30, or 60 mg/kg acrylamide three times/week for 8 weeks.The average number of tumors per animal increased from 0.4 to 2.2.The number of lung adenomas increased with the dose up to 30 mg/kg.The dose-response relationship was statistically significant (p<0.01) by the logit regression model.Because acrylamide increased the lung tumor yield by two routes of administration in the absence of a promoter, the authors concluded that acrylamide acted as a complete carcinogen in this test system. In a subsequent study , groups of 40 female Swiss-ICR mice were administered an oral dose of 0, 12.5, 25, or 50 mg/kg acrylamide six times in a 2-week period.Ethyl carbamate served as a positive control and was administered in the same way at concentrations of 50 mg/kg.Two weeks after the last dose, a tumor promotion regimen was started.The regimen consisted of 3 weekly applications of 2.5 fig TPA dissolved in acetone to the shaved back of each animal.Another group of mice treated with 50 mg/kg acrylamide did not receive promotion treatment.The appearance of skin tumors was observed weekly, and after 52 weeks of study, the surviving animals were sacrificed and evaluated histologically for skin and lung tumors.When TPA treatment followed, acrylamide produced a dose-related increase in the number of animals that bore skin tumors (33% in the high-dose group versus none in the control group).Without TPA treatment there was no significant increase.The number of lung tumors (adenoma and carcinoma) was increased by acrylamide treatment in a dose-related manner (4 tumors in the control group and 11 tumors in the 50-mg/kg group).This increase was also observed in the absence of TPA (14 tumors in the 50 mg/kg group).This study confirms the initiating effects of acrylamide on the skin of Senear mice and the carcinogenic effects of acrylamide on the lungs of A /J mice. Acrylamide administered in drinking water to female and male F344 rats for 2 years caused a statistically significant increase in the incidence of benign and malignant tumors at several sites in both sexes .Groups of 90 male and 90 female rats were maintained on drinking water providing acrylamide intakes of 0, 0.01, 0.1, 0.5, or 2.0 mg/kg per day.Ten rats per sex per treatment group were randomly selected for examination after 6, 12, or 18 months of study.Cumulative mortality showed no apparent dose relationship until the 21st month of study.From that time to the conclusion of the study at 24 months, mortality increased in the group receiving 2.0 mg/kg per day.No overt signs of neurotoxicity or other effects were attributable to acrylamide treatment.Rats in the group receiving the highest dose had an increased number of palpable masses, subsequently identified as subcutaneous or skin tumors.The number of tumors by site is listed in Table 5.In females, tumor incidence increased in the mammary glands, CNS, thyroid gland follicular epithelium, oral tissues, uterus, and clitoral gland.In males, tumor incidence increased in the CNS, the thyroid gland follicular epithelium, and the scrotal mesothelium.These increases occurred in the group receiving the highest dose (2.0 mg/kg per day).The only statistically significant increases (p<0.05) at the 0.5-mg/kg per day dose were the incidence of scrotal mesotheliomas in male rats and the incidence of combined mammary and clitoral gland tumors in female rats .1 Includes only adrenal benign tumors. Tumors only (no "proliferations"). # METHODS FOR MONITORING EXPOSURES # EXPOSURE MONITORING A worker's exposure to airborne acrylamide should be determined by using a personal sampling train consisting of a glass-fiber filter in a Swinnex cassette (13-mm) followed by a silica gel tube.Plastic cassettes (37-mm) yielded poor recoveries of acrylamide and are therefore unsuitable.Samples should be collected at a maximum flowrate of 1 liter/min for a minimum of 2 hr; the maximum air volume should be 120 liters.The silica gel tube should then be treated with methanol to extract the acrylamide.An important step in this method is the transfer of the glass-fiber filters to glass vials containing 1 ml of methanol immediately after sampling to avoid losses of acrylamide from the filter by evaporation.Analysis should be conducted by gas chromatography using a nitrogen/phosphorus detector.The limit of detection for this procedure is 1.3 parts per billion (ppb) (0.004 mg/m3).This method is described in Method 21 of the OSHA Analytical Methods Manual . # BIOLOGICAL MONITORING The International Programme on Chemical Safety (IPCS) has recommended that a biological monitoring method for acrylamide be developed based on the determination of the adduct formed with hemoglobin .However, no biological monitoring test acceptable for routine use has yet been developed for acrylamide. # RELATIONSHIP BETWEEN EXPOSURE AND ADVERSE HEALTH EFFECTS No data are available from studies in humans to establish an occupational exposure limit for acrylamide on the basis of neurotoxic, developmental, reproductive, or carcinogenic effects.However, many studies demonstrate a relationship between exposure and adverse health effects in animals.These studies are the bases for occupational exposure limits recommended by many organizations and government agencies.A few of these studies are described here. 5 NOEL = no-observable-effect level; LOEL = lowest-observable-effect level. The linearized multistage procedure was followed by EPA , with GLOBAL 86 as the computer program.Among the models that showed adequate fit with one to six stages, the model that gave the least q^ (slope factor) was selected as the model with which to calculate carcinogenic risks using the lifetime average daily exposures provided by the exposure assessment for acrylamide.For the female rats with tumors of the thyroid, oral cavity, uterus, CNS, or mammary glands, this model had two stages.The cancer potency factor obtained for acrylamide by the linearized multistage procedure was 4.5 (mg/kg per day)'1.The cancer potency factor describes the increased risk of developing cancer over a 70-year lifetime per unit of exposure where the unit of exposure is expressed as mg chemical/kg body weight per day.When based on an experimental animal study, the cancer potency factor is the 95% upper confidence limit slope of the dose-response relationship for a carcinogen as the dose approaches zero.Calculated upper-bound excess risks for individuals exposed to acrylamide are presented in Table 7.The highest risks were estimated for sewer repair workers, whose excess risks ranged from 10'1 to 10'2.EPA calculated that exposure to airborne concentrations of 0. # RESEARCH NEEDS Very few studies address dermal absorption o f acrylamide, although the dermal route may be the most significant one for acrylamide exposure in the workplace .Therefore, quantitative studies should be performed to assess the absorption o f aciylam ide through the skin. Because dermal exposure appears to be a significant route o f acrylamide uptake and it is difficult to monitor dermal exposures routinely, it is important to develop biom onitoring that can accurately reflect total exposure to acrylamide.A valid biomonitoring technique for acrylamide is presently unavailable.However, the literature on the toxicokinetics o f acrylamide indicates that biom oni toring may be feasible either in urine or blood.M ore than 50% o f the given dose is reported to be excreted in urine as the m etabolite N-acetyl-S-(3-amino-3-oxy-propyl)cysteine .By collecting the urine o f workers whose exposure is monitored, it may be feasible to correlate the total exposure (that is, both inhalation and skin) to acrylamide with measured concentrations or total amounts o f m etabolites in 24-hr urine samples. Another possibility for biomonitoring is measurement o f acrylamide binding to red blood cells.Hashimoto and Aldridge observed that after rats received a single i.v.dose o f UC acrylamide, the radioactivity in blood after 24 hr was entirely associated with red blood cells.Miller et al. found that the concentration o f 14C in whole blood reached a plateau at 12% o f the total dose after 1 hr and remained constant throughout the time period examined (7 days).The binding to erythrocytes accounted for essentially all o f the remaining radioactivity in the w hole blood.In vitro studies showed that acrylamide was covalently bound to cysteine residues in protein and, on acidic hydrolysis, the adduct yielded a compound with chromatographic properties identified as S-( 2 # SUMMARY Acrylamide is an odorless, white, crystalline solid used as a monomer or as a raw material in the production o f polyacrylamides.Workers potentially exposed to acrylamide monomer are employed in acrylamide manufacturing and processing, grouting operations, and research and analytical laboratories. Only the acrylamide monomer is toxic; polyacrylamide products are generally nontoxic.Acrylamide monomer may be neurotoxic, carcinogenic, genotoxic, and hazardous to reproduction.Recent studies confirm that acrylamide exposures cause cancer and reproductive effects in animals, but epidem iologic studies have not demonstrated these effects in humans.Key Words: Acrylamide, carcinogenicity, dermal exposures, grouting, neurotoxic effects, occupational exposure, polyacrylamide, reproductive effects. # APPENDIX.INTERNATIONAL STANDARDS FOR WORKPLACE EXPOSURES TO ACRYLAMIDE This appendix lists occupational exposure lim its for airborne acrylamide in various countries (Table A -
# Table of Contents List of Tables, Figures , and Boxes # Summary Preexposure Prophylaxis for HIV Prevention in the United States -2013: A Clinical Practice Guideline provides comprehensive information for the use of daily oral antiretroviral preexposure prophylaxis (PrEP) to reduce the risk of acquiring HIV infection in adults.The key messages of the guideline are as follows:  Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults; therefore, o PrEP is recommended as one prevention option for sexually-active adult MSM (men who have sex with men) at substantial risk of HIV acquisition (IA) 1 o PrEP is recommended as one prevention option for adult heterosexually active men and women who are at substantial risk of HIV acquisition. (IA) o PrEP is recommended as one prevention option for adult injection drug users (IDU) at substantial risk of HIV acquisition. (IA) o PrEP should be discussed with heterosexually-active women and men whose partners are known to have HIV infection (i.e., HIV-discordant couples) as one of several options to protect the uninfected partner during conception and pregnancy so that an informed decision can be made in awareness of what is known and unknown about benefits and risks of PrEP for mother and fetus (IIB)  Currently the data on the efficacy and safety of PrEP for adolescents are insufficient. Therefore, the risks and benefits of PrEP for adolescents should be weighed carefully in the context of local laws and regulations about autonomy in health care decision-making by minors. (IIIB)  Acute and chronic HIV infection must be excluded by symptom history and HIV testing immediately before PrEP is prescribed. (IA)  The only medication regimen approved by the Food and Drug Administration and recommended for PrEP with all the populations specified in this guideline is daily TDF 300 mg co-formulated with FTC 200 mg (Truvada) (IA) o TDF alone has shown substantial efficacy and safety in trials with IDUs and heterosexually active adults and can be considered as an alternative regimen for these populations, but not for MSM, among whom its efficacy has not been studied. (IC) o The use of other antiretroviral medications for PrEP, either in place of or in addition to TDF/FTC (or TDF) is not recommended. (IIIA) o The prescription of oral PrEP for coitally-timed or other noncontinuous daily use is not recommended. (IIIA)  HIV infection should be assessed at least every 3 months while patients are taking PrEP so that those with incident infection do not continue taking it.The 2-drug regimen of TDF/FTC is inadequate therapy for established HIV infection, and its use may engender resistance to either or both drugs. (IA)  Renal function should be assessed at baseline and monitored at least every 6 months while patients are taking PrEP so that those in whom renal failure is developing do not continue to take it. (IIIA)  When PrEP is prescribed, clinicians should provide access, directly or by facilitated referral, to proven effective risk-reduction services.Because high medication adherence is critical to PrEP efficacy but was not uniformly achieved by trial participants, patients should be encouraged and enabled to use PrEP in combination with other effective prevention methods. (IIIA) # Introduction Recent findings from several clinical trials have demonstrated safety 1 and a substantial reduction in the rate of HIV acquisition for men who have sex with men (MSM) 2 , men and women in heterosexual HIV-discordant couples 3 , and heterosexual men and women recruited as individuals 4 who were prescribed daily oral antiretroviral preexposure prophylaxis (PrEP) with a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC).In addition, one clinical trial among injection drug users (IDU) 5 and one among men and women in heterosexual HIV-discordant couples 3 have demonstrated substantial efficacy and safety of daily oral PrEP with TDF alone.The demonstrated efficacy of PrEP was in addition to the effects of repeated condom provision, sexual risk-reduction counseling, and the diagnosis and treatment of sexually transmitted infection (STI), all of which were provided to trial participants, including those in the drug treatment group and those in the placebo group.In July 2012, after reviewing the available trial results, the U.S. Food and Drug Administration (FDA) approved an indication for the use of Truvada † (TDF/FC) "in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk" 6,7 . On the basis of these trial results and the FDA approval, the U.S. Public Health Service recommends that clinicians evaluate their male and female patients who are sexually active or who are injecting illicit drugs and consider offering PrEP as one prevention option to those whose sexual or injection behaviors and epidemiologic context place them at substantial risk of acquiring HIV infection. The evidence base for these recommendations is derived from a systematic search and review of published literature.To identify all PrEP safety and efficacy trials pertaining to the prevention of sexual and injection acquisition of HIV, a search of the clinical trials registry () was performed by using combinations search terms (preexposure prophylaxis, pre-exposure prophylaxis, PrEP, HIV, Truvada, tenofovir, and antiretroviral).In addition, the same search terms were used to search conference abstracts for major HIV conferences (e.g., International AIDS Conference, Conference on Retroviruses and Opportunistic Infections) for the years 2009-2013.These same search terms were used to search PubMed and Web of Science databases for the years 2006-2013.Finally, a review of references from published PrEP trial data and the data summary prepared by FDA for its approval decision 8 confirmed that no additional trial results were available. This publication provides a comprehensive clinical practice guideline for the use of PrEP for the prevention of HIV infection in the United States.It incorporates and extends information provided in interim guidance for PrEP use with MSM 9 , with heterosexually active adults 10 , and with IDU (also called persons who injection drugs ) 11 .Currently, prescribing daily oral PrEP with TDF/FTC is recommended as one prevention option for MSM, heterosexual men, heterosexual women, and IDU at substantial risk of HIV acquisition.As the results of additional PrEP clinical trials and studies in these and other populations at risk of HIV acquisition become known, this guideline will be updated. The intended users of this guideline include  primary care clinicians who provide care to persons at risk of acquiring HIV infection  clinicians who provide substance abuse treatment  infectious disease and HIV treatment specialists who may provide PrEP or serve as consultants to primary care physicians about the use of antiretroviral medications  health program policymakers. # Evidence of Need for Additional HIV Prevention Methods Approximately 50,000 people in the United States are infected with HIV each year 12 .From 2008 through 2010, HIV incidence remained stable or declined among IDU and heterosexuals of all races and Hispanic/Latino ethnicity, but incidence increased among MSM (12% increase), especially among adolescent and young adult MSM (aged 13-24 years) (22% increase) 12 .The greatest number of new HIV infections among MSM occurred in young African American MSM (4,800).In 2010, 63% of the estimated 47,500 new infections were attributed to male-male sexual activity without injection drug use, 4% to male-male sexual activity with injection drug use, 25% to male-female sexual contact without injection drug use, and 8% to injection drug use.Among the 25% of persons newly infected through heterosexual activity, 66% were African-American women and men.These data indicate a need for additional methods of HIV prevention to further reduce new HIV infections, especially (but not exclusively) among young adult and adolescent MSM of all races and Hispanic/Latino ethnicity and for African American heterosexuals (populations with higher HIV prevalence and at higher risk of HIV infection among those without HIV infection). # Evidence of the Safety and Efficacy of Antiretroviral Prophylaxis The biological plausibility and the short-term safety of antiretroviral use to prevent HIV acquisition in other exposure situations have been demonstrated in 2 studies conducted prior to the PrEP trials.In a randomized placebo-controlled trial, perinatal transmission was reduced 68% among the HIV-infected women who received zidovudine during pregnancy and labor and whose infants received zidovudine for 6 weeks after birth 13 .That is, these infants received both preexposure and postexposure prophylaxis.In 1995, investigators used case-control surveillance data from health-care workers to demonstrate that zidovudine provided within 72 hours after percutaneous exposure to HIV-infected blood and continued for 28 days (PEP, or postexposure prophylaxis) was associated with an 81% reduction in the risk of acquiring HIV infection . Evidence from these human studies of blood-borne and perinatal transmission as well as studies of vaginal and rectal exposure among animals suggested that PrEP (using antiretroviral drugs) could reduce the risk of acquiring HIV infection from sexual and drug-use exposures.Clinical trials were launched to evaluate the safety and efficacy of PrEP in populations at risk of HIV infection through several routes of exposure.The results of completed trials published as of August 2013 are summarized below.See also Tables 2-6. # PUBLISHED TRIALS OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG MEN WHO HAVE SEX WITH MEN # IPREX (PREEXPOSURE PROPHYLAXIS INITIATIVE) TRIAL The iPrEx study 2 was a phase 3, randomized, double-blind, placebo-controlled trial conducted in Peru, Ecuador, Brazil, Thailand, South Africa, and the United States among men and male-tofemale transgender adults who reported sex with a man during the 6 months preceding enrollment.Participants were randomly assigned to receive a daily oral dose of either the fixeddose combination of TDF and FTC or a placebo.All participants (drug and placebo groups) were seen every 4 weeks for an interview, HIV testing, counseling about risk-reduction and adherence to PrEP medication doses, pill count, and dispensing of pills and condoms.Analysis of data through May 1, 2010, revealed that after the exclusion of 58 participants (10 later determined to be HIV-infected at enrollment and 48 who did not have an HIV test after enrollment), 36 of 1,224 participants in the TDF/FTC group and 64 of 1,217 in the placebo group had acquired HIV infection.Enrollment in the TDF/FTC group was associated with a 44% reduction in the risk of HIV acquisition (95% CI, 15-63).The reduction was greater in the as-treated analysis: at the visits at which adherence was ≥50% (by self-report and pill count/dispensing), the reduction in HIV acquisition was 50% (95% CI, .The reduction in the risk of HIV acquisition was 73% at visits at which self-reported adherence was ≥90% (95% CI, 41-88) during the preceding 30 days.Among participants randomly assigned to the TDF/FTC group, plasma and intracellular drug-level testing was performed for all those who acquired HIV infection during the trial and for a matched subset who remained HIV-uninfected: a 92% reduction in the risk of HIV acquisition (95% CI, 40-99) was found in participants with detectable levels of TDF/FTC versus those with no drug detected.Generally, TDF/FTC was well tolerated, although nausea in the first month was more common among participants taking medication than among those taking placebo (9% versus 5%).No differences in severe (grade 3) or life-threatening (grade 4) adverse laboratory events were observed between the active and placebo group, and no drug-resistant virus was found in the 100 participants infected after enrollment.Among 10 participants who were HIV-negative at enrollment but later found to have been infected before enrollment, FTC-resistant virus was detected in 2 of 2 men in the active group and 1 of 8 men in the placebo group.Compared to participant reports at baseline, over the course of the study participants in both the TDF/FTC and placebo groups reported fewer total numbers of sex partners with whom the participants had receptive anal intercourse and higher percentages of partners who used condoms. # US MSM SAFETY TRIAL The US MSM Safety Trial 1 was a phase 2 randomized, double-blind, placebo-controlled study of the clinical safety and behavioral effects of TDF for HIV prevention among 400 MSM in San Francisco, Boston, and Atlanta.Participants were randomly assigned 1:1:1:1 to receive daily oral TDF or placebo immediately or after a 9-month delay.Participants were seen for follow-up visits 1 month after enrollment and quarterly thereafter.Among those without directed drug interruptions, medication adherence was high: 92% by pill count and 77% by pill bottle openings recorded by Medication Event Monitoring System (MEMS) caps.Temporary drug interruptions and the overall frequency of adverse events did not differ significantly between TDF and placebo groups.In multivariable analyses, back pain was the only adverse event associated with receipt of TDF.In a subset of men at the San Francisco site (n=184) for whom bone mineral density (BMD) was assessed, receipt of TDF was associated with small decrease in BMD (1% decrease at the femoral neck, 0.8% decrease for total hip) 20 .TDF was not associated with reported bone fractures at any anatomical site.Among 7 seroconversions, no HIV with mutations associated with TDF resistance was detected.No HIV infections occurred while participants were being given TDF; 3 occurred in men while taking placebo, 3 occurred among men in the delayed TDF group who had not started receiving drug; 1 occurred in a man who had been randomly assigned to receive placebo and who was later determined to have had acute HIV infection at the enrollment visit. Daily oral PrEP with TDF/FTC is recommended as one HIV prevention option for sexuallyactive MSM at substantial risk of HIV acquisition because the iPrEx trial presents evidence of its safety and efficacy in this population, especially when medication adherence is high. (IA) # PUBLISHED TRIALS OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG HETEROSEXUAL MEN AND WOMEN # PARTNERS PREP TRIAL The Partners PrEP trial 3,21 was a phase 3 randomized, double-blind, placebo-controlled study of daily oral TDF/FTC or TDF for the prevention of acquisition of HIV by the uninfected partner in 4,758 HIV-discordant heterosexual couples in Uganda and Kenya.The trial was stopped after an interim analysis in mid-2011 showed statistically significant efficacy in the medication groups (TDF/FTC or TDF) compared with the placebo group.In 48% of couples, the infected partner was male.HIV-positive partners had a median CD4 count of 495 cells/µL and were not being prescribed antiretroviral therapy because they were not eligible by local treatment guidelines.Participants had monthly follow-up visits and the study drug was discontinued among women who became pregnant during the trial. Adherence to medication was very high: 98% by pills dispensed, 92% by pill count, and 82% by plasma drug-level testing among randomly selected participants in the TDF and TDF/FTC study groups.Rates of serious adverse events and serum creatinine or phosphorus abnormalities did not differ by study group.Modest increases in gastrointestinal symptoms and fatigue were reported in the antiretroviral medication groups compared with the placebo group, primarily in the first month of use.Among participants of both sexes combined, efficacy estimates for each of the 2 antiretroviral regimens compared with placebo were 67% (95% CI, 44-81) for TDF and 75% (95% CI, 55-87) for TDF/FTC.Among women, the estimated efficacy was 71% for TDF and 66% for TDF/FTC.Among men, the estimated efficacy was 63% for TDF and 84% for TDF/FTC.Efficacy estimates by drug regimen were not statistically different among men, women, men and women combined, or between men and women.In a Partners PrEP substudy that measured plasma TDF levels among participants randomly assigned to receive TDF/FTC, detectable drug was associated with a 90% reduction in the risk of HIV acquisition.TDF-or FTC-resistant virus was detected in 3 of 14 persons determined to have been infected when enrolled (2 of 5 in the TDF group; 1 of 3 in the TDF/FTC group) 8 .No TDF or FTC resistant virus was detected among those infected after enrollment.Among women, the pregnancy rate was high (10.3 per 100 person -years) and rates did not differ significantly between the study groups. # TDF2 TRIAL The Botswana TDF2 Trial 22 , a phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of daily oral TDF/FTC, enrolled 1,219 heterosexual men and women in Botswana, and follow-up has been completed.Participants were seen for monthly follow-up visits, and study drug was discontinued in women who became pregnant during the trial.Among participants of both sexes combined, the efficacy of TDF/FTC was 62% (22%-83%).Efficacy estimates by sex did not statistically differ from each other or from the overall estimate, although the small number of endpoints in the subsets of men and women limited the statistical power to detect a difference.Compliance with study visits was low: 33.1% of participants did not complete the study per protocol.However, many were re-engaged for an exit visit, and 89.3% of enrolled participants had a final HIV test.Among 3 participants later found to have been infected at enrollment, TDF/FTC-resistant virus was detected in 1 participant in the TDF/FTC group and a low level of TDF/FTC-resistant virus was transiently detected in 1 participant in the placebo group.No resistant virus was detected in the 33 participants who seroconverted after enrollment. Medication adherence by pill count was 84% in both groups.Nausea, vomiting, and dizziness occurred more commonly, primarily during the first month of use, among those randomly assigned to TDF/FTC than among those assigned to placebo.The groups did not differ in rates of serious clinical or laboratory adverse events.Pregnancy rates and rates of fetal loss did not differ by study group. # FEM-PREP TRIAL The FEM-PrEP trial 23 was a phase 3 randomized, double-blind, placebo-controlled study of the HIV prevention efficacy and clinical safety of daily TDF/FTC among heterosexual women in South Africa, Kenya, and Tanzania.Participants were seen at monthly follow-up visits, and study drug was discontinued among women who became pregnant during the trial.
The trial was stopped in 2011, when an interim analysis determined that the trial would be unlikely to detect a statistically significant difference in efficacy between the two study groups. Adherence was low in this trial: study drug was detected in plasma samples of <50% of women randomly assigned to TDF/FTC.Among adverse events, only nausea and vomiting (in the first month) and transient, modest elevations in liver function test values were more common among those assigned to TDF/FTC than those assigned to placebo.No changes in renal function were seen in either group.Initial analyses of efficacy results showed 4.7 infections per 100/ personyears in the TDF/FTC group and 5.0 infections per 100 person-years in the placebo group.The hazard ratio 0.94 (95% CI, 0.59-1.52) indicated no reduction in HIV incidence associated with TDF/FTC use.Of the 68 women who acquired HIV infection during the trial, TDF or FTC resistant virus was detected in 5 women: 1 in the placebo group and 4 in the TDF/FTC group.In multivariate analyses, there was no association between pregnancy rate and study group. # PHASE 2 TRIAL OF PREEXPOSURE PROPHYLAXIS WITH TENOFOVIR AMONG WOMEN IN GHANA, CAMEROON, AND NIGERIA A randomized, double-blind, placebo-controlled trial of oral tenofovir TDF was conducted among heterosexual women in West Africa -Ghana (n = 200), Cameroon (n = 200), and Nigeria (n = 136) 24 .The study was designed to assess the safety of TDF use and the efficacy of daily TDF in reducing the rate of HIV infection.The Cameroon and Nigeria study sites were closed prematurely because operational obstacles developed, so participant follow-up data were insufficient for the planned efficacy analysis.Analysis of trial safety data from Ghana and Cameroon found no statistically significant differences in grade 3 or 4 hepatic or renal events or in reports of clinical adverse events.Eight HIV seroconversions occurred among women in the trial: 2 among women in the TDF group (rate=0.86 per 100 person-years) and 6 among women receiving placebo (rate, 2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% CI, 0.03-1.93; P=0.24).Blood specimens were available from 1 of the 2 participants who seroconverted while taking TDF; standard genotypic analysis revealed no evidence of drug-resistance mutations. # VOICE (VAGINAL AND ORAL INTERVENTIONS TO CONTROL THE EPIDEMIC) TRIAL VOICE (MTN-003) 25 was a phase 2B randomized, double-blind study comparing oral (TDF or TDF/FTC) and topical vaginal (tenofovir) antiretroviral regimens against corresponding oral and topical placebos among 5,029 heterosexual women enrolled in eastern and southern Africa.Of these women, 3,019 were randomly assigned to daily oral medication (TDF/FTC, 1,003; TDF, 1,007; oral placebo, 1,009).In 2011, the trial group receiving oral TDF and the group receiving topical tenofovir were stopped after interim analyses determined futility 26 .The group receiving oral TDF/FTC continued to the planned trial conclusion. After the exclusion of 15 women later determined to have had acute HIV infection when enrolled in an oral medication group and 27 with no follow-up visit after baseline, 52 incident HIV infections occurred in the oral TDF group, 61 in the TDF/FTC group, and 60 in the oral placebo group.Effectiveness was not significant for either oral PrEP medication group; −49%% for TDF (hazard ratio 1.49; 95% CI, 0.97-2.29) and −4.4% for TDF/FTC (HR, 1.04; 95% CI, 0.73-1.49) in the modified-intent-to-treat analysis. Face-to-face interview, audio computer-assisted self-interview, and pill-count medication adherence were high in all 3 groups (84%-91%).However, among 315 participants in the random cohort of the case-cohort subset for whom quarterly plasma samples were available, tenofovir was detected, on average, in 30% of samples from women randomly assigned to TDF and in 29% of samples from women randomly assigned to TDF/FTC.No drug was detected at any quarterly visit during study participation for 58% of women in the TDF group and 50% of women in the TDF/FTC group.The percentage of samples with detectable drug was less than 40% in all study drug groups and declined throughout the study.In a multivariate analysis that adjusted for baseline confounding variables (including age, marital status), the detection of study drug was not associated with reduced risk of HIV acquisition. The number of confirmed creatinine elevations (grade not specified) observed was higher in the oral TDF/FTC group than in the oral placebo group.However, there were no significant differences between active product and placebo groups for other safety outcomes.Of women determined after enrollment to have had acute HIV infection at baseline, two women from the TDF/FTC group had virus with the M184I/V mutation associated with FTC resistance.One woman in the TDF/FTC group who acquired HIV infection after enrollment had virus with the M184I/V mutation; No participants with HIV infection had virus with a mutation associated with tenofovir resistance. In summary, although low adherence and operational issues precluded reliable conclusions regarding efficacy in 3 trials (VOICE, FEM-PrEP and the West African trial) 27 , 2 trials (Partners PrEP and TDF2) with high medication adherence have provided substantial evidence of efficacy among heterosexual men and women.All 5 trials have found PrEP to be safe for these populations. Daily oral PrEP with TDF/FTC is recommended as one HIV prevention option for heterosexually-active men and women at substantial risk of HIV acquisition because these trials present evidence of its safety and 2 present evidence of efficacy in these populations, especially when medication adherence is high. (IA). # PUBLISHED TRIAL OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG INJECTION DRUG USERS # BANGKOK TENOFOVIR STUDY (BTS) BTS 5 was a phase 3 randomized, double-blind, placebo-controlled study of the safety and efficacy of daily oral TDF for HIV prevention among 2,413 IDUs in Bangkok, Thailand.The study was conducted at drug treatment clinics; 22% of participants were receiving methadone treatment at baseline.At each monthly visit, participants could choose to receive either a 28-day supply of pills or to receive medication daily by directly-observed therapy.Study clinics (n=17) provided condoms, bleach (for cleaning injection equipment), methadone, primary medical care, and social services free of charge.Participants were followed for 4.6 years (mean) and received directly-observed therapy 87% of the time. In the modified intent-to-treat analysis (excluding 2 participants with evidence of HIV infection at enrollment), efficacy of TDF was 48.9% (95% CI, 9.6-72.2; P = .01).A post-hoc modified intent-to-treat analysis was done, removing 2 additional participants in whom HIV infection was identified within 28 days of enrollment, including only participants on directly observed therapy who met pre-established criteria for high adherence (taking a pill at least 71% of days and missing no more than two consecutive doses), and had detectable levels of tenofovir in their blood.Among this set of participants, the efficacy of TDF in plasma was associated with a 73.5% reduction in the risk for HIV acquisition (95% CI, 16.6-94.0; P = .03).Among participants in an unmatched case-control study that included the 50 persons with incident HIV infection and 282 participants at 4 clinics who remained HIV uninfected, detection of TDF in plasma was associated with a 70.0% reduction in the risk for acquiring HIV infection (95% CI, 2.3-90.6; P = .04). Rates of nausea and vomiting were higher among TDF than among placebo recipients in the first 2 months of medication but not thereafter.The rates of adverse events, deaths, or elevated creatinine did not differ significantly between the TDF and the placebo groups.Among the 49 HIV infections for which viral RNA could be amplified (of 50 incident infections and 2 infections later determined to have been present at enrollment), no virus with mutations associated with TDF resistance were identified.Among participants with HIV infection followed up for a maximum of 24 months, HIV plasma viral load was lower in the TDF than in the placebo group at the visit when HIV infection was detected (P = .01), but not thereafter (P = .10). Daily oral PrEP with TDF/FTC (or TDF alone) is recommended as one HIV prevention option for IDUs at substantial risk of HIV acquisition because this trial presents evidence of the safety and efficacy of TDF as PrEP in this population, especially when medication adherence is high. (IA) # Identifying Indications for PrEP Taking a sexual history is recommended for all adult and adolescent patients as part of ongoing primary care, but the sexual history is often deferred because of urgent care issues, provider discomfort, or anticipated patient discomfort.This deferral is common among providers of primary care 29 , STI care, 30 and HIV care . Routinely taking a sexual history is a necessary first step to identify which patients in a clinical practice are having sex with same-sex partners, which are having sex with opposite-sex partners, and what specific sexual behaviors may place them at risk for, or protect them from, HIV acquisition.The clinician can introduce this topic by stating that taking a brief sexual history is routine practice, go on to explain that the information is necessary to the provision of individually appropriate sexual health care, and close by reaffirming the confidentiality of patient information. # ASSESSING RISK OF SEXUAL HIV ACQUISITION Because offering PrEP is currently indicated for MSM at substantial risk of HIV acquisition, it is important to consider that although 76% of MSM surveyed in 2008 in 21 US cities reported a health care visit during the past year 34 , other studies reported that health care providers do not ask about, and patients often do not disclose, same-sex behaviors 35 . Box A1 contains a set of brief questions designed to identify men who are currently having sex with men and to assess a key set of sexual practices that are associated with the risk of HIV acquisition.In studies to develop scored risk indexes predictive of incident HIV infection among MSM 36,37 (see Providers' Supplement, Section 5), several critical factors were identified. BOX A1: RISK BEHAVIOR ASSESSMENT FOR MSM 36 Box A2 contains a set of brief questions designed to identify women and men who are currently having sex with opposite-sex partners (heterosexually active) and to assess a key set of sexual practices that are associated with the risk of HIV acquisition as identified both in PrEP trials and epidemiologic studies . In the past 6 months:  Have you had sex with men, women, or both? (if men or both sexes) How many men have you had sex with? How many times did you have receptive anal sex (you were the bottom) with a man who was not wearing a condom? How many of your male sex partners were HIV-positive? (if any positive) With these HIV-positive male partners, how many times did you have insertive anal sex (you were the top) without you wearing a condom? Have you used methamphetamines (such as crystal or speed)? # BOX A2: RISK BEHAVIOR ASSESSMENT FOR HETEROSEXUAL MEN AND WOMEN In addition, for all sexually active patients, clinicians may want to consider reports of diagnoses of bacterial STIs (chlamydia, syphilis, gonorrhea) during the past 6 months as evidence of sexual activity that could result in HIV exposure.For heterosexual women and men, sex without a condom (or its correct use) may also be indicated by recent pregnancy of a female patient or sexual partner of a male patient. Clinicians should also briefly screen all patients for alcohol abuse 41 (especially before sexual activity) and the use of illicit non-injection drugs (e.g., amyl nitrite, stimulants).42,43 The use of these substances may affect sexual risk behavior 44 , hepatic or renal health, or medication adherence, any of which may affect decisions about the appropriateness of prescribing PrEP medication.In addition, if substance abuse is reported, the clinician should provide referral for appropriate treatment or harm-reduction services acceptable to the patient. Lastly, clinicians should consider the epidemiologic context of the sexual practices reported by the patient.The risk of HIV acquisition is determined by both the frequency of specific sexual practices (e.g., unprotected anal intercourse) and the likelihood that a sex partner has HIV infection.The same behaviors when reported as occurring in communities and demographic populations with high HIV prevalence or occurring with partners known to have HIV infection, are more likely to result in exposure to HIV and so will indicate greater need for intensive riskreduction methods (PrEP, multisession behavioral counseling) than when they occur in a community or population with low HIV prevalence (see or /). After assessing the risk of HIV acquisition, clinicians should discuss with the patient which of several effective prevention methods (e.g., PrEP, behavioral interventions) 45 will be pursued.When supporting consistent and correct condom use is feasible and the patient is motivated to achieve it, high levels of protection against both HIV and several STIs 46,47 are afforded without the side effects or cost of medication.A clinician can support consistent condom use by providing brief clinical counseling (see Providers' Supplement, Section 7), by referring the patient to behavioral medicine or health education staff in the clinical setting, or by referring the patient to community-based or local health department counseling and support services. # In the past 6 months:  Have you had sex with men, women, or both? (if opposite sex or both sexes) How many men/women have you had sex with? How many times did you have vaginal or anal sex when neither you nor your partner wore a condom? How many of your sex partners were HIV-positive? (if any positive) With these HIV-positive partners, how many times did you have vaginal or anal sex without a condom? Reported consistent ("always") condom use is associated with an 80% reduction in HIV acquisition among heterosexual couples 48 .However, inconsistent condom use is less effective, 37,49 and studies have reported low rates of recent consistent condom use among MSM 50 and other sexually active adults 51 .Especially low rates have been reported when condom use was measured over several months rather than during most recent sex or the past 30 days 52 .Therefore, unless the patient reports confidence that consistent condom use can be achieved, additional HIV prevention methods, including the consideration of PrEP should be provided while continuing to support condom. A patient who reports that 1 or more regular sex partners is of unknown HIV status should be offered HIV testing for those partners, either in the clinician's practice or at a confidential testing site (see zip code lookup at /). Lastly, for any regular sex partner reported to be HIV-positive, clinicians should determine whether the partner is receiving antiretroviral therapy and whether a recent evaluation indicates an undetectable viral load.In addition to the known health benefits of viral load suppression, a recent clinical trial (HPTN 052 53 ) demonstrated that viral load suppression is highly, but not completely, protective against HIV transmission to a heterosexual partner (96% reduction).No similar trial has been done with MSM in HIV-discordant couples, so it is unknown how much viral load suppression reduces HIV transmission among partners who are MSM.Persons who know they have HIV infection may not be in care, may not be receiving antiretroviral therapy, may not be receiving highly effective regimens, may not be adherent to their medications, or for other reasons may not have viral loads that are associated with the least risk of transmission to an uninfected sex partner 54 . 56 substantial proportions of IDU report sharing syringes (34%) and sharing injection equipment (58%).In addition, in NHBS and epidemiologic studies conducted with IDU, most IDU report sexual behaviors that also confer risk of HIV acquisition 57 .Because of the efficacy and safety demonstrated in the PrEP trial with IDU, providing PrEP to those who report injection behaviors that place them at substantial risk of acquiring HIV infection could contribute to HIV prevention for IDU at both the individual and the population level. Although current evidence is insufficient for a recommendation that all patients be screened for injection or other illicit drug use, the US Preventive Services Task Force recommends that clinicians be alert to the signs and symptoms of illicit drug use in patients.26 Clinicians should determine whether patients who are currently using illicit drugs are in (or want to enter) behavioral, medication-assisted, or in-patient drug treatment.For persons with a history of injecting illicit drugs but who are currently not injecting, clinicians should assess the risk of relapse along with the patients' use of relapse prevention services (e.g., a drug-related behavioral support program, use of mental health services, 12-step program). Box A3 contains a set of brief questions that may help identify persons who are injecting illicit drugs, and to assess a key set of injection practices that are associated with the risk of HIV acquisition as identified in the PrEP trial with IDU 5 and in epidemiologic studies 56,58 .PrEP or other HIV prevention should be integrated with prevention and clinical care services for the many health threats IDU may face (e.g., hepatitis B and C infection, abscesses, septicemia, endocarditis, overdose) 59 .In addition, referrals for drug treatment, mental health services, and social services may be indicated 59 . # LABORATORY TESTS AND OTHER DIAGNOSTIC PROCEDURES All patients whose sexual or drug injection history indicates consideration of PrEP and who are interested in taking PrEP must undergo laboratory testing to identify those for whom this intervention would be harmful or for whom it would present specific health risks that would require close monitoring. # HIV TESTING HIV testing and the documentation of results are required to confirm that patients do not have HIV infection when they start taking PrEP medications.For patient safety, HIV testing and should be repeated at least every 3 months (before prescriptions are refilled or reissued).This requirement should be explained to patients during the discussion about whether PrEP is appropriate for them.
The Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force recommends that MSM, IDUs, patients with a sex partner who has HIV infection, and others at substantial risk of HIV acquisition undergo an HIV test at least annually or for those  Have you ever injected drugs that were not prescribed to you by a clinician? (if yes), When did you last inject unprescribed drugs? In the past 6 months, have you injected by using needles, syringes, or other drug preparation equipment that had already been used by another person? In the past 6 months, have you been in a methadone or other medication-based drug treatment program?  Adult person  Without acute or established HIV infection  Any injection of drugs not prescribed by a clinician in past 6 months AND at least one of the following  Any sharing of injection or drug preparation equipment in past 6 months  Been in a methadone, buprenorphine, or suboxone treatment program in past 6 months  Risk of sexual acquisition (also evaluate by criteria in Box B1 or B2) with additional risk factors, every 3-6.60 However, outside the context of PrEP delivery, testing is often not done as frequently as recommended.61 At a minimum, clinicians should document a negative antibody test result within the week before initiating (or reinitiating) PrEP medications. # ACUTE HIV INFECTION In the iPrEx trial, drug-resistant virus developed in 2 persons with unrecognized acute HIV infection at enrollment and for whom TDF/FTC had been dispensed.These participants had negative antibody test results before they started taking PrEP, tested positive at a later study visit, and PCR (polymerase chain reaction) on stored specimens from the initial visit detected the presence of virus.When questioned, most of the 10 acutely infected participants (8 of whom had been randomly assigned the placebo group) reported signs and symptoms consistent with a viral syndrome 2 .Both acutely infected patients to whom TDF/FTC had been dispensed had the M184V/I mutation associated with emtricitabine resistance, but not the K65R mutation associated with tenofovir resistance 2 .Among participants who were dispensed PrEP medication in the US MSM Safety Trial and in the Partners PrEP, TDF2, and VOICE trials (see Table 6), the M184V mutation, developed in several persons who were enrolled and had started taking medication with unrecognized acute HIV infection but K65R developed in only one (in the TDF2 study).However, no mutations emerged in persons who acquired infection after baseline. In the one trial with very low medication adherence that has published its resistance testing results, the emtricitabine resistance mutation, but not the K65R mutation was found in a few persons with incident infection after baseline (4 persons in the FEM-PrEP trial). PrEP is indicated for MSM, heterosexual men and women, and IDUs who report injection or sexual behaviors that place them at substantial risk of HIV acquisition.Therefore clinicians should suspect acute HIV infection in persons known to have been exposed recently (e.g., a condom broke during sex with an HIV-infected partner, relapse to injection drug use with shared injection equipment).In addition, clinicians should solicit a history of nonspecific signs or symptoms of viral infection during the preceding month or on the day of evaluation (Table 7) in all PrEP candidates with a negative or an indeterminate result on an HIV antibody test.Optional adjustment for low actual body weight 71 If the actual body weight is less than the IBW (ideal body weight) use the actual body weight for calculating the eCrCl. # Optional adjustment of high actual body weight 71 Used only if the actual body weight is 30% greater than the IBW.Otherwise, the IBW is used. # HEPATITIS SEROLOGY Sexually active adults (especially MSM), and persons who inject illicit drugs, are at risk of acquiring HBV infection 74 and hepatitis C virus (HCV) infection 75 .Vaccination against HBV is recommended for all adolescents and adults, especially for MSM 76 .Therefore, HBV and HCV infection status should be documented by screening serology before TDF/FTC is prescribed as PrEP (see Table 8).Those patients determined to be susceptible to HBV infection should be vaccinated. In addition, both TDF and FTC are active against HBV.This has 2 implications for PrEP use.First, if patients with active HBV infection stop taking these medications, liver function must be closely monitored because reactivated HBV infection can result in hepatic damage 77 .In addition, a recent study demonstrated a lower rate of incident HBV infections among HIV-infected MSM whose treatment regimens included TDF or lamivudine (closely related to FTC) than among men whose regimens did not contain these drugs (0.7 vs 6.7 infections per 100 person-years).78 # Providing PrEP # GOALS OF PREP THERAPY The ultimate goal of PrEP is to reduce the acquisition of HIV infection with its resulting morbidity, mortality, and cost to individuals and society.Therefore clinicians initiating the provision of PrEP should Prescribe medication regimens that are proven safe and effective for uninfected persons who meet recommended criteria to reduce their risk of HIV acquisition Educate patients about the medications and the regimen to maximize their safe use Provide support for medication-adherence to help patients achieve and maintain protective levels of medication in their bodies Provide HIV risk-reduction support and prevention services or service referrals to help patients minimize their exposure to HIV Provide effective contraception to women who are taking PrEP and who do not wish to become pregnant Monitor patients to detect HIV infection, medication toxicities, and levels of risk behavior in order to make indicated changes in strategies to support patients' long-term health # INDICATED MEDICATION The medication proven safe and effective, and currently approved by FDA for PrEP in healthy adults at risk of acquiring HIV infection, is the fixed-dose combination of TDF and FTC in a single daily dose (see Table 9).Therefore, TDF/FTC is the recommended medication that should be prescribed for PrEP for MSM, heterosexually active men and women, and IDU who meet recommended criteria.Because TDF alone has been proven effective in trials with IDU and heterosexually active men and women, it can be considered as an alternative regimen for these specific populations.As PrEP for MSM, TDF alone is not recommended because no trials have been done, so the efficacy of TDF alone for MSM is unknown.In addition to the safety data obtained in PrEP clinical trials, data on drug interactions and longer-term toxicities have been obtained by studying the component drugs individually for their use in treatment of HIV-infected persons.Studies have also been done in small numbers of HIVuninfected, healthy adults (see Table 10). # No data WHAT NOT TO USE No antiretroviral regimens should be used for PrEP other than a daily oral dose of TDF/FTC, or a daily dose of TDF alone as an alternative only for IDU and heterosexually active adults. Other medications and other dosing schedules have not yet been shown to be safe or effective in preventing HIV acquisition among otherwise healthy adults and are not approved by FDA for PrEP. Do not use other antiretroviral medications (e.g., 3TC), either in place of, or in addition to, TDF/FTC or TDF. Do not use other than daily dosing (e.g., intermittent, episodic , or other discontinuous dosing)  Do not provide PrEP as expedited partner therapy (i.e., do not prescribe for an uninfected person not in your care). # TIME TO ACHIEVING PROTECTION The time from initiation of daily oral doses of TDF/FTC to maximal protection against HIV infection is unknown.There is not scientific consensus on what intracellular concentrations are protective for either drug or the protective contribution of each drug in specific body tissues.It has been shown that the pharmacokinetics of TDF and FTC vary by tissue 80 . Data from exploratory pharmacokinetic studies conducted with HIV-uninfected men and women does provide preliminary data on the lead-time required to achieve steady state levels of tenofovir diphosphate (TFV-DP, the activated form of the medication) in blood (PBMCs ), rectal, and vaginal tissues 81,82 .These data suggest that maximum intracellular concentrations of TFV-DP are reached in blood after approximately 20 days of daily oral dosing, in rectal tissue at approximately 7 days, and in cervicovaginal tissues at approximately 20 days.No data are yet available about intracellular drug concentrations in penile tissues susceptible to HIV infection to inform considerations of protection for male insertive sex partners. # MANAGING SIDE EFFECTS Patients taking PrEP should be informed of side effects among HIV-uninfected participants in clinical trials (see Table 5).In these trials, side effects were uncommon and usually resolved within the first month of taking PrEP ("start-up syndrome").Clinicians should discuss the use of over-the-counter medications for headache, nausea, and flatulence should they occur.Patients should also be counseled about signs or symptoms that indicate a need for urgent evaluation (e.g., those suggesting possible acute renal injury or acute HIV infection). # CLINICAL FOLLOW-UP AND MONITORING Once PrEP is initiated, patients should return for follow-up approximately every 3 months.Clinicians may wish to see patients more frequently at the beginning of PrEP (e.g., 1 month after initiation, to assess and confirm HIV-negative test status, assess for early side effects, discuss any difficulties with medication adherence, and answer questions. All patients receiving PrEP should be seen as follows:  At least every 3 months to o Repeat HIV testing and assess for signs or symptoms of acute infection to document that patients are still HIV negative (see Figure) o Repeat pregnancy testing for women who may become pregnant o Provide a prescription or refill authorization of daily TDF/FTC for no more than 90 days (until the next HIV test) o Assess side effects, adherence, and HIV acquisition risk behaviors o Provide support for medication adherence and risk-reduction behaviors o Respond to new questions and provide any new information about PrEP use  At least every 6 months to o Monitor eCrCl If other threats to renal safety are present (e.g., hypertension, diabetes), renal function may require more frequent monitoring or may need to include additional tests (e.g., urinalysis for proteinuria) A rise in serum creatinine is not a reason to withhold treatment if eCrCl remains ≥60 ml/min. If eCrCl is declining steadily (but still ≥60 ml/min), consultation with a nephrologist or other evaluation of possible threats to renal health may be indicated.o Conduct STI testing recommended for sexually active adolescents and adults (i.e., syphilis, gonorrhea, chlamydia) 83  At least every 12 months to o Evaluate the need to continue PrEP as a component of HIV prevention OPTIONAL ASSESSMENTS # BONE HEALTH Decreases in bone mineral density (BMD) have been observed in HIV-infected persons treated with combination antiretroviral therapy (including TDF-containing regimes) 84,85 .However, it is unclear whether this 3%-4% decline would be seen in HIV-uninfected persons taking fewer antiretroviral medications for PrEP.The iPrEx trial (TDF/FTC) and the CDC PrEP safety trial in MSM (TDF) conducted serial dual-emission x-ray absorptiometry (DEXA) scans on a subset of MSM in the trials and determined that a small (~1%) decline in BMD that occurred during the first few months of PrEP either stabilized or returned to normal 20,86 .There was no increase in fragility (atraumatic) fractures over the 1-2 years of observation in these studies comparing those persons randomized to receive PrEP medication and those randomized to receive placebo. Therefore, DEXA scans or other assessments of bone health are not recommended before the initiation of PrEP or for the monitoring of persons while taking PrEP.However, any person being considered for PrEP who has a history of pathologic or fragility bone fractures or who has significant risk factors for osteoporosis should be referred for appropriate consultation and management. # THERAPEUTIC DRUG MONI TORING Similar to the limited use of therapeutic drug monitoring (TDM) in the treatment of HIV infection 66 , several factors mitigate against the routine use of TDM during PrEP.These factors include (1) a lack of established concentrations in blood associated with robust efficacy of TDF or FTC for the prevention of HIV acquisition in adults after exposure during penile-rectal or penile-vaginal intercourse 87 and (2) the limited but growing availability of clinical laboratories that perform quantitation of antiretroviral medicine concentrations under rigorous quality assurance and quality control standards. However, some clinicians may want to use TDM periodically to assess adherence to PrEP medication.If so, a key limitation should be recognized.The levels of medication in serum or plasma reflect only very recent doses, so they are not valid estimates of consistent adherence 88 .However, if medication is not detected or is detected at a very low level, support to reinforce medication adherence would be indicated. # Persons with Documented HIV Infection All persons with HIV-positive test results whether at screening or while taking TDF/FTC or TDF alone as PrEP should be provided the following services 66 . Laboratory confirmation of HIV status (see Figure )  Determination of CD4 lymphocyte count and viral load to guide therapeutic decisions  Documentation of results of genotypic HIV viral resistance testing to guide future treatment decisions  Provision of, or referral to, an experienced provider for the ongoing medical management of HIV infection  Counseling about their HIV status and steps they should take to prevent HIV transmission to others and to improve their own health  Assistance with, or referral to, the local health department for the identification of sex partners who may have been recently exposed to HIV so that they can be tested for HIV infection, considered for nonoccupational postexposure prophylaxis (nPEP), and counseled about their risk-reduction practices 89 In addition, a confidential report of new HIV infection should be provided to the local health department. # Discontinuing PrEP Patients may discontinue PrEP medication for several reasons, including personal choice, changed life situations resulting in lowered risk of HIV acquisition, intolerable toxicities, chronic nonadherence to the prescribed dosing regimen despite efforts to improve daily pill-taking, or acquisition of HIV infection. Upon discontinuation for any reason, the following should be documented in the health record:  HIV status at the time of discontinuation  Reason for PrEP discontinuation  Recent medication adherence and reported sexual risk behavior For persons with incident HIV infection, see Persons with Documented HIV Infection. For persons with active hepatitis B infection, see Special Clinical Considerations. Any person who wishes to resume taking PrEP medications after having stopped should undergo all the same pre-prescription evaluation as a person being newly prescribed PrEP.In addition, a frank discussion should clarify the changed circumstances since discontinuing medication that indicate the need to resume medication, and the commitment to, take it, # Special Clinical Considerations The patient with certain clinical conditions requires special attention and follow-up by the clinician. # WOMEN WHO BECOME PREGNANT OR BREASTFEED WHILE TAKING PREP MEDICATION Women without HIV infection who have sex partners with documented HIV infection are at substantial risk of HIV acquisition during attempts to conceive (i.e., without a condom).In addition, pregnancy is associated with an increased risk of HIV acquisition 90 .PrEP use periconception and during pregnancy by the uninfected partner may offer an additional tool to reduce the risk of sexual HIV acquisition.Both the FDA labeling information 6 and the perinatal antiretroviral treatment guidelines 91 permit this use.However, data directly related to the safety of PrEP use for a developing fetus are limited.Providers should discuss available information about potential risks and benefits of beginning or continuing PrEP during pregnancy so that an informed decision can be made. (See Clinical Providers' Supplement, Section 5 at ). In the PrEP trials with heterosexual women, medication was promptly discontinued for those who became pregnant, so the safety for exposed fetuses could not be adequately assessed.A single small study of periconception use of TDF in 46 uninfected women in HIV-discordant couples found no ill effects on the pregnancy and no HIV infections.92 Additionally, because TDF and FTC are widely used for the treatment of HIV infection and continued during pregnancies that occur, 76,77,93 The data on pregnancy outcomes in the Antiretroviral Pregnancy Registry provide no evidence of adverse effects among fetuses exposed to these medications 94 . Providers should educate HIV-discordant couples who wish to become pregnant about the potential risks and benefits of all available alternatives for safer conception 95 and if indicated make referrals for assisted reproduction therapies.Whether or not PrEP is elected, the HIVinfected partner should be prescribed effective antiretroviral therapy before conception attempts 96 : if the infected partner is male, to reduce the risk of transmission-related viral load in semen; and in both sexes, for the benefit of their own health 53 . In addition, health care providers are strongly encouraged to prospectively and anonymously submit information about any pregnancies in which PrEP is used to the Antiretroviral Pregnancy Registry at /. The safety of PrEP with TDF/FTC or TDF alone for infants exposed during lactation has not been adequately studied.However, data from studies of infants born to HIV-infected mothers and exposed to TDF or FTC through breast milk suggest limited drug exposure.93,97 Additionally, the World Health Organization has recommended the use of TDF/FTC or 3TC/efavirenz for all pregnant and breastfeeding women for the prevention of perinatal and postpartum mother-tochild transmission of HIV 98 .Therefore, providers should discuss current evidence about the potential risks and benefits of beginning or continuing PrEP during breastfeeding so that an informed decision can be made. # PATIENTS WITH CHRONIC ACTIVE HEPATITIS B VIRUS INFECTION TDF and FTC are each active against both HIV infection and HBV infection and thus may prevent the development of significant liver disease by suppressing the replication of HBV.Only TDF, however, is currently FDA-approved for this use.Therefore, in persons with substantial risk of both HIV acquisition and active HBV infection, daily doses of TDF/FTC may be especially indicated.
All persons screened for PrEP who test positive for hepatitis B surface antigen (HBsAg) should be evaluated by a clinician experienced in the treatment of HBV infection.For clinicians without this experience, co-management with an infectious disease or a hepatic disease specialist should be considered.Patients should be tested for HBV DNA by the use of a quantitative assay to determine the level of HBV replication 99 before PrEP is prescribed and every 6-12 months while taking PrEP. TDF presents a very high barrier to the development of HBV resistance.However, it is important to reinforce the need for consistent adherence to the daily doses of TDF/FTC to prevent reactivation of HBV infection with the attendant risk of hepatic injury, and to minimize the possible risk of developing TDF-resistant HBV infection 100 . If PrEP is no longer needed to prevent HIV infection, a separate determination should be made to about whether to continue TDF/FTC as a means of providing TDF to treat HBV infection.Acute flares resulting from the reactivation of HBV infection have been seen in HIV-infected persons after the cessation of TDF and other medications used to treat HBV infection.Such flares have not yet been seen in HIV-uninfected persons with chronic active HBV infection who have stopped taking TDF-containing PrEP regimens.Nonetheless, when such patients discontinue PrEP, they should continue to receive care from a clinician experienced in the management of HBV infection so that if flares occur, they can be detected promptly and treated appropriately. # PATIENTS WITH CHRONIC RENAL FAILURE HIV-uninfected patients with chronic renal failure, as evidenced by an eCrCl of <60 ml/min, should not take PrEP because the safety of TDF/FTC for such persons was not evaluated in the clinical trials.TDF is associated with modestly reduced renal function when used as part of an antiretroviral treatment regimen in persons with HIV infection (which itself can affect renal function).Because other HIV prevention options are available, the only PrEP regimen proven effective to date (TDF/FTC) and approved by FDA for PrEP is not indicated for persons with chronic renal failure.6 ADOLESCENT MINORS 101 As a part of primary health care, HIV screening should be discussed with all adolescents who are sexually active or have a history of injection drug use.Parental/guardian involvement in an adolescent's health care is often desirable but is sometimes contraindicated for the safety of the adolescent.However, laws and regulations that may be relevant for PrEP-related services (including HIV testing), such as those concerning consent, confidentiality, parental disclosure, and circumstances requiring reporting to local agencies, differ by jurisdiction 5 .Clinicians considering providing PrEP to a person under the age of legal adulthood (a minor) should be aware of local laws, regulations, and policies that may apply 102 . Although the FDA labeling information specifies PrEP indications for "adults," an age above which an adolescent is considered an adult is not provided.6 None of the completed PrEP trials have included persons under the age of 18.Therefore, clinicians should consider carefully the lack of data on safety and effectiveness of PrEP taken by persons under 18 years of age, the possibility of bone or other toxicities among youth who are still growing, and the safety evidence available when TDF/FTC is used in treatment regimens for HIV-infected youth 103 .These factors should be weighed against the potential benefit of providing PrEP for an individual adolescent at substantial risk of HIV acquisition. # NONOCCUPATIONAL POSTEXPOSURE PROPHYLAXIS Persons not receiving PrEP who seek care within 72 hours after an isolated sexual or injectionrelated HIV exposure should be evaluated for the potential need for nPEP 104 .If such exposures are not isolated, and the person is determined not to have HIV infection, clinicians should consider beginning PrEP immediately because PrEP during the first 28 days is consistent with a recommended nPEP regimen 104 .If the exposure is isolated (e.g., sexual assault, infrequent condom failure), nPEP should be prescribed, but continued antiretroviral medication is not indicated after completion of the 28-day PEP course. Persons who repeatedly seek nPEP should be evaluated for possible PrEP use after confirming they have not acquired HIV infection 105 .Because HIV infection has been reported in association with exposures soon after an nPEP course 98 , daily PrEP may be more protective than repeated episodes of nPEP. # Improving Medication Adherence Data from the published studies of daily oral PrEP indicate that medication adherence is critical to achieving the maximum prevention benefit (see Table 4) and reducing the risk of selecting for a drug-resistant virus if non-adherence leads to HIV acquisition 106,107 .Three additional studies reinforce the need to prescribe, and support adherence to uninterrupted daily doses of TDF/FTC. A study of the pharmacokinetics of directly observed TDF dosing in MSM in the STRAND trial found that the intracellular levels of the active form of TDF (tenofovir diphosphate), when applied to the drug detection-efficacy statistical model with iPrEx participants, corresponded to an HIV risk reduction efficacy of 99% for 7 doses per week, 96% for 4 doses per week, and 76% for 2 doses per week 87 .This finding adds to the evidence that despite some "forgiveness" for occasional missed doses, a high level of prevention efficacy requires a high level of adherence to daily medication. A pilot study of daily TDF/FTC as PrEP with young MSM was stopped when the iPrEx trial results were reported.108 Among the 68 men enrolled (mean age, 20 years; 53% African American; 40% Hispanic/Latino) plasma specimens were tested to objectively measure medication adherence.At week 4, 63% had detectable levels of tenofovir, but at week 24, only 20% had detectable levels of tenofovir. In addition, a study with MSM and commercial sex workers in Kenya evaluated adherence to daily, fixed-interval (Mondays and Fridays), and coitally-timed (single post-coital) TDF/FTC dosing schedules by the use of pill bottles with caps monitored by an electronic medication event monitoring system (MEMS) and monthly interviews about sexual behavior 12 .Among the 67 men and 5 women in this study, 83% adhered to daily dosing, 55% to fixed-interval dosing, and 26% to post-coital dosing regimens.These findings suggest that adherence is better with daily dosing, as currently recommended, than with non-daily regimens (not yet proven effective as PrEP).These data confirm that medication education and adherence counseling (also called medication self-management) will need to be provided to support daily PrEP use. A recent review of the antiretroviral treatment adherence studies over the past 15 years and adherence data from the completed PrEP trials suggests various approaches to effectively support medication adherence 109 .These approaches include educating patients about their medications; helping them anticipate and manage side effects; helping them establish dosing routines that mesh with their work and social schedules; providing reminder systems and tools; addressing financial, substance abuse, or mental health needs that may impede adherence; and facilitating social support. Although many published articles address antiretroviral medication adherence among persons being treated for HIV infection, these findings may be only partially applicable to PrEP users.HIV treatment regimens include more than 2 drugs (commonly including more than 1 pill per day), resulting in an increased pill burden, and the possibility of side effects and toxicities with 3 or more drugs may occur that would not occur with TDF/FTC alone.The motivations of persons being treated for HIV infection and persons trying to prevent HIV infection may differ.Because PrEP will be used in otherwise healthy adults, studies of the use of medications in asymptomatic adults for the prevention of potential serious future health outcomes may also be informative for enhancing adherence to PrEP medications.The most cost-effective interventions for improving adherence to antihypertensive and lipid-lowering medications were initiated soon after the patients started taking medication and involved personalized, regularly scheduled education and symptom management (patients were aware that adherence was being monitored) 110 .Patients with chronic diseases reported that the most important factors in adherence to medications were incorporating medication into their daily routines, knowing that the medications work, believing that the benefits outweigh the risks, knowing how to manage side effects, and low out-of pocket costs.111,112 When initiating a PrEP regimen, clinicians must educate patients so that they understand clearly how to take their medications (i.e., when to take them, how many pills to take at each dose) and what to do if they experience problems (e.g., what constitutes a missed dose , what to do if they miss a dose).Patients should be told to take a single missed dose as soon as they remember it, unless it is almost time for the next dose.If it is almost time for the next dose, patients should skip the missed dose and continue with the regular dosing schedule. Side effects can lead to non-adherence, so clinicians need a plan for addressing them.Clinicians should tell patients about the most common side effects and should work with patients to develop a specific plan for handling them, including the use of specific over-the-counter medications that can mitigate symptoms 113 .The importance of using condoms during sex, especially for patients who decide to stop taking their medications, should be reinforced. # Box D: Key Components of Medication Adherence Counseling Using a broad array of a health care professionals (e.g., physicians, nurses, case-managers, physician assistants, clinic-based and community pharmacists) that work together on a health care team to influence and reinforce adherence instructions 114 significantly improves medication adherence and may alleviate the time constraints of individual providers.115,116 This broad-team approach may also provide a larger number of providers to counsel patients about selfmanagement of behavioral risks. For additional information on adherence counseling, see the Clinical Providers' Supplement, Section 6 at . # Reducing HIV Risk Behaviors The adoption and the maintenance of safer behaviors (sexual, injection, and other substance abuse) are critical for the lifelong prevention of HIV infection and are important for the clinical management of persons prescribed PrEP. 117 have reduced STI incidence in a general clinic population.However, they take a general approach, so they do not allow tailoring to the sexual risk-reduction needs of individual patients (e.g., as partners change, PrEP is initiated or discontinued). # Establish trust and bidirectional communication Interactive, client-centered counseling (in which content is tailored to a patient's sexual risk behaviors and the situations in which risks occur), in conjunction with goal-setting strategies is effective in HIV prevention 105, .An example of this method is Project Respect: although this counseling protocol alone did not reduce HIV incidence significantly 20-minute clinical counseling sessions to develop and review patient-specific, incremental risk-reduction plans led to reduced incidence of STIs in a heterosexual population, 121 .Project Aware included MSM and heterosexuals attending STD clinics and provided a single brief counseling session (using the Respect-2 protocol) while conducting rapid HIV testing.There was no reduction in the incidence of STIs attributed to counseling 122 .However, in the context of PrEP delivery, brief, repeated counseling sessions can take advantage of multiple visits for follow-up care 123 while addressing the limited time available for individual visits 124 and the multiple prevention 115,116 and treatment topics that busy practitioners need to address. Reducing or eliminating injection risk practices can be achieved by providing access to drug treatment and relapse prevention services (e.g., methadone, buprenorphine for opiate users) for persons who are willing to participate 125 .For persons not able (e.g., on a waiting list or lacking insurance) or not motivated to engage in drug treatment, providing access to unused injection equipment through syringe service programs (where available), prescriptions for syringes or purchase from pharmacies without a prescription (where legal) can reduce HIV exposure.In addition, providing or referring for cognitive or behavioral counseling and any indicated mental health or social services may help reduce risky injection practices.See the Substance Abuse Treatment and Mental Health Treatment Locators at /. For additional information on risk reduction interventions, see Clinical Providers' Supplement, Section 7 at . # Box E: Key Components of Behavioral Risk-Reduction Counseling # Financial Case-Management Issues for PrEP One critical component in providing PrEP medications and related clinical and counseling services is identifying insurance and other reimbursement sources.Although some commercial insurance and employee benefits programs have defined policies for the coverage of PrEP, others have not yet done so.Similarly, public insurance sources vary in their coverage policy. For patients who do not have health insurance, whose insurance does not cover PrEP medication, and whose personal resources are inadequate to pay out-of-pocket, Gilead Sciences has established a PrEP medication assistance program.In addition to providing Truvada to providers for eligible patients and access to free HIV testing, the program provides co-pay assistance for medical care visits and free condoms to patients on request 126 .Providers may obtain applications for their patients at /. # Decision Support, Training and Technical Assistance Decision support systems (electronic and paper), flow sheets, checklists (see Clinical Providers' Supplement, Section 1 for a PrEP provider/patient checklist at ), feedback reminders, and involvement of nurse clinicians and pharmacists will be helpful in managing the many steps indicated for the safe use of PrEP and to increase the likelihood that patients will follow them.Often these systems are locally developed but may become available from various sources including training centers and Web sites funded by government agencies; professional associations, or interested private companies.Examples include downloadable applications (widgets) to support the delivery of nPEP or locate nearby sites for confidential HIV tests (); and confidential commercial services to electronically monitor # Related DHHS Guidelines This document is consistent with several other guidelines from several DHHS agencies related to sexual health, HIV prevention, and the use of antiretroviral medications.Clinicians should refer to these other documents for detailed guidance in their respective areas of care. # III.Expert opinion The quality of scientific evidence ratings in Table 2 are based on the GRADE rating system.28 # Appendices # APPENDIX 1 HIV TEST TABLES The working groups and expert panels listed here were convened by teleconference before trial results were available (2009-2010) and some were reconvened after each trial results for each population group was published.As technical experts, prevention partners, and key stakeholders, they were asked to assist us to identify relevant scientific/medical literature and share thoughts on topics that would inform the development of possible future guidelines for PrEP use in the US.They did not participate in the writing of these guidelines.No financial disclosures were sought.See Providers' Supplement section 10 for a description of the criteria use for constitution of the working groups.Institutional associations listed for participants are those at the time of the group discussions and may have changed since.
This report is being published as a courtesy to both the National Association of State Public Health Veterinarians, Inc., and to the MMWR readership.Its publication does not imply endorsement by CDC.# Copies also can be accessed at the CDC website at and the American Veterinary Medical Association website at . # Compendium of Measures To Control Chlamydia psittaci Infection Among Humans (Psittacosis) and Pet Birds (Avian Chlamydiosis), 2000 # INTRODUCTION Chlamydia psittaci is a bacterium that can be transmitted from pet birds to humans.In humans, the resulting infection is referred to as psittacosis (also known as parrot fever and ornithosis).Psittacosis typically causes influenza-like symptoms and can lead to severe pneumonia and nonrespiratory health problems.With appropriate treatment, the disease is rarely fatal.From 1988 through 1998, CDC received reports of 813 cases of psittacosis (1 ), which is an underrepresentation of the actual number of cases because psittacosis is difficult to diagnose and cases often go unreported.During the 1980s, approximately 70% of the psittacosis cases with a known source of infection resulted from exposure to pet birds.The largest group affected (43%) included bird fanciers and owners of pet birds.Pet shop employees accounted for an additional 10% of cases.Other persons at risk include pigeon fanciers and persons whose occupation places them at risk for exposure (e.g., employees in poultry slaughtering and processing plants, veterinarians, veterinary technicians, laboratory workers, workers in avian quarantine stations, farmers, wildlife rehabilitators, and zoo workers).Because human infection can result from brief, passing exposure to infected birds or their contaminated droppings, persons with no identified leisure-time or occupational risk can become infected. In this report, C. psittaci infection in birds is referred to as avian chlamydiosis (AC).C. psittaci has been isolated from approximately 100 bird species but is most commonly identified in psittacine (parrot-type) birds, especially cockatiels and parakeets.Among caged, nonpsittacine birds, infection with C. psittaci occurs most frequently in pigeons, doves, and mynah birds.AC is less frequently diagnosed in canaries and finches. The recommendations in this compendium provide standardized procedures for controlling AC in the pet bird population, an essential step in efforts to control psittacosis among humans.Development of and participation in aviary and pet shop accreditation programs is encouraged.This compendium is intended to guide public health officials, physicians, veterinarians, the pet bird industry, and others concerned with the control of C. psittaci infection and the protection of public health. # PART I. INFECTION AMONG HUMANS (PSITTACOSIS) Transmission Because several diseases affecting humans can be caused by other species of Chlamydia, the disease resulting from the infection of humans with C. psittaci is referred to as psittacosis.Most C. psittaci infections in humans result from exposure to pet psittacine birds.However, transmission has been documented from free-ranging birds, including doves, pigeons, birds of prey, and shore birds.Infection with C. psittaci usually occurs when a person inhales the organism, which has been aerosolized from dried feces or respiratory secretions of infected birds.Other means of exposure include mouth-to-beak contact and the handling of infected birds' plumage and tissues.Even brief exposures can lead to symptomatic infection; therefore, some patients with psittacosis might not recall or report having any contact with birds. Mammals occasionally transmit C. psittaci to humans.Certain strains of C. psittaci infect sheep, goats, and cattle, causing chronic infection of the reproductive tract, placental insufficiency, and abortion in these animals.These strains of C. psittaci are transmitted to persons when they are exposed to the birth fluids and placentas of infected animals.Another strain of C. psittaci, feline keratoconjunctivitis agent, typically causes rhinitis and conjunctivitis in cats.Transmission of this strain from cats to humans rarely occurs. Person-to-person transmission has been suggested but not proven.Standard infection-control precautions are sufficient for patients with psittacosis, and specific isolation procedures (e.g., private room, negative pressure air flow, and masks) are not indicated. # Clinical Signs and Symptoms The onset of illness typically follows an incubation period of 5-14 days, but longer periods have been reported.The severity of this disease ranges from inapparent illness to systemic illness with severe pneumonia.Before antimicrobial agents were available, 15%-20% of persons with C. psittaci infection died.However, <1% of properly treated patients now die as a result of the infection. Persons with symptomatic infection typically have abrupt onset of fever, chills, headache, malaise, and myalgia.They usually develop a nonproductive cough that can be accompanied by breathing difficulty and chest tightness.A pulse-temperature dissociation (fever without elevated pulse), enlarged spleen, and rash are sometimes observed and are suggestive of psittacosis in patients with community-acquired pneumonia.Auscultatory findings can underestimate the extent of pulmonary involvement.Radiographic findings include lobar or interstitial infiltrates.The differen-tial diagnosis of psittacosis-related pneumonia includes infection with Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species, and respiratory viruses such as influenza.C. psittaci can affect organ systems other than the respiratory tract and result in endocarditis, myocarditis, hepatitis, arthritis, keratoconjunctivitis, and encephalitis.Severe illness with respiratory failure, thrombocytopenia, hepatitis, and fetal death has been reported among pregnant women. # Case Definitions In 1997, CDC and the Council of State and Territorial Epidemiologists established case definitions for confirmed and probable psittacosis for epidemiologic purposes (2 ).These definitions should not be used as the sole criteria for establishing clinical diagnoses.A patient is considered to have a confirmed case of psittacosis if clinical illness is compatible with psittacosis and the case is laboratory confirmed by one of three methods: a) C. psittaci is cultured from respiratory secretions; b) antibody against C. psittaci is increased by fourfold or greater (to a reciprocal titer of 32 between paired acute-and convalescent-phase serum specimens collected at least 2 weeks apart) as demonstrated by complement fixation (CF) or microimmunofluorescence (MIF); or c) immunoglobulin M antibody is detected against C. psittaci by MIF (to a reciprocal titer of 16).A patient is considered to have a probable case of psittacosis if clinical illness is compatible with psittacosis and a) the patient is epidemiologically linked to a confirmed human case of psittacosis or b) a single antibody titer of 32, demonstrated by CF or MIF, is present in at least one serum specimen obtained after onset of symptoms. # Diagnosis Most diagnoses are established by using serologic methods in which paired sera are tested for chlamydial antibodies by CF test.However, because chlamydial CF antibody is not species-specific, high CF titers also can result from C. pneumoniae and C. trachomatis infections.Acute-phase serum specimens should be obtained as soon as possible after onset of symptoms, and convalescent-phase serum specimens should be obtained 2 weeks after onset of symptoms.Because antibiotic treatment can delay or diminish the antibody response, a third serum sample might help confirm the diagnosis.All sera should be tested simultaneously at the same laboratory.If the patient's epidemiologic and clinical history indicate a possible diagnosis of psittacosis, MIF and polymerase chain reaction (PCR) assays can be used to distinguish C. psittaci infection from infection with other chlamydial species.The infectious agent also can be isolated from the patient's sputum, pleural fluid, or clotted blood during acute illness and before treatment with antimicrobial agents; however, culture of C. psittaci is performed by few laboratories because of technical difficulty and safety concerns. # Laboratories that Test Human Specimens for C. psittaci Information about laboratory testing is available from most state public health laboratories.Few commercial laboratories have the capability to differentiate Chlamydia species.The following laboratories (Table 1) accept human specimens to confirm C. psittaci.Other sources might be available. # Treatment Tetracyclines are the drugs of choice (3 ).Most patients respond to oral therapy (100 mg of doxycycline administered twice a day or 500 mg of tetracycline hydrochloride administered four times a day).For initial treatment of severely ill patients, doxycycline hyclate can be administered intravenously at a dosage of 4.4 mg/kg (2 mg/lb) body weight per day divided into two infusions per day (up to 100 mg per dose).Remission of symptoms usually is evident within 48-72 hours.However, relapse can occur, and treatment must continue for at least 10-14 days after fever abates.Although its in vivo efficacy has not been determined, erythromycin probably is the best alternative agent in patients for whom tetracycline is contraindicated (e.g., children aged <9 years and pregnant women). # PART II.INFECTION AMONG BIRDS (AVIAN CHLAMYDIOSIS) Transmission C. psittaci is excreted in the feces and nasal discharges of infected birds.The organism is resistant to drying and can remain infectious for several months.If infected, birds can appear healthy and shed the organism intermittently.Shedding can be activated by stress factors, including shipping, crowding, chilling, and breeding (3 ). # Clinical Signs The time between exposure to C. psittaci and onset of illness ranges from 3 days to several weeks.However, active disease can appear years after exposure.Whether the bird exhibits acute or chronic signs of illness or dies depends on the species of bird, virulence of the strain, infectious dose, stress factors, age, and extent of treatment or prophylaxis (4 ).Signs of AC include lethargy, anorexia, and ruffled feathers, similar to signs of other systemic illnesses.Other signs include serous or mucopurulent ocular or nasal discharge, diarrhea, and excretion of green to yellow-green urates.Anorectic birds can produce sparse, dark green droppings, followed by emaciation, dehydration, and death. # Case Definitions A confirmed case of AC is defined on the basis of at least one of the following laboratory results: a) isolation of C. psittaci from a clinical specimen, b) identification of chlamydial antigen by immunofluorescence (fluorescent antibody ) of the bird's tissues, c) a greater than fourfold change in serologic titer in two specimens from the bird obtained at least 2 weeks apart and assayed simultaneously at the same laboratory, or d) identification of C. psittaci within macrophages in smears stained with Gimenez or Macchiavellos stain or sections of the bird's tissues. A probable case of AC is defined as compatible illness and at least one of the following laboratory results: a) a single high serologic titer in one or more specimens obtained after the onset of signs or b) the presence of C. psittaci antigen (identified by enzyme-linked immunosorbent assay , PCR, or FA) in feces, a cloacal swab, or respiratory or ocular exudates. A suspected case of AC is defined as a) compatible illness that is epidemiologically linked to another case in a human or bird but that is not laboratory confirmed, b) a subclinical infection with a single high serologic titer or detection of chlamydial antigen, c) compatible illness with positive results from a nonstandardized test or a new investigational test, or d) compatible illness that is responsive to appropriate therapy. # Diagnosis Several diagnostic methods are available for identifying AC in birds (Appendix A). # Treatment Treatment should be supervised by a licensed veterinarian (Appendix B). # PART III.RECOMMENDATIONS AND REQUIREMENTS # Recommendations for Controlling Infection Among Humans and Birds To prevent transmission of C. psittaci to persons and birds, the following control measures are recommended: - Protect persons at risk.Inform all persons in contact with infected birds about the nature of the disease.Instruct them to wear protective clothing, gloves, a disposable surgical cap, and a respirator with an N95 rating or a higher-efficiency respirator when cleaning cages or handling infected birds.Surgical masks might not be effective in preventing transmission of C. psittaci.When necropsies are performed on potentially infected birds, wet the carcass with detergent and water to prevent aerosolization of infectious particles and work under a biological safety cabinet (or equivalent). - Maintain accurate records of all bird-related transactions to aid in identifying sources of infected birds and potentially exposed persons.Records should include the date of purchase, species of birds purchased, source of birds, and any identified illnesses or deaths among birds.In addition, the seller should record the name, address, and telephone number of the customer and the band numbers if applicable. - Avoid purchasing or selling birds that have signs of AC.Signs include ocular or nasal discharge, diarrhea, or low body weight. - Isolate newly acquired birds.Isolate the birds -including those that have been to shows, exhibitions, fairs, and other events -for 30-45 days, and test or prophylactically treat them before adding them to a group. - Test birds before they are to be boarded or sold on consignment.House them in a room separate from other birds. - Practice preventive husbandry.Position cages to prevent the transfer of fecal matter, feathers, food, and other materials from one cage to another.Do not stack cages, and be sure to use solid-sided cages or barriers if cages are adjoining.The bottom of the cage should be made of a wire mesh.Litter that will not produce dust (e.g., newspapers) should be placed underneath the mesh.Clean all cages, food bowls, and water bowls daily.Soiled bowls should be emptied, cleaned with soap and water, rinsed, placed in a disinfectant solution, and rinsed again before reuse.Between occupancies by different birds, cages should be thoroughly scrubbed with soap and water, disinfected, and rinsed in clean, running water.Exhaust ventilation should be sufficient to prevent accumulation of aerosols. - Prevent the spread of infection.Isolate birds requiring treatment.Rooms and cages where infected birds were housed should be cleaned immediately and disinfected thoroughly.When the cage is being cleaned, transfer the bird to a clean cage.Thoroughly scrub the soiled cage with a detergent to remove all fecal debris, rinse the cage, disinfect it (allowing at least 5 minutes of contact with the disinfectant), and rerinse the cage to remove the disinfectant.Discard all items that cannot be adequately disinfected (e.g., wooden perches, ropes, nest material, and litter).Minimize the circulation of feathers and dust by wetmopping the floor frequently with disinfectants and preventing air currents and drafts within the area.Reduce contamination from dust by spraying the floor with a disinfectant or water before sweeping it.Do not use a vacuum cleaner, as it can aerosolize infectious particles.Frequently remove waste material from the cage (after moistening the material), and burn or double-bag the waste for disposal.Care for healthy birds before handling isolated or sick birds. - Use disinfection measures.C. psittaci is susceptible to most disinfectants and detergents as well as heat; however, it is resistant to acid and alkali.A 1:1,000 dilution of quaternary ammonium compounds (e.g., Roccal ® or Zephiran ® ) is effective, as is 70% isopropyl alcohol, 1% Lysol ® , 1:100 dilution of household bleach (i.e., 2.5 tablespoons per gallon), or chlorophenols.Many disinfectants are respiratory irritants and should be used in a well-ventilated area.Avoid mixing disinfectants with any other product. # Recommendations for Treating and Caring for Infected Birds All birds with confirmed or probable AC should be isolated and treated, preferably under the supervision of a veterinarian (Appendix B).Birds with suspected AC or birds previously exposed to AC should be isolated and retested or treated.Because treated birds can be reinfected, they should not be exposed to untreated birds or other potential sources of infection.To prevent reinfection, contaminated aviaries should be thoroughly cleaned and sanitized.No AC vaccines are available. The following general recommendations should be followed when treating and caring for birds with confirmed, probable, or suspected cases of AC: - Protect birds from undue stress (e.g., chilling or shipping), poor husbandry, and malnutrition.These problems reduce the effectiveness of treatment and promote the development of secondary infections with other bacteria or yeast. - Observe the birds daily, and weigh them every 3-7 days.If the birds are not maintaining weight, have them reevaluated by a veterinarian. - Avoid high dietary concentrations of calcium and other divalent cations because they inhibit the absorption of tetracyclines.Remove oyster shell, mineral blocks, and cuttlebone. - Isolate birds that are to be treated in clean, uncrowded cages. - Clean up all spilled food promptly; wash food and water containers daily. - Provide fresh water and appropriate vitamins daily. - Continue medication for the full treatment period to avoid relapses.Birds can appear clinically improved and have reduced chlamydial shedding after 1 week. # Responsibilities of Physicians and Veterinarians Persons exposed to birds with AC should seek medical attention if they develop influenza-like symptoms or other respiratory illness.The physician should collect specimens for laboratory analysis (see Part I) and initiate early and specific treatment for psittacosis.Most states require physicians to report cases of psittacosis to the appropriate state or local health authorities.Timely diagnosis and reporting can help identify the source of infection and control the spread of disease.Local and state authorities may conduct epidemiologic investigations and institute additional disease control measures (see Local and State Epidemiologic Investigations).Birds that are suspected sources of human infection should be referred to veterinarians for evaluation and treatment. Veterinarians should be aware that AC is not a rare disease among pet birds.They should consider a diagnosis of AC for any lethargic bird that has nonspecific signs of illness, especially if the bird was purchased recently.If AC is suspected, the veterinarian should submit appropriate laboratory specimens to confirm the diagnosis.Laboratories and attending veterinarians should follow local and state regulations or guidelines regarding case reporting.Veterinarians should work closely with authorities on investigations and inform clients that infected birds should be isolated and treated.In addition, they should educate clients about the public health hazard posed by AC and the appropriate precautions that should be taken to avoid the risk for transmission. # Quarantine of Birds The appropriate animal and public health authorities may issue a quarantine for all affected and susceptible birds on a premises where C. psittaci infection has been identified.The purpose of imposing a quarantine is to prevent further disease transmission.Reasonable options should be made available to the owners and operators of pet stores.
For example, with the approval of state or local authorities, the owner of quarantined birds may choose to a) treat the birds in a separate quarantine area to prevent exposure to the public and other birds, b) sell the birds if they have completed at least 7 days of treatment, provided that the new owner agrees in writing to continue the quarantine and treatment and is informed of the disease hazards, or c) euthanize the infected birds.After completion of the treatment or removal of the birds, a quarantine can be lifted when the infected premises are thoroughly cleaned and disinfected.The area can then be restocked with birds. # Bird Importation Regulations The Veterinary Services of the Animal and Plant Health Inspection Service, U.S. Department of Agriculture (USDA), regulates the importation of pet birds to ensure that exotic poultry diseases are not introduced into the United States.These regulations are set forth in the Code of Federal Regulations, Title 9, Chapter 1 (5 ).Current minimum treatment protocols under these regulations are not always sufficient to clear AC from all birds.Illegally smuggled birds are also a source of new AC infection to domestic flocks.In general, current USDA regulations regarding the importation of birds include the following requirements: - Before shipping the birds, the importer must obtain an import permit from the USDA and a health certificate issued and/or endorsed by a veterinarian of the national government of the exporting country. - A USDA veterinary inspection must be conducted at the first port of entry in the United States and a quarantine be imposed for a minimum of 30 days at a USDAapproved facility to determine whether the birds are free of evidence of communicable diseases of poultry.In addition, the birds must be tested to ensure they are free of exotic Newcastle disease and pathogenic avian influenza. - During the 30-day U.S. quarantine, psittacine birds must receive a balanced, medicated feed ration containing >1% chlortetracycline (CTC) with <0.7% calcium for the entire quarantine period as a precautionary measure against AC.The USDA recommends that importers continue CTC prophylactic treatment of psittacine birds for an additional 15 days (i.e., for 45 continuous days). # Local and State Epidemiologic Investigations Public health or animal health authorities at the local or state level might need to conduct epidemiologic investigations to help control the transmission of C. psittaci to humans and birds.An epidemiologic investigation should be initiated if a) a bird with confirmed or probable AC was procured from a pet store, breeder, or dealer within 60 days of the onset of signs of illness, b) a person has confirmed or probable psittacosis, or c) several suspect avian cases have been identified from the same source.Other situations can be investigated at the discretion of the appropriate local or state public health department or animal health authorities. Investigations involving recently purchased birds should include a visit to the site where the infected bird is located and identification of the location where the bird was originally procured (e.g., pet shop, dealer, breeder, or quarantine station).During such investigations, authorities should consider documenting the number and types of birds involved, the health status of potentially affected persons and birds, locations of facilities where birds were housed, relevant ventilation-related factors, and any treatment protocol.Examination of sales records for other birds that had contact with the infected bird may be considered.To help identify multistate outbreaks of C. psittaci infection, local and state authorities should report suspected outbreaks to the Respiratory Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC, telephone (404) 639-2215. # METHODS FOR DIAGNOSING AVIAN CHLAMYDIOSIS # Pathologic Findings In birds that have avian chlamydiosis (AC), cloudy air sacs and an enlarged liver and spleen usually are observed, but no specific gross lesion is pathognomonic.The chromatic or immunologic staining of tissue-impression smears can be used to identify organisms. # Culture Technique Isolation of the etiologic agent, Chlamydia psittaci, from the bird's spleen, liver, air sacs, pericardium, heart, or intestines is the optimal means for verifying the diagnosis.Chlamydia species are obligate intracellular bacteria that must be isolated in tissue culture, mice, or chick embryos.Specialized laboratory facilities and training are necessary for reliable identification of chlamydial isolates and adequate protection of microbiologists.Consequently, few laboratories perform chlamydial cultures. In live birds, depending on which clinical signs they exhibit, combined choanal and cloacal swab specimens should be collected, refrigerated, and sent to the laboratory packed in ice but not frozen.The proper handling of samples is critical for maintaining the viability of organisms for culture, and a special transport medium is required.The diagnostic laboratory should be contacted for specific procedures required for collection and submission of specimens. Live birds being screened for C. psittaci might not shed the microorganism daily.Therefore, to reduce laboratory costs, serial specimens should be collected for 3-5 consecutive days and pooled before being cultured.Tissue samples from the bird's liver and spleen are the preferred necropsy specimens for isolation of C. psittaci.Use of culture is recommended to avoid limitations associated with other tests. # Tests for Antibody A positive serologic test result is evidence that the bird was infected by C. psittaci at some point, but it might not indicate that the bird has an active infection.False-negative results can occur for birds that have acute infection when they are sampled before seroconversion.Treatment with an antimicrobial agent can diminish the antibody response. A single testing method might not be adequate because of the diversity of reactions with immunoglobulins from the various avian species.Therefore, use of a combination of antibody-and antigen-detection methods is recommended, particularly when only one bird is tested.When specimens are obtained from a single bird, serologic testing is most useful when a) signs of disease and the history of the flock or aviary are considered and b) serologic results are compared with the white blood cell counts and liverenzyme activities.A greater than fourfold increase in titer of paired samples or a combination of a titer and antigen identification is needed to confirm a diagnosis of AC.Some of the advantages and disadvantages of two serologic tests for antibodies are described in the following sections. # Direct Complement Fixation (CF) Direct CF is more sensitive than agglutination methods.False-negative results are possible in specimens from small psittacine birds (e.g., budgerigars, young African grey parrots, and lovebirds).High titers can persist after treatment and complicate interpretation of subsequent tests.Modified direct CF is more sensitive than direct CF. # Elementary-Body Agglutination (EBA) EBA is commercially available and can detect early infection.Titers >10 in budgerigars, cockatiels, and lovebirds and titers >20 in larger birds are frequently seen in cases of recent infection.However, elevated titers can persist after treatment is completed. # Tests for Antigen Enzyme-Linked Immunosorbent Assay (ELISA) ELISA tests (e.g., QuickView ® ) were originally developed for identification of Chlamydia trachomatis in humans.The exact sensitivity and specificity of these tests for identifying C. psittaci are not known.They are now used to identify C. psittaci in birds.These tests give rapid results and do not require live, viable organisms; however, falsepositive results from cross-reacting antigens can occur.False-negative results can occur if insufficient antigen is present.As with all nonculture tests, the results must be evaluated in conjunction with clinical findings.If a bird has a positive ELISA result but is clinically healthy, the veterinarian should attempt to verify that the bird is shedding antigen through isolation of the organism.When a clinically ill bird has a negative ELISA result, a diagnosis of AC cannot be excluded without further testing (e.g., culture, serologic testing, or polymerase chain reaction). # Immunofluorescent Antibody Tests (IFA) Monoclonal or polyclonal antibodies, fluorescein-staining techniques, and fluorescent microscopy are used to identify the organism in impression smears or other specimens.These tests have similar advantages and disadvantages as ELISA. # Polymerase Chain Reaction (PCR) Numerous laboratories offer diagnostic testing using PCR technology.The PCR test promises to be sensitive and specific for detection of target DNA sequences in collected specimens (e.g., choanal and cloacal swabs, blood).Results from tests that have not been validated can be difficult to interpret. # Additional Tests Additional diagnostic techniques are in use or under development.Readers are encouraged to research peer-reviewed reports on such tests before use. Although these treatment protocols are usually successful, knowledge is evolving and no protocol assures safe treatment or complete elimination of infection.Therefore, treatment for avian chlamydiosis (AC) should be supervised by a licensed veterinarian.In quarantine situations, compliance might be easiest to monitor when treatment is provided by medicated feed.All birds with AC should be treated for 45 days, except as noted in the following sections. # Medicated Feed Medicated feed should be the only food provided to the birds during the entire treatment.Birds' acceptance of medicated feed is variable.Thus, food consumption should be monitored.Acceptance can be enhanced by first adapting the birds to a similar, nonmedicated diet.Treatment begins when the birds accept the medicated feed as the sole food in their diet.The following options are available: q Medicated mash diets (i.e., >1% chlortetracycline with <0.7% calcium) prepared with corn, rice, and hen's scratch can be used. - Pellets and extruded products containing 1% CTC can be used.They are available and appropriate for use with most pet birds.Select a pellet size appropriate for the size of bird being treated. - A special diet might be necessary for lories and lorikeets, which feed on nectar and fruit in the wild. # Medicated Water Limited pharmacological studies indicate that dosages of 400 mg doxycycline hyclate/liter of water in cockatiels and 400-600 mg/liter of water in African grey parrots, blue-fronted Amazon parrots, and Goffin's cockatoos will maintain therapeutic concentrations (Keven Flammer, North Carolina State University, unpublished data, 2000).Research data are lacking for other species, but empiric use of 400-mg/liter of water has been successful for many psittacine birds (excluding budgerigars).Drug toxicity can occur when using this regimen, so an experienced avian veterinarian should monitor birds during treatment.Signs of toxicity include general signs of illness (depression, inactivity, decreased appetite), green or yellow stained urine, and altered hepatic tests (elevated aspartate aminotransferase , lactate dehydrogenase , and bile acids).If toxicity occurs, medication should be immediately stopped and supportive care provided until the bird recovers.Treatment with a different regimen can be started at a later date. # Oral Doxycycline Doxycycline is the drug of choice for oral treatment; either the monohydrate or calcium-syrup formulations can be used.Dosage recommendations are as follows: 40-50 mg/kg body weight by mouth once a day for cockatiels, Senegal parrots, and bluefronted and orange-winged Amazon parrots; and 25 mg/kg body weight by mouth once a day for African grey parrots, Goffin's cockatoos, blue and gold macaws, and greenwinged macaws.Precise dosages cannot be extrapolated for other species; however, 25-30 mg/kg body weight administered by mouth once a day is the recommended starting dosage for cockatoos and macaws, and 25-50 mg/kg by mouth once a day is recommended for other psittacine species.If the bird regurgitates the drug, another treatment method should be used. # Injectable Doxycycline Intramuscular (IM) injection into the pectoral muscle is often the easiest method of treatment, but not all injectable doxycycline formulations are suitable for IM injection.All available formulations can cause irritation at the injection site.The Vibrovenos® formulation (Pfizer Laboratories, London) is available in Europe and is effective if administered at doses of 75-100 mg/kg body weight IM every 5-7 days for the first 4 weeks and subsequently every 5 days for the duration of treatment.The injectable hyclate formulation labeled for intravenous (IV) use in humans can be used IV in birds.This formulation is not suitable for IM use because severe tissue reactions will occur at the site of injection. # Injectable Oxytetracycline Limited information exists for the use of an injectable, long-acting oxytetracycline product (LA-200®; Pfizer Laboratories, Exton, Pennsylvania).Current dosage recommendations are as follows: subcutaneous injection of 75 mg/kg body weight every 3 days in Goffin's cockatoos, blue-fronted and orange-winged Amazon parrots, and blue and gold macaws.This dosage might be suitable for but has not been tested on other species.This product causes irritation at the site of injection and is best used to initiate treatment in ill birds or those that are reluctant to eat.After stabilization with oxytetracycline treatment, the birds should be switched to another form of treatment to reduce the muscle irritation that is caused by repeated oxytetracycline injection. # Experimental Methods Treatment protocols using late-generation macrolides and pharmacist-compounded injectable doxycycline are under investigation.Information about these treatment protocols might be available in the scientific literature or from avian veterinary specialists. # Sources of Medications The following sources (Table B) are not listed as an endorsement of the companies or products.Other sources might be available.1) If the animal is slaughtered within 7 days of being bitten, its tissues may be eaten without risk for infection, provided that liberal portions of the exposed area are discarded.Federal meat inspectors must reject for slaughter any animal known to have been exposed to rabies within 8 months.2) Neither tissues nor milk from a rabid animal should be used for human or animal consumption.Pasteurization temperatures will inactivate rabies virus; therefore, drinking pasteurized milk or eating cooked meat does not constitute a rabies exposure.3) Having more than one rabid animal in a herd or having herbivore-toherbivore transmission is rare; therefore, restricting the rest of the herd if a single animal has been exposed to or infected by rabies might not be necessary. c. Other Animals.Other animals bitten by a rabid animal should be euthanized immediately.Animals maintained in USDA-licensed research facilities or accredited zoological parks should be evaluated on a case-by-case basis.6.Management of Animals That Bite Humans.a. A healthy dog, cat, or ferret that bites a person should be confined and observed daily for 10 days; administration of rabies vaccine is not recommended during the observation period.Such animals should be evaluated by a veterinarian at the first sign of illness during confinement. Any illness in the animal should be reported immediately to the local health department.If signs suggestive of rabies develop, the animal should be euthanized, its head removed, and the head shipped under refrigeration (not frozen) for examination of the brain by a qualified laboratory designated by the local or state health department.Any stray or unwanted dog, cat, or ferret that bites a person may be euthanized immediately and the head submitted as described above for rabies examination.b. Other biting animals that might have exposed a person to rabies should be reported immediately to the local health department.Prior vaccination of an animal might not preclude the necessity for euthanasia and testing if the period of virus shedding is unknown for that species.Management of animals other than dogs, cats, and ferrets depends on the species, the circumstances of the bite, the epidemiology of rabies in the area, and the biting animal's history, current health status, and potential for exposure to rabies. # C. Control Methods in Wildlife The public should be warned not to handle wildlife.Wild mammals and hybrids that bite or otherwise expose persons, pets, or livestock should be considered for euthanasia and rabies examination.A person bitten by any wild mammal should immediately report the incident to a physician who can evaluate the need for antirabies treatment (See current rabies prophylaxis recommendations of the ACIP).State-regulated wildlife rehabilitators may play a role in a comprehensive rabies-control program.Minimum standards for persons who rehabilitate wild mammals should include receipt of rabies vaccination, appropriate training, and continuing education. 1.Terrestrial Mammals.The use of licensed oral vaccines for the mass immunization of free-ranging wildlife should be considered in selected situations, with the approval of the state agency responsible for animal rabies control.Continuous and persistent government-funded programs for trapping or poisoning wildlife are not cost effective in reducing wildlife rabies reservoirs on a statewide basis.However, limited control in high-contact areas (e.g., picnic grounds, camps, or suburban areas) may be indicated for the removal of selected high-risk species of wildlife.The state wildlife agency and state health department should be consulted for coordination of any proposed vaccination or population-reduction programs.2.Bats.Indigenous rabid bats have been reported from every state except Hawaii and have caused rabies in at least 33 humans in the United States.Bats should CDC.Human rabies prevention-United States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR 1999;48(No.RR-1). # Appendix A Laboratories that Test Avian Specimens for C. psittaci Many state diagnostic laboratories and veterinary colleges perform routine chlamydial diagnostics.Additional laboratories are included in the following list (Table A).Other sources might be available.Inclusion in Table A does not imply endorsement by the Committee of the National Association of State Public Health Veterinarians or constituent institutions.The purpose of this Compendium is to provide rabies information to veterinarians, public health officials, and others concerned with rabies prevention and control.These recommendations serve as the basis for animal rabies-control programs throughout the United States and facilitate standardization of procedures among jurisdictions, thereby contributing to an effective national rabies-control program.This document is reviewed annually and revised as necessary.Immunization procedure recommendations are contained in Part I; all animal rabies vaccines licensed by the United States Department of Agriculture (USDA) and marketed in the United States are listed in Part II; Part III details the principles of rabies control. # Part I: Recommendations for Parenteral Immunization Procedures # A. Vaccine Administration All animal rabies vaccines should be restricted to use by, or under the direct supervision of, a veterinarian. # B. Vaccine Selection Part II lists all vaccines licensed by USDA and marketed in the United States at the time of publication.
New vaccine approvals or changes in label specifications made subsequent to publication should be considered as part of this list.Vaccines used in state and local rabies-control programs should have a 3-year duration of immunity.This constitutes the most effective method of increasing the proportion of immunized dogs and cats in any population. # C. Route of Inoculation All vaccines must be administered in accordance with the specifications of the product label or package insert.Adverse reactions and vaccine failures should be reported to USDA, Animal and Plant Health Inspection Service, Center for Veterinary Biologics at (800) 752-6255 or by e-mail at CVB@usda.gov. # D. Vaccination of Wildlife and Hybrid Animals The efficacy of parenteral rabies vaccination of wildlife and hybrids (the offspring of wild animals crossbred to domestic dogs and cats) has not been established, and no such vaccine is licensed for these animals.Zoos or research institutions may establish vaccination programs that attempt to protect valuable animals, but these programs should not replace appropriate public health activities that protect humans. # E. Accidental Human Exposure to Vaccine Accidental inoculation might occur during administration of animal rabies vaccine.Such exposure to vaccines listed in Part II constitutes no rabies hazard. # F. Identification of Vaccinated Animals All agencies and veterinarians should adopt the standard tag system.This practice will aid the administration of local, state, national, and international control procedures.Animal license tags should be distinguishable in shape and color from rabies tags.Anodized aluminum rabies tags should be no less than 0.064 inches in thickness. 1.Rabies Tags.be excluded from houses and adjacent structures to prevent direct association with humans.Such structures should then be made bat-proof by sealing entrances used by bats.Controlling rabies in bats by programs designed to reduce bat populations is neither feasible nor desirable. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy.To receive an electronic copy on Friday of each week, send an e-mail message to listserv@listserv.cdc.gov.The body content should read SUBscribe mmwr-toc.Electronic copy also is available from CDC's World-Wide Web server at or from CDC's file transfer protocol server at ftp.cdc.gov.To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments.The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday.Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd.,N.E., Atlanta, GA 30333; telephone (888) 232-3228. 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. # IU.S. Government Printing Office: 2000-533-206/28022 Region IV
Chairman/Criteria Group NIOH In an Italian factory for production of n-butyl phthalate, isobutyl phthalate, and DEHP, G ilioli et al (36) measured to tal phthalate exposure 3 concentrations between 1 and 60 mg/m with an average air concentration 3 (not stated whether arithmetic or geometric) around 5 mg/m .Nielsen et al (64) measured total phthalic acid esters in air in a PVCprocessing industry in Sweden where diisodecyl phthalate, DEHP, and some 3 butylbenzylphthalate were used.Concentrations between 0.01 and 2.0 mg/m were recorded in 96 2-hour personal samples from 54 workers.Air concentrations of to tal phthalates were measured in a Russian PVCprocessing plant using mainly dibutyl phthalate and higher alkyl phthalates but also some DEHP and other phthalates.Concentrations between 1.7 and 66 3 mg/m were recorded (59).3 DEHP a ir concentrations between 0.09 and 0.16 mg/m were reported from a German factory for phthalate production (110).Experiments with radioactive (^C-labeled) DEHP have indicated that at least 50% of the radioactivity of a single oral dose (2.9 mg/kg) is absorbed in the rat intestine since 42 % and 14 % were excreted in urine and in bile, respectively (27).The same authors also found that DEHP was rapidly hydrolyzed by pancreatic lipase, indicating the possibility that DEHP is hydrolyzed in the gut before absorption.DEHP analysis in liver further supported this supposition in that no unmetabolized DEHP was found in liver after administration of smaller (0.5 g/kg) the analyses were positive (8).At a dose of 2 g/kg given p.o.to rats the bioavailability of DEHP was 14% as measured with a HPLC technique in blood.When a higher dose (4 g/kg) was given i.p .,only 5% was recovered in blood, again indicating a role for hydrolysis in the gut in the kinetics of DEHP (77).Experiments with p.o.administration of MEHP indicated that this metabolite was well absorbed (109).Radioactive MEHP or# Mention of the name of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health. (The literatu re is followed to August, 1987.)Diethylhexylphthalate (DEHP), a diester of phthalic acid, is used primarily as a softener in plastics, primarily for polyvinyl chloride (PVC).Smaller amounts are used as lubricants.Occupational exposure occurs during the production of DEHP, during the addition of DEHP to plastics, and in the processing of softened plastics. (20 °C) 0.0013 kPa DEHP is a colourless to yellow, oily liquid at room temperature and normal atmospheric pressure.DEHP is available in a variety of technical grades. # D I S C L A I M E R The solubility of DEHP in water is low, 0.3-0.4 mg/1 at 20-25 °C, it is much less soluble in sa lt water.DEHP is miscible with most common organic solvents and it is more soluble in blood than water.DEHP is lipophilic and the distribution ratio in dichloromethane -Krebs bicarbonate buffer is 1130.The log n-octanol-water partition coefficient is 3-4. # OCCUPATIONAL EXPOSURE TO DEHP DURING MANUFACTURE, FORMULATION, OR USE Few data on occupational exposure to DEHP have been reported. In a phthalate manufacturing industry where DEHP was produced from phthalic anhydride and alcohols, Liss et al (56) DEHP was given to rats and 16 times more radioactivity from MEHP than from DEHP was recovered in plasma. P.o.administration of DEHP to young rats (1 g/kg) lead to a larger MEHP area under the plasma concentration time curve than in older rats when measured with gas chromatography (103), indicating either a more rapid hydrolysis of DEHP or a more efficient absorption of MEHP in young rats. The systemic availability of DEHP is low (5% when 4 g/kg was given) after i.p .administration.Relatively low amounts of MEHP were recovered in blood in these experiments (77). # Distribution Intravenously (i.v .)administered DEHP is rapidly eliminated from blood.This has been demonstrated in experiments where radioactive DEHP was injected i.v .and blood levels were followed by TLC (92).At' a low dose (0.1 mg/kg) there was an in itia l phase with a half-time of 4.5 min and a second phase with a half-time of 22 min.At a higher dose (200 mg/kg) the in itia l phase had a half-time of 9 min.This indicated that DEHP was taken up in a tissue compartment by a saturable process (92).Radioactivity from DEHP was rapidly distributed to liver, carcass, lung and spleen when administered i.v. (27,92). Perorally administered DEHP is mainly distributed as MEHP (77,109).In the liver unmetabolized DEHP was recovered only after high doses (>0.5 g/kg) of DEHP, indicating a threshold phenomenon in its absorption and distribution (1,8 (77,109).The in vitro plasma protein binding of MEHP is extensive (103). Newborn infants receiving exchange transfusions may reach plasma levels of about 10 Mg/ml of DEHP (104).This level is about twice as high as those found in leukaemia patients receiving p latelet concentrates and about five times as high as levels found in haemodialysed patients.After treatment this level rapidly fe ll to about 3 Mg/ml within 2 hours, and then a further drop with a half-time of about 12 hours (104). # Metabolism DEHP is hydrolyzed in vitro by pancreatic lipase to MEHP (27), indicating that this metabolism mainly occurs in the gut lumen.In rats about 80% of a p.o.dose of DEHP undergoes mono-de-esterification (77), while in traarterially administered DEHP was only slowly converted to MEHP (77). The hydrolysis in rat liver has been studied with both negative (27) and positive ( 6) results. MEHP may be further metabolized in the gut wall (77) or other organs.Rat liver cells in culture as well as the intact rat converts MEHP to several metabolites (7,55).The -and w-l-carbon oxidation products constitute more than 85% of the metabolites (7,55,60).The ethyl side chain may also be oxidized (55).It has been suggested that oj-oxidation leads to a product which is further metabolized by p-oxidation in the peroxisomes (7,55).A non-linear dose-dependency of this metabolism in the rat has been observed; the dominating role of u>-oxidation over co-1-oxidation was increased by high doses of MEHP (55). 14 Small amounts of radiolabel derived from 2-ethyl-(l-C)-hexyl-labeled DEHP was recovered in a DNA fraction (8).However, the metabolite responsible for this radioactivity or the nature of its binding was not fully explored. There are marked animal species differences in the metabolism of DEHP.Thus the ^-oxidation seems to play a dominate role in the rat and guinea pig (8,54,55), but seems to be a minor pathway in the mouse, hamster, green monkey, cynomolgus monkey, and marmoset (8,54).In urine of DEHP treated rats, no conjugated metabolites have been detected.A minor portion is conjugated in the hamster and a major portion is conjugated in the marmoset, mouse, guinea pig, green monkey and, man (8,54).Only glucuronides have been found in these species (8). The amount of unmetabolized MEHP excreted in urine also varies considerably between species; it is low in the rat and hamster, but high in mouse, guinea pig, green monkey and man (8). Repeated oral administration of DEHP or MEHP at high doses (500 mg/kg) to rats leads to a change in the metabolic profile.There was an increase in -oxidized metabolites and a decrease in co-1-oxidized metabolites (55).Drug metabolizing enzyme activ ities have been studied after DEHP administration and in some cases changes have been observed (2,37,119). The same metabolites as those found in rat urine can be detected in human urine.One study on i.v .injected DEHP (8) and one on orally administered DEHP (90) indicated that man metabolizes DEHP by to and 0) -1-oxidation as well as by oxidation of the ethyl side chain.However, the U) -oxidation pathway seems to be a minor pathway in man.More than half of the metabolites recovered in human urine were conjugated metabolites (8,90).Time-averaged concentrations of DEHP, MEHP and phthalic acid in blood, reported for patients undergoing maintenance hemodialysis, were 1.9, 1.3 and 5.2 Mg/ml respectively (76).These patients are considered to be at risk of potential DEHP toxicity through prolonged contact periods with medical plastic products that contain DEHP.The relatively high circulating level of phthalic acid may indicate an altered metabolism of DEHP in uremic patients (76). Levels of DEHP and MEHP in plasma were studied in newborn infants receiving blood exchange transfusions.In one case the MEHP h a lf-life was the same as for DEHP (about 12 hours), indicating that the hydrolysis of DEHP was the rate limiting metabolic step.However, in other children the half-time of MEHP was longer than that of DEHP, suggesting a low oxidizing capacity in most newborns (10A). # A.4 Excretion Radioactivity from intravenously injected ^C-labeled DEHP is mainly recovered in urine and feces after 2A hours (92), indicating that urine and bile are major excretory pathways.At a low dose (0.1 mg/kg) given to rats, 50-60% of injected radioactivity was recovered in urine and feces after 2A hours, while less than 50% was recovered at a high dose of 200 mg/kg (92).Seven days after an oral dose (2.9 mg/kg) of DEHP, 42% of the radioactivity was recovered in urine and 57% in feces (27).In these experiments on rats the biliary excretion was also quantitated, and it was found that 14% of the radioactivity was recovered in bile after 4 days (27).The almost 100% recovery documented by Daniel & Bratt (27) has been confirmed by Teirlynck & Belpaire (109).Oral administration of MEHP (50-500 mg/kg) gave a higher urinary recovery than orally administered DEHP (50-500 mg/kg) as measured after 24 hours (55).Urinary excretion in man has been quantitated after oral administration of non-radioactive DEHP (0.45 mg/kg).It was found that 15-25% was excreted in urine as MEHP or oxidized metabolites within 2-3 days (90). In the rat no unmetabolized DEHP is excreted in urine, while small amounts are found in mouse or green monkey urine (8).Major amounts of MEHP are excreted in the urine by mouse, guinea pig, green monkey and man (8).However, oxidized metabolites constitutes a major portion of excretion products in urine from ra t, mouse, hamster, green monkey, and man (8). Changes in excretion pathways have been observed after prolonged administration of DEHP.In control rats the fecal excretion pathway dominated after p.o.administration, while in habituated rats (7 days feeding with DEHP) the urinary pathway dominated (27). # Retention and turnover At least two elimination phases of radioactivity, given as DEHP, have been observed in ra t blood, but these have short half-lives (4.5-9 and 22 min respectively) (92).In the liver after 7 weeks of oral administration the elimination phase was considerably slower, with a h a lf-life of 3-5 days (27).No accumulation of DEHP or MEHP was observed after dosing with 2.8 g/kg/day for 7 days (109).No accumulation was reported from a long term feeding study at doses of 1000 or 5000 ppm in the food (corresponding to a daily dose of about 50 and 250 mg/kg) for 5-7 weeks (27). Analysis of the to tal amount of urinary metabolites, measured as derivatized phthalic acid, indicated a weak positive correlation between occupational exposure to phthalate and the metabolites (56,64).In the f ir s t study (64) workers were mainly exposed to DEHP and diisodecyl phthalate.In the second study (56) workers were exposed to DEHP and phthalic anhydride.The authors concluded that phthalic anhydride influenced the urinary level more than did DEHP. # Summary DEHP is hydrolyzed in the gut.In the liver unhydrolyzed DEHP can only be found after administration of high doses.The hydrolyzed metabolite MEHP is rapidly absorbed and is further metabolized in the liver.In the rat the w -and to -1-carbon oxidation products constitute more than 85 % of the metabolites.I t has been suggested that oxidation products are further metabolized by 3-oxidation in the peroxisomes.This metabolism is dose-and frequency of administration-dependent.The metabolism is changed by repeated administration of DEHP.There are great species variations, and the 0) -oxidation pathway seems to play a minor role in man.Major excretory pathways are urine and bile.In feces and urine almost 100 % of an administered dose can be recovered.No accumulation of DEHP or MEHP has been observed. # EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS # Single Exposure Numerous LD^^ values have been reported for DEHP.The oral LD^q values in rats generally exceeded 25 g/kg and in mice, 30 g/kg (66, 125).The oral LD^q value for the rabbit is given as 33.9 g/kg (95), and for the guinea pig, 26.3 g/kg (49).After i.p .administration to rats an LD^q value of 30.7 g/kg has been reported (95).In mice the value is noted to be 37.8 g/kg (51).In other studies LD^q values in the range 14-75 g/kg have been calculated for the mouse after i.p .administration (125).LD50 values in the range 200-250 mg/kg were reported for the rat after i.v .doses of DEHP solubilized in nonionic detergent (84,91). From the information provided in the acute studies the main sign of toxicity after single oral or intraperitoneal dosing is diarrhoea, possibly due to the oily nature of the ester.An i.p.dose of 500 mg/kg in rats decreased spontaneous running activity indicating behavioural changes (85).After i.v.dosing, lung lesions characterized by oedema, haemorrhage, and in filtratio n s of polymorphonuclear leucocytes have been observed in the rat (93).The effects were evident at doses as low as 50 mg/kg.The mechanism of the aetiology of the lung lesions is unknown.I t has, however, been suggested that some changes could be due to the release of lysosomal enzymes from alveolar macrophages, which has been seen in vitro in rabbit tissues treated with DEHP (11).Treatment i.v.of rabbits with DEHP induced a fa ll in blood pressure and an increase in breathing rate at a dose of 350 mg/kg.No deaths occurred after doses up to 650 mg/kg (20). The monoester, MEHP, may be more toxic than the diester but data are very limited.In a short note (118) the oral LD^q in the rat was reported to be 1.3A g/kg (female) and 1.8 g/kg (male). # Short-Term Exposures The most obvious sign of toxicity in the rat after oral administration is a reduction in the rate of weight gain, usually evident within a few days of dosing of 0.A g/kg/day or above (A0, 65).Reduction in body weights were observed in rats given dietary levels of 12,500 and 25,000 ppm for 13 weeks.Dosages of 1600-6300 ppm resulted in either slight elevations of body weight or had no effect (62). Reductions in haemoglobin, packed cell volume and erythrocytes have been observed in rats given 1% or 2% dietary DEHP for 17 weeks but not at 0.2% for the same period (A0).Doses of more than 3 g/kg/day for periods up to 90 days were necessary to cause deaths in rats (65,95).No deaths occurred in rats after dietary dosing for 1A days at 50,000 ppm or below (62). MEHP also reduced the body weight gain when given in the diet of rats at 6,400 ppm (22).No effects on body weight occurred at dietary levels up to 625 ppm for 3 months.At 625 ppm a significant reduction in blood glucose was observed. Decreases in body weight have also been observed in mice given dietary DEHP for 14 days at levels from 6,300 ppm to 100,000, or for 13 weeks at 1000 ppm to 12,500 ppm (62).Cystic kidneys and centrilobular necrosis were noted in one strain of mice (ddY) fed 0.25 or 2.5% DEHP for 2 weeks but not in another study using a different strain (B6C3F^), higher exposure levels, and longer periods (125).DEHP administered i.v .at 25-500 mg/kg/day for 2-4 weeks to beagle dogs resulted in pulmonary haemorrhage and inflammatory response similar in appearance to the "shock-lung" effect (125). A few inhalation studies have been reported.However, due to the omission of experimental details they can not be assessed. # Biochemical effects A large amount of research work has been carried out on the hepatic effects such as cell proliferation, of DEHP in laboratory animals.A single dose of DEHP, 500 mg/kg, resulted in a six-fold increase of male rat hepatocytes in S-phase and a 15-fold increase of male mouse hepatocytes in S-phase 24 h after dosing.Three weeks of feeding DEHP at 6000 ppm in the diet increased liver/body weight ratios to approximately 140% that of controls in female rats and 170% of controls in male mice (19).However, at the end of 2 years of feeding DEHP at 0.03, 0.1 or 1.2% in the diet there was no detectable liver cell proliferation as studied by H-thymidine incorporation (78).In vitro studies also have shown that DEHP decreases the protein kinase c activity ( 100). The cell proliferation induced by DEHP forms the basis of one theory of DEHP hepatocarcinogenesis.This theory argues that the increased cellular growth induced by DEHP may result in spontaneous mutational events or promotional effects (16,19).Peroxisomes (microbodies) are small cytoplasmatic organelles.Functionally, peroxisomes have been implicated in gluconeogenesis, detoxification of and in lipid metabolism (82).Some chemical agents may cause peroxisome proliferation in mouse and rat liver.This property was f ir s t discovered for some hypolipidemic drugs, such as clofibrate and naphenopin, but has later been found to be common to a structurally diverse group of chemicals including DEHP.Peroxisome proliferators including DEHP and other phthalates are liver carcinogens, when administered in the diet (80). There seems to be a fair correlation between the ab ility of a chemical to induce peroxisome proliferation and its liver carcinogenic properties (81). According to the peroxisome proliferation hypothesis for liver carcinogene sis, DEHP and/or its metabolites reduces lipid synthesis and oxidation so that fatty acid derivatives (e.g. triglycerides) are accumulated in the hepatocyte.
Genes for lipid metabolizing enzymes, including peroxisomal beta-oxidation enzymes, are then expressed.It has recently been shown that MEHP and the (j J -1-carbon oxidation products are the DEHP metabolites responsible for peroxisome proliferation in primary hepatocyte cultures (60). The increased lipid metabolism in the peroxisomes may generate increased amounts of H^O^. Since catalase, the enzyme which catalyzes the breakdown of to water, is only slightly induced by DEHP the result w ill be an increased formation of oxygen radicals which may damage membranes and/or DNA (16).If the exposure is prolonged a series of cellular insults may result in permanently altered cells which form foci and ultimately tumors.I t should, however, be clear that this hypothesis has only limited experimental support. DEHP is a moderately effective inducer of peroxisome proliferation in the rat.Chronic administration of doses of 50 mg/kg/day seems to be effective as measured by an increase in peroxisomal enzymes (61).However, doses of 25 mg/kg/day seem not to increase these enzyme activ ities in the rat liver (50). Another experiment has shown a large increase of hepatic peroxisomes in the rat after 1A days of oral DEHP administration at 2000 mg/kg/day.When the same dose was given to marmosets there was no peroxisome proliferation.Moreover, peroxisomal enzymes showed a pronounced rise in the rat but not in the marmoset (83).The difference may have been caused not only by a less efficient hydrolysis of DEHP and therefore less efficient absorption in the marmoset ( 83) but also by different intrinsic responsiveness to MEHP by the rat and marmoset hepatocytes (60).There is some experimental support for both of these explanations.Some experiments suggest that human hepatocytes may be similar to marmoset hepatocytes in their peroxisomal response to MEHP (16). Nothing is known about ra t, marmoset, or human peroxisome responses to DEHP by inhalation exposure. In vitro, rat liver microsomal cytochrome P-450 levels were not affected by DEHP (37).However, when rats were treated in vivo with DEHP by i.p.injections (119) or repeatedly given DEHP orally (2), an increase in cytochrome P-450 levels has been observed. In the liver, mitochondrial enzymes and mitochondrial morphology have been affected by DEHP administration (74, 96).The significance of the effects on mitochondria is not known as the mitochondrial functions usually appear to be normal (125). In male rats given DEHP in the diet, urinary excretion of Zn is enhanced and the testicular levels of Zn decreased (42,68).See also 6 . A number of studies has shown that DEHP given in the diet (0.5-2%) causes lowering of triglyceride and cholesterol levels in the plasma of the rat (13,14,15,24,87,127,128).DEHP inhibits the biosynthesis of cholesterol, an effect which is accompanied by phospholipidosis.The same effects are seen with MEHP (72). # Skin and eye irritatio n ; sensitization The data available indicate that DEHP is a weak irrita n t to mammalian skin on topical or intradermal exposures (20,125). In one study no irrita tio n in the rabbit eye occurred when DEHP was in stilled into the eye (51). There are no data indicating that DEHP should be a sensitizing agent. # Long-Term Exposures In a 24 month study (44) groups of 43 male and 43 female Wistar rats were fed diets containing 0, 0.1 or 0.5% DEHP, with interim k ills at 3, 6 and 12 months.Because of high mortality only two control, four low dose and seven high dose animals were alive at termination.During the f irs t year DEHP slightly reduced body weights but by the second year the weights of a ll groups were sim ilar.During the firs t six months an increase in relative liver and kidney weights were seen in DEHP treated animals but later they were sim ilar in control and treated animals.After 3 months 1/8 rats in the low dose group were found to have mild tubular atrophy in the kidney.After In another 24 month study (21) groups of 32 male and 32 female Sherman rats were given diets containing 0, 0.04, 0.13 or 0.4% DEHP.Because of reduced life-expectancy of the animals and the small numbers of animals used, the study is inadequate to assess the chronic toxicity of DEHP. In a 12 month study (65) a group of 20 male and 20 female Wistar rats were given a diet containing 0.35% DEHP.A control group received the diet only.The only gross or micropathology noted in dosed animals at necropsy was hepatomegaly.During the study, however, about 30% of the animals died due to congestion of the small intestine and loss of the gastric or intestinal mucosa, which was complicated by purulent pneumonia and endometritis. In a 2 year study (47,62) groups of F344 rats were given dietary levels of 0, 6000 or 12000 ppm DEHP.A decreased body weight in exposed groups was noted from around week 30 u ntil termination.Except for neoplastic effects (section 8 ) and testicu lar atrophy (section 6 ) a compound related hypertrophy of cells of the anterior pituitary were noted at necropsy of the high dose rats.In both of the exposed groups an increased incidence of clear cell changes in the livers was observed. In the same study (47,62) B6C3F^ mice were exposed to 3000 or 6000 ppm DEHP.A dose related decrease in dosed female mice body weights was observed.There was no increased incidence of non-neoplastic lesions except for seminiferous tubular degeneration of the testes in male mice (section 6 ). In a study with groups of male and female guinea pigs fed diets containing 0, 400 or 1300 ppm DEHP for 12 months (21), dosed animals had sta tistic a lly higher body weights than controls and a slight increase in liver weights was noted in dosed females.No other compound related lesions were found. # Summary Based on LD^q studies DEHP has a low acute toxicity.A prolonged dosing of DEHP to animals produced proliferation of liver peroxisomes, hepatomegaly and a reduction of body weight gain. DEHP is a weak irrita n t to mammalian skin but there are no data indicating that DEHP should act as a sensitizing agent. # REPRODUCTIVE, EMBRYOTOXIC, AND TERATOGENIC EFFECTS # .1 Reproductive effects The effects of DEHP on male reproductive organs have been studied extensively.The majority of the studies have been carried out using rats or mice given DEHP in the diet. Seminiferous tubular atrophy, comprising a loss of spermatids and spermatocytes, was the result when 4-week-old Wistar rats were administered 2800 mg DEHP/kg by oral intubation for 10 days (39).In sim ilarly treated 10-week-old rats about 50% of the tubules were atrophic and the remainder unaffected.No testicular damage was seen in treated 15-week-old rats.When DEHP was given in the diet (2%; approximately 1200 mg DEHP/kg) daily to 4week-old rats, the lesions produced were reversible whether treatment was stopped prior to, or continued until after the control rats had reached sexual maturity. In rats given 1 or 2% dietary DEHP the effect was dose-dependent with visible signs of atrophy after approximately 2 weeks of feeding (AO).The atrophy was accompanied by pituitary changes, namely enlargement and vacuolization of the basophils of the pars d ista lis corresponding to the formation of the so-called castration cells seen after gonadectomy (AO).Similarly, there was a concomitant reduction in testicular and prostatic zinc levels with increased urinary excretion of zinc (A2). In a rat study with orally administered DEHP (2% in the diet) the serum testosterone levels were reduced by approximately 50% but the levels in testes rose by 150% (70).Simultaneous administration of testosterone or zinc had no protective effect on the atrophy but did prevent the weightreduction of the accessory sex organs (39,73).DEHP in the diet (2%) given to 7 young Wistar rats for one week decreased the testicular weight significantly (p < 0.05) compared to controls (67).The testicu lar zinc concentration was decreased as well.In another study (68) groups of 20 male rats were given 2.0 g/kg/day by gavage for 1A days.Ten rats were then killed and the remaining 10 rats were followed for an additional A5 day period without administration of DEHP.The histopathological changes of the testes seen at day 15 were: a marked shrinkage of the seminiferous tubules; germinal epithelium consisting only of Sertoli cells; very few spermatogonia.After A5 days the percentage of spermatogenic tubules had increased from 0 (at day 15) to 12.8%, indicating a limited reversibility of the testicular atrophy. Similar degeneration of the seminiferous tubules were seen (89) when 13week-old Wistar rats were given 2 g DEHP/kg p.o.for 7 consecutive days. The changes induced in rats by DEHP may be age dependent (106).Younger animals appeared to be more susceptible to testicu lar injury and were slower to recover (39).If treatment was withdrawn before the rats were sexually mature the effects were reversible (39).Plasma levels of DEHP were similar in sexually mature and immature rats indicating no difference in absorption (107).Rats given i.p .injections of DEHP did not show any strong evidence for testicular atrophy (25).As with oral dosing, however, i.p .administration of DEHP decreased serum testosterone levels (69).Both routes have also altered the activ ities of some testicular enzymes (25,94).Some degenerated primary spermatocytes and altered Sertoli cells were observed in Sprague-Dawley rats given 3 h infusions of an emulsion at a rate of 1 ml/h corresponding to a daily dose of 500 mg DEHP/kg (103).The infusions were given every other day on six occasions.The emulsion contained DEHP, fractionated egg yolk phosphatides, glycerol, and water.No effects were observed when emulsions corresponding to 0, 5, or 50 mg DEHP/kg were given. In another study (26) groups of Swiss-Webster mice were given daily i.p.injections of 50 or 100 mg DEHP/kg for 5 days or alternate daily i.p.injections of 50 or 100 mg DEHP/kg for 20 days (10 injections).The animals were killed 24 h following the last injection.No significant alterations in testicular weight or zinc levels occurred.In Sprague-Dawley rats given similar treatment the gonadal zinc level decreased about 30%. In a NTP-sponsored study (58) with CD-I mice given 0.3% DEHP in the diet, the animals had significantly diminished te s tis and epididymis weights compared to controls.In addition, the sperm concentration in the cauda epididymis was decreased and the percent abnormal sperm in the cauda was significantly higher in the treated mice. A high oral dose (4.2 g/kg) of DEHP gave a minimal tubular atrophy in hamsters but did not produce any effects on urinary zinc excretion, testicular zinc levels or on testicular weights (42). The effects of the monoester (MEHP) has not been as well studied.An oral dose of 1 g/kg/day for 5 days to rats produced a significant decrease in testes weights and an extensive testicular atrophy (42).On the other hand, rats given i.p.doses of up to 100 mg/kg of MEHP for 5 days showed no abnormal histology (25) and i.p .doses of 50 mg/kg on alternate days for 20 days produced only a reduction in prostatic zinc levels (26). In mice fed diets containing 2% MEHP for 1 week (71) testicular zinc and testosterone levels were markedly reduced but there were no reductions in testicular weights.Hamsters given 1 g/kg/day of MEHP for 9 days showed more severe testicu lar effects than those given DEHP at levels of 4.2 g/kg/day for the same period (42). These studies indicate that the rat is the most susceptible species to DEHP-induced testicu lar atrophy.The mechanism of phthalate-induced testicu lar damage is not fully understood.The testicular zinc depletion has been suggested as a primary event (34,35).Zinc is essential for normal testicular function and its depletion is known to lead to testicular atrophy (12).Inhibition of dehydrogenase enzymes, e.g. those controlling the biosynthesis of testosterone, lead to reduced testosterone levels.DEHP administration has been shown to reduce serum testosterone in the rat (69,70) as well as in the mouse (42), although in the mouse no testicular atrophy was observed.Supplementation with testosterone or zinc did not prevent the testicular damage induced by DEHP (39,73). In vitro studies have indicated that the Sertoli cell is the target.Mixed cultures of Sertoli and germ cells prepared from rat testes were exposed to DEHP or MEHP (10 ^-10 ^M) (38,41).DEHP had no effect but MEHP caused a dose-dependent increase in the rate of germ cell detachment from Sertoli cells, accompanied by changes in Sertoli cell morphology. In another study (58) CD-I mice were given 0, 0.01, 0.1 or 0.3% DEHP in the diet during a 7 day pre-mating period and a subsequent 98-day cohabitation period.This resulted in complete suppression of fe rtility in the 0.3% group and a significant reduction in the fe rtility in the 0.1 group compared to controls.There was no effect of DEHP on fe rtility in the 0.01% treatment group. In a f e r tility study (3) groups of ICR male mice were administered DEHP subcutaneously at dose levels of 1, 2, 5 and 10 ml/kg on day 1, 5 and 10 of the study.At day 21 each male was housed with one virgin female for 7 days.There was a reduction in the incidence of pregnancies in the treated groups (3/8 at the three highest dose levels; 5/8 at the lowest dose level; 14/16 in the control group).On the other hand, repeated matings with virgin females starting on day 2 , 6 , 1 1 , 16 and 2 1 , and at weekly intervals through 8 weeks, revealed no decrease in the incidence of pregnancy.In the treated groups, examination of pregnant females on day 13 of gestation revealed an increase in the incidence of preimplantation losses and early fetal deaths. Only one study (94) has investigated the effects of phthalates on female reproductive organs.Three doses of 4.93 g DEHP/kg at 5-day intervals were given i.p .to female rats.No histopathological changes of the ovaries were seen 22 days after the firs t injection, but reductions of some enzyme activités were noted.However, i.p.injections of DEHP to male rats did not result in histopathological changes of the testes. It appears that rats and guinea pigs are sensitive to testicu lar atrophy caused by DEHP while mice are fairly and hamsters highly resistant.That at least some of the effects associated with this pathology can be produced in vitro argues against a hormonally mediated indirect effect.The earliest effects are seen in Sertoli cells and are described as vacuolation (5). # Embryotoxicity, Teratogenicity In a study (65) with female Wistar rats given 0.34 or 1.7 g DEHP/kg by gavage during the f ir s t 21 days of gestation, the only untoward effects seen were reductions in fetal body weight.Two percent (2%) DEHP in the diet of Fischer 344 rats during the firs t 20 days of gestation increased the number of resorptions (123). Intraperitoneal injections of 4.93 and 9.86 g DEHP/kg to Sprague-Dawley rats on days 5, 10, and 15 of gestation resulted in an increased number of resorptions and reduced fetal weights (101).In the highest dose group gross abnormalities, such as twisted hind legs and anopthalmia, were noted but no skeletal defects were observed. Plasma extracts of two polyvinyl chloride (PVC) plastics containing DEHP were administered intravenously to groups of pregnant Sprague-Dawley rats daily from the 6th to the 15th day of gestation (52).The animals were killed at day 20.The daily doses of DEHP were equivalent to 1.3 mg/kg (low dose) and 5.2 mg/kg (high dose).No significant teratogenic or embryotoxic effects were noted. Groups of ICR mice were given DEHP in the diet at levels of 0.05 to 1.0% for days 0-18 of gestation whereafter they were sacrificed (97,99).The food intake was about 7 g/day as an average.At 0.4 and 1.0% levels no live fetuses were found.At the 0.2% level, 40% of the fetuses had malformations including exencephaly, spina bifida and malformed ta il.A delayed ossification was seen in about 15% of the fetuses at the 0.1 and 0.2% dose levels. Dietary administration of 0.025 to 0.15% DEHP on days 0-17 of gestation to CD-I mice increased the number of resorptions at the 0.1 and 0.15% levels (124). A single p.o.administration of 0.1 ml/kg DEHP on day 7 of gestation to SPF mice decreased the number and the body weights of living fetuses (116).In another study (126) DEHP was given orally to SPF mice at day 6 , 7, 8 , 9 or 10 of gestation.When 5.0 or 10.0 ml/kg was given on day 7 there were no live fetuses.2.5 ml/kg administered the same day produced 14% of living embryos and 1.0 ml/kg gave 40% living embryos.The percentages of live embryos when 10.0 ml/kg was given on day 8 , 9 or 10 of gestation were 18, 92 and 95% respectively.Gross and skeletal abnormalities occurred in fetuses given 2.5 and 7.5 ml/kg on day 7 or 8 .The abnormalities included exencephaly, open eyelid and club-foot. In a later study (98) groups of ICR mice were given DEHP by stomach intubation on days 7, 8 and 9 of gestation.The DEHP doses (in olive oil) were 250, 500, 1000, and 2000 mg/kg.The mice were sacrificed on day 18.In the two higher dose groups the numbers of resorptions and malformed fetuses were significantly increased.The malformations most commonly produced were anencephaly and exencephaly.When doses of up to 8000 mg/kg were given i.p.at days 7,8, and 9 of gestation no effects were noted. The monoester, MEHP, at oral doses of 225, 450 and 900 mg/kg produced significant signs of maternal toxicity when given to pregnant Wistar rats on days 6-15 of gestation (86).In the highest dose group a 73% mortality was observed in the dams.
In the SPF mouse, oral dosing with 0.1 or 1.0 g/kg MEHP on day 7 of gestation led to increased incidence of early embryonic deaths but dosing on day 8 or 9 had less effect (117,126).The fetuses had reduced body weight and a higher incidence of gross abnormalities in fetuses from the high dose group on days 8 and 9 as compared to controls.The mice dosed on day 8 produced fetuses with high incidences of skeletal effects. Intravenous injections with 11.38 mg/kg MEHP to rabbits on days 6-17 of gestation gave a high incidence of resorptions (114).The incidence of fetal anomalies was similar to controls. The mechanism of teratogenicity of DEHP or MEHP is not known.Teratogenic activity could result from zinc deficiency, which is known to produce teratogenic effects (108). In a study (65) with DEHP at doses at 0.34 or 1.7 g/kg/day given to female Wistar rats by gavage for 3 months prior to mating, no effects were seen on the number of resorptions, fetal weights or incidence of skeletal anomalies. 6 .3 Summary DEHP can cause testicular damage in rats.The no-effect level is about 0.3 -0.5 % in the diet.There is evidence that DEHP and its metabolite MEHP are teratogenic and embryolethal to rodents.In rats 2 % in the diet throughout the gestation period produced an increased incidence of resorptions and in mice 0.1 % also produced fetal abnormalities.F ertility studies provided contradictory results. # MUTAGENICITY AND RELATED END-POINTS The possible genotoxic effect of DEHP has been thoroughly investigated in several different short-term tests.Effects of the major metabolites of DEHP; the monoester (MEHP) and 2-ethylhexanol, as well as phthalic acid and phthalic anhydride, have also been studied. Studies on the possible mutagenic effect of DEHP have been performed in bacteria, fungi and in cultured mammalian cells.Drosophila melanogaster has also been used and results from a few in vivo studies on mice have been published. Many laboratories have used several strains of Salmonella typhimurium and doses of DEHP up to 10,000 Mg/plate.Incubations both with and without exogenous activation systems have usually been performed.S9-mix from Aroclor 1254 induced rats is commonly used, but other species as well as other inducers have also been used to produce metabolic activation systems.With one exception (115) these test results have been negative (see e.g., 4,46,130,131) and in a IPCS study (9) a ll five laboratories reported negative results.Other bacteria than S. typhimurium have also been used.Negative results were obtained with E. coli WP2 at doses up to 2000 Mg/plate in one laboratory (130). The major metabolites of DEHP have also been tested for mutagenic activity in bacteria.Doses up to 3333 Mg/plate for MEHP and phthalic anhydride (131) and 2000 ng/plate for 2-ethylhexanol and phthalic acid (4) were used with negative results in strains of Salmonella (see also 46,130).However, one laboratory (115) reported a significant increase in revertants in TA 100 for both DEHP and MEHP, with and without S9, respectively. The same investigators (115) also detected a dose-dependent (400 and 500 Mg/plate) DNA damaging effect to B. su btilis in the Rec-assay for MEHP, while DEHP, phthalic acid and 2-ethyl-hexanol were a ll negative.In this study MEHP showed a positive response in E. coli WP2 b/r as well. Negative results were obtained when pooled urine from rats, treated with DEHP 2000 mg/kg/day for 15 days, were tested for genotoxic activity.A direct plating procedure was used with S. typhimurium strains TA-98, TA-100, TA-1535, TA-1537 and TA-1538, both with and without S9 and 3glucuronidase/aryl sulfatase as activation system.When 2-ethylhexanol was tested according to the same protocol was also negative (30). # Mutation The induction of mutations by DEHP has been studied in different species of fungi.In the IPCS collaborative study on in vitro assay systems (9) DEHP was considered to be negative in six out of seven assays.Positive results were obtained with Saccharomyces cerevisiae both with and without S9 activation at the lowest effective concentrations of 1541 Mg/ml and 3081 Mg/ml, respectively.Other laboratories using other strains of S. cerevisiae or Schizosaccharomyces pombe reported negative results at maximum tested doses of 5000 Mg/ml.Mouse lymphoma cells (L5178Y), Chinese hamster V79 cells, as well as human lymphoblasts have been used to study the mutagenic effect of DEHP in cultured mammalian cells.Several investigators have reported negative resu lts, but a few positive results can also be found in the literature. In the IPCS study ( 9) only one out of ten investigators reported a positive response.Mouse lymphoma cells were exposed to DEHP, without S9, and two doses were positive (7.5 pg/ml and 20 Mg/ml), indicating a positive response for DEHP without S9 in this te st.In a separate study (46) where MEHP and 2-ethylhexanol, as well as DEHP were tested in the mouse lymphoma cell assay, a ll three substances were found to be negative.The doses were 0.016-1.0 pl/ml -S9 and 0.067-5.0 nl/ml +S9 for DEHP and 0.013-1.0 yl/ml for MEHP and 2-ethylhexanol.DEHP has also been tested for mutagenicity in Drosophila melanogaster, using the sex-linked recessive lethal (SLRL) and different somatic recombination and mutation assays.20 ppm of DEHP administered via injection did not induce SLRLs (129).In the IPCS study (9), however, DEHP gave a positive response in the unstable eye mosaic test in two separate experiments, but only at one dose (6.1 mg/ml), and were weakly active at 611 Mg/ml in another eye mosaic assay.No activity however, was seen in the wing spot te st at single doses of 6.1 mg/ml.I t was concluded that the DEHP test results may be interpreted to show marginal-positive responses (9). # DNA damage Different end-points, such as unscheduled DNA synthesis (UDS), and single strand breaks have been used to detect damage to DNA induced by DEHP in different mammalian test systems.In a IPCS study (9) negative results were obtained when single strand breaks were measured, either by alkaline elution in hepatocytes, up to 3907 Mg/ml or alkaline sucrose sedimentation in CHO cells, up to pg/ml.In the IPCS study UDS was also measured in either isolated hepatocytes or cultured HeLa cells by four different laboratories.One investigator detected a positive response of DEHP using isolated hepatocytes.However, since this result was only sta tistic a lly significant at one dose and not dose-related, the consensus was that DEHP was negative for UDS. In a separate study DEHP did not induce DNA-repair in primary rat hepatocytes (18).Similarly neither DEHP nor MEHP induced any DNA-repair in primary human hepatocytes, from three different subjects.In this study concentrations as high as 10 mM of DEHP and up to 0.5 mM of MEHP were used and exposure continued for 18 hours.No induction of DNA-repair or increased alkaline elution of DNA were seen in hepatocytes from either female or male F-344 rats treated with DEHP in vivo.Peroxisomal proliferation was induced in male rats treated with 500 mg/kg DEHP at 2, 12, 24 or 48 h before sacrifice, or with 150 mg/kg/day DEHP for 14 consecutive days.Female rats were treated with either 12000 ppm in the diet for 30 days, or 500 mg/kg 2 h before sacrifice, or the combination of both treatments. Similar in vivo/in vitro measurements of unscheduled DNA synthesis (UDS) in hepatocytes were reported by Kornbrust et al (48).Unscheduled DNA synthesis was not observed in primary rat hepatocytes exposed in vitro to -5 -2 10 -10 M DEHP or in vivo by a single gavage dose of 5 g/kg 2, 15 or 24 h prior to isolation of hepatocytes.Dietary concentration of 2% DEHP led to a marked proliferation of peroxisomes after 4 weeks.Neither this treatment nor the additional administration of a single gavage dose of 5 g/kg DEHP 15 h before sacrifice to animals fed the 2% diet for 8 weeks, or 4 weeks with or without pretreatment with 3-am ino-l,2,4-triazole (to inhibit endogenous catalase activity) induced any detectable DNA-repair in hepatocytes. Radioactivity from carbonyl-labeled DEHP did not associate with purified protein, RNA or DNA from rat liver in vivo.Label from 2 -eth y l-(l-^C )hexyl-labeled DEHP or MEHP did appear to associate strongly with purified 14 DNA, but label from free C-labeled 2-ethylhexanol did not.However the apparent binding of DEHP and MEHP was not further characterized (8). In a similar study (57) DEHP radiolabeled in different positions was administered orally to female F344 rats with or without pretreatment for 4 14 weeks with 1% unlabeled DEHP in the diet.Administration of Ccarboxylate-labeled DEHP resulted in no measurable DNA radioactivity while 14 radioactivity clearly was measurable after administration of DEHP, C-or 3 H-labeled in the alcohol moiety, as well as after administration of 2ethyl(l-^C )hexanol.HPLC analysis showed that the normal nucleosides had incorporated radiolabel, while fractions expected to contain carcinogenmodified nucleoside adducts did not contain any radioactivity. DNA isolated from the livers of male F344 rats administered 2000 mg/kg DEHP daily by gavage for 3 days was analyzed for possible carcinogen-DNA adducts 32 by the P-postlabeling technique (43).No adducts were detected in the -3 DNA, which also was the case when DNA from hepatocytes exposed to 10 M DEHP in vitro for 4 h was analyzed. # Chromosomal Effects Chromosomal effects of DEHP have mainly been studied in vitro, although some studies on the induction of micronuclei in peripheral blood erythrocytes of mice have been published.DEHP did not induce any increase in the level of siste r chromatid exchange (SCE) in Chinese hamster ovary (CHO) cells, treated for 1 hour, either with or without S9, with doses up to 10 mM (32).On the other hand, MEHP has been reported to induce SCEs in V79 cells treated with 25 or 50 Mg/ml for 24 hours, and 1500 Mg/ml for 3 hours (115).MEHP also induced chromosomal aberrations in CHO cells and RL^ cells (from rat liv er), but only at cytotoxic concentrations in CHO cells (1.0 and 1.3 mM; ± S9).MEHP was less 7.3 DNA-binding toxic to RL^ cells and nontoxic concentrations between 2.0 and 6.5 mM gave a dose-related increase in aberrations (75). The induction of aneuploidy by DEHP was investigated both in mammalian cells and in fungi in the IPCS study (9).The mammalian assays, using either a fibroblast cell line or Chinese hamster primary liver cells, gave a positive response at 50 Mg/ml and at doses between 5 and 50 pg/ml, respectively.Two out of four studies using fungi were also positive and the consensus was that DEHP had the potential of inducing aneuploidy in vitro in both fungi and mammalian cells.DEHP and its major metabolites have also been tested for their potential of inducing micronuclei.DEHP (0.6, 3.0 or 6.0 g/kg/day/5 days) failed to induce micronuclei in peripheral blood erythrocytes of B^C^F^ male mice during a A week period (32).Negative results were also obtained in another mouse micronucleus test after both a single dose 5 g/kg, as well as after multiple doses of 5 g/kg/day.In this study MEHP and 2-ethylhexanol were also negative ( 10). # Cell Transformation DEHP induced cellular transformation has been studied in several different experimental systems.In a te st program (10) the BALB/3T3 cell transforma tion assay was used with and without ra t primary hepatocyte activation.DEHP (0.875-1 nl/ml) as well as the two metabolites MEHP and 2ethylhexanol were reported negative.On the other hand, the majority of transformation tests in the IPCS study (9) were positive for DEHP.Negative results were obtained with BALB/c-3T3 cells, while a study measuring the enhancement of v iral transformation of Syrian hamster embryo (SHE) cells, was considered to be inconclusive.Positive responses were obtained by four other investigators (9), using SHE cells, with doses of 1-300 \|ig/ml (two different laboratories), embryonic mouse fibroblasts at 1000 ng/ml with S9 and 10 ng/ml without S9, or retrovirus-infected Fischer ra t embryo cells, at the highest dose tested, 2000 pg/ml.In a separate study (115) both DEHP (7500 mg/kg and 15000 mg/kg) and MEHP (375 mg/kg and 750 mg/kg) induced morphological transformation, as well as chromosomal aberrations, in SHE cells after transplacental administration. The induction of anchorage independence in JB6 mouse epidermal cells has been used to study tumour promoting activity in vitro.This assay gave a positive response for DEHP at concentrations of 500 to 20,000 ppm/ml culture medium (31).In another study (120) There are also a few studies on DEHP induced inhibition of metabolic cooperation, which may be indicative of the promoting potential of a substance.Metabolic cooperation in Chinese hamster V79 cells was not inhibited by DEHP at non-cytotoxic concentrations, 300 nM (0.12 Mg/ml) or below (48).In the IPCS study ( 9) one investigator reported an inhibition in V79 cells at non-cytotoxic concentrations of DEHP Mg/ml in two separate experiments and 5-25 ng/ml in another), while another investigator, using V79 cells in a microassay method, detected a slight but non-significant increased inhibition with doses between 10 and 200 nM. # Summary Numerous studies on possible genotoxic effects of DEHP have been performed using different short term tests.The results indicate that DEHP is not a direct acting genotoxic agent in vitro.With few exceptions mutagenicity studies both in bacteria and eucaryotic cells have been negative and essentially no positive response has been obtained in assays measuring DNAdamage.This is also consistent with results obtained in DNA-binding studies, which have been unable to detect any covalent binding of DEHP or its metabolites to DNA.Tests measuring chromosomal abberations and SCE have also largely been negative.However, MEHP has been found to be a clastogen in vitro but i t has been argued that this effect could be related to the surface active properties of MEHP.A few in vivo assays, measuring the induction of micronuclei, UDS or strand breaks in DNA, have also been performed with negative results.Neither could any mutagenic metabolites be detected in the urine from DEHP treated rats, using a Salmonella assay.In contradiction to these negative results, a few in vitro assays measuring aneuploidy have mainly been positive.Different cell transformation assays that have been performed have also mainly been positive.Although DEHP is not as thoroughly tested in these assays, the mainly positive results obtained indicate that DEHP can affect the cellular genome in vitro. In a carcinogenicity study (47,62) groups of 50 male and female Fischer 344 rats and male and female B6C3F^ mice were fed diets containing 6000 or 12000 (rats) or 3000 or 6000 (mice) mg DEHP/kg for 103 consecutive weeks.Concurrent controls (50 of each sex and species) were fed diet without the addition of DEHP.All of the animals were given control diet for 1-2 weeks after 103 weeks of treatment and were then killed and examined both grossly and microscopically.Food and water were supplied ad libitum.The administered concentrations of DEHP were estimated to be half maximally tolerated doses and maximally tolerated doses.Under these conditions, DEHP caused an increased incidence in female rats and male and female mice of hepatocellular carcinomas, and an increased incidence in male rats of either hepatocellular carcinomas or neoplastic nodules. (See Table I.) Twenty of the 57 hepatocellular carcinomas in the DEHP-treated mice (sexes and doses combined) had metastasized to the lung.The 9 hepatocellular carcinomas in control male mice are said to be within a normal range (62). The reported decreased incidence of tumors of the thyroid, pituitary, and te s tis could be related to an increased endocrine activity of the pituitary gland (62). The carcinogenicity of DEHP was supported by the results of another chronic study (78) even though the group sizes were small in that study. IARC (45) has made the evaluation that there is sufficient evidence for the carcinogenicity of DEHP phthalate in mice and rats, based on a significantly increased incidence of liver cell tumors in animals of both species, and an observed dose-response relationship. Two other long-term studies have been performed (21,44), but due to the small numbers of animals used, the studies are inadequate to assess the carcinogenic potential of DEHP. # SPECIAL STUDIES Since DEHP in most test systems lacks genotoxic activity it has been hypothetized that the carcinogenic effect is exerted during the promotion phase of hepatocarcinogenicity.DEHP has therefore been tested in several initiation/promotion experiments in rats and mice where the end point has been the number and/or volume of foci of altered liver cells.As expected, DEHP lacks in itiatin g activity in these experiments (78,120).DEHP is a probable promoter of such foci in the mouse liver and accordingly a possible tumor promoter in the mouse (120).In the ra t, however, DEHP does not promote altered foci during two years of feeding ( 78) and even seems to accelerate the regression or inhibit the appearance of some kinds of such foci (28,29).The reasons for this, as well as for the divergent responses in rats and mice, are unclear. Extrapolation from mouse data to humans is considered impossible since the mechanism of altered foci promotion in mice is unknown. # EFFECTS ON MAN Two adult subjects who were given 5 or 10 g of DEHP experienced no untoward effects apart from mild gastric disturbances and moderate catharsis at the 10 g dose (95).Three cases of non-specific hepatitis were described among 27 hemodialysis patients with terminal renal failure.The PVC blood tubings used released DEHP in an amount of 10-20 mg/1 perfusate.The symptoms and signs of hepatitis disappeared rapidly when the use of tubings not containing DEHP was resumed (63). There are very few data on effects on man of specific DEHP occupational exposure on man. Two studies report symptoms and signs of polyneuropathy among 47 out of 147 and 12 out of 23 workers examined in a Russian PVC-processing plant and an Italian plant for phthalate production.
The workers were exposed to mixed phthalates and DEHP was a minor exposure, at least in the Russian plant.The to tal phthalate air concentrations recorded varied between 1.7 and 66 3 3 mg/m and 1 and 60 mg/m respectively (36,59). In a study from a Swedish PVC-processing factory the presence of symptoms and signs from the peripheral nervous system were examined among 54 male workers exposed mainly to DEHP, diisodecylphthalate and some butylbenzylphthalate.The workers were divided into three groups of equal size with mean phthalate exposures 0 .1 , 0.2 and 0.7 mg/m , respectively.None of the outcome variables studied showed a significant association with exposure (64).No subject reported work related obstructive lung disease and conventional lung function tests showed no association with exposure. Several biochemical parameters showed significant associations with exposure.There was a slight decrease of the hemoglobin level with time of employment as well as exposure in the last year.Alpha-l-antitrypsin in serum increased slightly with time of employment and immunoglobulin A in serum rose with rising exposure during the last year (64). One case of occupational asthma due to DEHP has been reported in a PVCprocessing worker (17).When the patient was exposed to DEHP in an inhalation chamber an asthmatic reaction was elicited .The action was inhibited by prior administration of sodium chromoglycate. A study of blood lipids, serum activ ities of liver enzymes and routine hematological tests was carried out among workers in a German plant for DEHP production.The study was negative and uninformative due to lack of a 3 control group and very low exposures, below 0.16 mg/m (112). Thiess & Flieg (110) investigated the frequency of chromosome aberrations in 10 workers engaged in DEHP production in the same plant from 10-30 years.There was no increase in chromosome aberrations compared to control groups but a ir exposure levels were very low, 0.09-0.16 mg/m . A mortality study of 221 workers exposed to DEHP in the same plant was also conducted in which there were only 8 deaths.The study is uninformative due to small cohort size, short follow-up and low exposures (111).IARC (45) concluded that no adequate data were available to assess the carcinogenicity of DEHP to humans.Dose dependent kinetics of DEHP or its metabolites have been indicated in several studies as well as marked animal species differences in metabolism.Induction phenomena have also been described.These facts complicate extrapolation from animal studies to man and also extrapolations from high doses to low doses. Data on effects of DEHP on humans are scarce and do not permit any conclusions on dose-effect or dose-response relationships. There are no data on health effects from DEHP exposure outside the occupational environment.A few studies of workers exposed to phthalate mixtures have been published.However, no consistent findings are reported. One case-report suggests that DEHP could cause asthma. In animals few inhalation studies have been performed.The oral and intraperitoneal LD^q values exceed 25 g/kg, which indicate that DEHP has low acute toxicity.Prolonged dosing of DEHP produces hepatomegaly and proliferation of peroxisomes.In the rat the no-effect level for feeding studies appears to be about 0.01% in the diet.The no-effect level in the rat for testicular atrophy fed DEHP is about 0.3-0.5% in the diet, and is more pronounced in young animals.Hamsters and mice appears to be more resistant to the testicu lar effects of DEHP. In rats 2% DEHP in the diet throughout gestation produced an increased incidence of resorptions but not of malformations.In the mouse, however, 0 .1% throughout pregnancy increased the incidence of embryolethality and abnormalities.Days 7-9 of gestation were most sensitive.The dose, 0.05 g/kg, to mice which induced fetotoxicity, is not expected to induce maternal toxicity.Contradictory results are obtained in fe rtility studies with DEHP. Results from several different genotoxicity tests indicate that DEHP and its major metabolites do not exhibit any direct genotoxic effect in either bacteria, fungi or mammalian cells in vitro.This has also been confirmed in binding studies with DEHP, which indicated that DEHP and its metabolites do not interact covalently with DNA.However, it has been established that DEHP has the potential of inducing aneuploidi in fungi, as well as in mammalian cells in vitro.These results, together with several positive results obtained in different cell transformation assays, indicate that DEHP can effect the cellular genome in vitro. DEHP acts as a tumor promoter in mouse liver but not in rat liver in established in vivo test systems. High doses (12000 mg/kg in rats; 6000 mg/kg in mice) of DEHP in a feeding study resulted in increased incidences of hepatocellular carcinoma. Based on animal data i t can be concluded that DEHP is carcinogenic and teratogenic.Due to a lack of human data the degree of risk to humans can not be evaluated, but DEHP should be considered as potentially carcinogenic and teratogenic to humans.
In 2010, the Advisory Committee on Immunization Practices (ACIP) first recommended annual influenza vaccination for all persons aged ≥6 months in the United States (1).Annual influenza vaccination of all persons aged ≥6 months continues to be recommended.This document 1) describes influenza vaccine virus strains included in the U.S. seasonal influenza vaccine for 2012-13; 2) provides guidance for the use of influenza vaccines during the 2012-13 season, including an updated vaccination schedule for children aged 6 months through 8 years and a description of available vaccine products and indications; 3) discusses febrile seizures associated with administration of influenza and 13-valent pneumococcal conjugate (PCV-13) vaccines; 4) provides vaccination recommendations for persons with a history of egg allergy; and 5) discusses the development of quadrivalent influenza vaccines for use in future influenza seasons.Information regarding issues related to influenza vaccination that are not addressed in this update is available in CDC's Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010 and associated updates (1,2). Methodology for the formulation of the ACIP annual vaccine recommendations has been described previously (1).The ACIP Influenza Work Group meets every 2-4 weeks throughout the year.Work Group membership includes several voting members of ACIP and representatives of ACIP Liaison Organizations.Meetings are held by teleconference and include discussion of influenza-related issues, such as influenza surveillance, vaccine effectiveness and safety, coverage in groups recommended for vaccination, program feasibility, cost-effectiveness, and anticipated vaccine supply.Presentations are requested from invited experts, and published and unpublished data are discussed.CDC's Influenza Division provides data on influenza surveillance, antiviral resistance, and vaccine effectiveness.CDC's Immunization Safety Office provides information on vaccine safety, and CDC's Immunization Services Division provides information on vaccine distribution and coverage. # Vaccine Strains for the 2012-13 Influenza Season U.S. influenza vaccines for 2012-13 will contain A/California/7/2009 (H1N1)-like, A/Victoria/361/2011 (H3N2)-like, and B/Wisconsin/1/2010-like (Yamagata lineage) antigens.The influenza A(H3N2) and B antigens differ from the respective 2010-11 and 2011-12 seasonal vaccine antigens (3).The influenza A(H1N1) vaccine virus strain is derived from an influenza A(H1N1)pdm09 (2009) virus and was included in the 2009(H1N1) monovalent pandemic vaccine as well as the 2010-11 and 2011-12 seasonal vaccines. # Recommendations for Vaccination Routine annual influenza vaccination is recommended for all persons aged ≥6 months.To permit time for production of protective antibody levels (4,5), vaccination optimally should occur before onset of influenza activity in the community.Therefore, vaccination providers should offer vaccination as soon as vaccine is available.Vaccination should be offered throughout the influenza season (i.e., as long as influenza viruses are circulating in the community). # Vaccine Dose Considerations for Children Aged 6 Months Through 8 Years Children aged 6 months through 8 years require 2 doses of influenza vaccine (administered a minimum of 4 weeks apart) during their first season of vaccination to optimize immune response.In a study of children aged 5 through 8 years receiving trivalent inactivated influenza vaccine (TIV) for the first time, # Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) -United States, 2012-13 Influenza Season Recommendations for routine use of vaccines in children and adolescents are issued by CDC and are harmonized to the greatest extent possible with recommendations made by the American Academy of Pediatrics, the American Academy of Family Physicians (AAFP), and the American College of Obstetrics and Gynecology (ACOG).CDC recommendations for routine use of vaccines in adults are harmonized to the greatest extent possible with recommendations made by AAFP, ACOG, and the American College of Physicians.The Advisory Committee on Immunization Practices (ACIP) is chartered as a federal advisory committee to provide expert external advice and guidance to the Director of CDC on use of vaccines in the civilian population of the United States.ACIP members are named by the Secretary of the U.S. Department of Health and Human Services.ACIP recommendations become CDC policy once approved by the Director of CDC, on the date published by MMWR. the proportion of children with protective antibody responses was significantly higher after 2 doses compared with a single dose (6).Several studies have indicated that the time interval between two initial doses (from 4 weeks up to 1 year) of the same antigen might not be critical (7)(8)(9).However, because of the antigenic novelty of the 2009(H1N1) pandemic virus, which is anticipated to continue circulating during 2012-13, exposure history to this antigen also must be considered.Children who last received seasonal (trivalent) influenza vaccine before the 2010-11 season but did not receive a vaccine containing 2009(H1N1) antigen (either seasonal vaccine since July 2010 or monovalent 2009 vaccine) will not have received this antigen.These children are recommended to receive 2 doses this season, even if 2 doses of seasonal influenza vaccine were received before the 2010-11 season.This is illustrated in two approaches for determining the number of doses required for children aged 6 months through 8 years, both of which are acceptable (Figure 1).1.The first approach takes into consideration only doses of seasonal influenza vaccine received since July 1, 2010.This recommendation is harmonized with that of the American Academy of Pediatrics (10).This approach has the advantage of simplicity, particularly in settings in which ascertaining vaccination history before the 2010-11 season is difficult.Using this approach, children aged 6 months through 8 years need only 1 dose of vaccine in 2012-13 if they received a total of 2 or more doses of seasonal vaccine since July 1, 2010.Children who did not receive a total of 2 or more doses of seasonal vaccine since July 1, 2010, require 2 doses in 2012-13.2.In settings where adequate vaccination history from before the 2010-11 season is available, the second approach may be used.By this approach, if a child aged 6 months through 8 years is known to have received at least 2 seasonal influenza vaccines during any previous season, and at least 1 dose of a 2009(H1N1)-containing vaccine (i.e., either 2010-11 or 2011-12 seasonal vaccine or the monovalent 2009 vaccine), then the child needs only 1 dose for 2012-13.Using this approach, children aged 6 months through 8 years need only 1 dose of vaccine in 2012-13 if they have received any of the following: -2 or more doses of seasonal influenza vaccine since July 1, 2010; or -2 or more doses of seasonal influenza vaccine before July 1, 2010, and 1 or more doses of monovalent 2009(H1N1) vaccine; or -1 or more doses of seasonal influenza vaccine before July 1, 2010, and 1 or more doses of seasonal influenza vaccine since July 1, 2010. Children for whom one of these conditions is not met require 2 doses in 2012-13. # Available Vaccine Products and Indications Multiple influenza vaccines (with the same antigenic composition) are expected to be available during the 2012-13 season (Table ).Current package inserts should be consulted for updated information and description of additional components of various vaccine formulations, indications, contraindications, and precautions. TIV preparations, with the exception of Fluzone Intradermal (Sanofi Pasteur), should be administered intramuscularly.For adults and older children, the deltoid is the preferred site.Infants and younger children should be vaccinated in the anterolateral thigh.Specific guidance regarding site and needle length for intramuscular administration can be found in ACIP's General Recommendations on Immunization (11).For intramuscular TIV preparations, children aged 6 through 35 months receive 0.25 mL per dose; persons aged ≥36 months receive 0.5 mL per dose (Table ).Fluzone Intradermal is administered intradermally via a single-dose, prefilled microinjection syringe.The preferred site for administration is over the deltoid muscle. Age indications for the various TIV products differ.All TIV preparations contain the same quantity of hemagglutinin (15 µg per vaccine virus strain per 0.5 mL dose; 45 µg total), except Fluzone Intradermal and Fluzone High-Dose (Sanofi Pasteur).Fluzone Intradermal is indicated for persons aged 18 through 64 years and contains 9 µg of hemagglutinin per vaccine virus strain (27 µg total) in a 0.1 mL dose.Fluzone High-Dose is indicated for persons aged ≥65 years and contains 60 µg of hemagglutinin per vaccine virus strain (180 µg total) in a 0.5 mL dose.Within specified age indications, ACIP expresses no preference for any given TIV formulation over another. The intranasally administered live-attenuated influenza vaccine (LAIV), FluMist (MedImmune), is indicated for healthy, nonpregnant persons aged 2 through 49 years.No preference is indicated for LAIV versus TIV in this age group - Vaccination providers should consult Food and Drug Administration-approved prescribing information for 2012-13 influenza vaccines for the most updated information, including indications, contraindications, and precautions. †Data on maximum ovalbumin content is supplied in package inserts of certain vaccines.Persons with a history of mild allergy to egg (specifically, those who experience only hives) should receive TIV with additional precautions (Figure 2). §Information is not included in package insert but is available upon request from the manufacturer, Sanofi Pasteur, by contacting 1-800-822-2463 or mis.emails@ sanofipasteur.com. ¶Figure 1 describes two approaches for determining the number of doses needed for children aged 6 months through 8 years. For adults and older children, the recommended site of vaccination is the deltoid muscle.The preferred site for infants and young children is the anterolateral aspect of the thigh. † †Age indication per package insert is ≥5 years; however, the Advisory Committee on Immunization Practices recommends that Afluria not be used in children aged 6 months through 8 years because of increased risk for febrile reactions noted in this age group with CSL's 2010 Southern Hemisphere TIV.If no other age-appropriate, licensed inactivated seasonal influenza vaccine is available for a child aged 5 through 8 years who has a medical condition that increases the child's risk for influenza complications, Afluria can be used; however, vaccination providers should discuss with the parents or caregivers the benefits and risks of influenza vaccination with Afluria before administering this vaccine.Afluria may be used in persons aged ≥9 years. § §A 0.5-mL dose contains 60 µg of each vaccine antigen (180 µg total). ¶ ¶A 0.1-mL dose contains 9 µg of each vaccine antigen (27 µg total). *A new quadrivalent formulation of FluMist was approved by the Food and Drug Administration in February 2012.It is anticipated that this formulation will replace the currently available seasonal trivalent LAIV formulation for the 2013-14 season.FluMist is shipped refrigerated and stored in the refrigerator at 35°F-46°F (2°C-8°C) after arrival in the vaccination clinic.The dose is 0.2 mL divided equally between each nostril.Health-care providers should consult the medical record, when available, to identify children aged 2 through 4 years with asthma or recurrent wheezing that might indicate asthma.In addition, to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving LAIV, parents or caregivers of children aged 2 through 4 years should be asked, "In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?"Children whose parents or caregivers answer "yes" to this question and children who have asthma or who had a wheezing episode noted in the medical record within the past 12 months should not receive FluMist. † † †Insufficient data available for use of LAIV in egg-allergic persons. § § §Flumist is indicated for healthy, nonpregnant persons aged 2 through 49 years.Persons who care for severely immunosuppressed persons who require a protective environment should not receive FluMist given the theoretical risk for transmission of the live-attenuated vaccine virus. (1).Persons with a history of egg allergy should receive TIV rather than LAIV.Persons who care for severely immunosuppressed persons who require a protective environment should not receive LAIV given the theoretical risk for transmission of the live-attenuated vaccine virus. # Febrile Seizures Associated with TIV and PCV13 Febrile seizures are common in young children.At least one febrile seizure is experienced by 2%-5% of children, and nearly all children who have a febrile seizure recover quickly and are healthy afterwards (12).Before the 2010-11 influenza season, an increased risk for febrile seizures after TIV administration had not been observed in the United States (13,14).During the 2010-11 influenza season, CDC and the Food and Drug Administration (FDA) conducted enhanced monitoring for febrile seizures after influenza vaccination because of reports of an increased risk for fever and febrile seizures in young children in Australia associated with a 2010 Southern Hemisphere vaccine produced by CSL Biotherapies (up to nine febrile seizures per 1,000 doses) (15).Because of the findings in Australia, ACIP does not recommend the U.S.-licensed CSL Biotherapies' TIV, Afluria, for children aged <9 years (2,16) (Table ). Surveillance for U.S.-licensed influenza vaccines during the 2010-11 season subsequently detected safety signals for febrile seizures in young children after TIV administration (17,18).Further assessment determined that the increased risk was in children aged 6 months through 4 years on the day of vaccination to the day after (the 0-1 day risk window).The risk was higher when children received concomitant PCV13 (i.e., when the two vaccines are administered at the same healthcare visit) and peaked at approximately age 16 months (18).No increased risk was observed in children aged ≥5 years after TIV or in children of any age after LAIV.The magnitude of the increased risk for febrile seizures in young children in the United States (<1 per 1,000 children vaccinated) was substantially lower than the risk observed in Australia in 2010 (15). After evaluating the data on febrile seizures from the 2010-11 influenza season and taking into consideration benefits and risks of vaccination, no policy change was recommended for use of TIV or PCV13 for the 2011-12 season (16,19,20).Surveillance data on febrile seizures in young children after administration of influenza vaccine for the 2011-12 influenza season (same vaccine formulation as 2010-11) were consistent with those from the 2010-11 influenza season (CDC, unpublished data, 2012).No changes in the use of TIV or PCV13 are recommended for the 2012-13 influenza season.As stated previously, ACIP does not recommend the U.S.-licensed CSL Biotherapies' TIV, Afluria, for children aged <9 years (2,16) (Table ). # Influenza Vaccination of Persons with a History of Egg Allergy Severe allergic and anaphylactic reactions can occur in response to a number of influenza vaccine components, but such reactions are rare.All currently available influenza vaccines are prepared by means of inoculation of virus into chicken eggs.The use of influenza vaccines for persons with a history of egg allergy has been reviewed recently by ACIP (16).For the 2011-12 influenza season, ACIP recommended that persons with egg allergy who report only hives after egg exposure should receive TIV, with several additional safety measures, as described in this document.Recent examination of VAERS data indicated no disproportionate reporting of allergy or anaphylaxis after influenza vaccination during the 2011-12 season (21).For the 2012-13 influenza season, ACIP recommends the following: 1.Persons with a history of egg allergy who have experienced only hives after exposure to egg should receive influenza vaccine, with the following additional safety measures (Figure 2): a) Because studies published to date involved use of TIV, TIV rather than LAIV should be used ( 22); b) Vaccine should be administered by a health-care provider who is familiar with the potential manifestations of egg allergy; and c) Vaccine recipients should be observed for at least 30 minutes for signs of a reaction after administration of each vaccine dose (22).Other measures, such as dividing and administering the vaccine by a two-step approach and skin testing with vaccine, are not necessary (22).2.Persons who report having had reactions to egg involving such symptoms as angioedema, respiratory distress, lightheadedness, or recurrent emesis; or who required epinephrine or another emergency medical intervention, particularly those that occurred immediately or within a short time (minutes to hours) after egg exposure, are more likely to have a serious systemic or anaphylactic reaction upon reexposure to egg proteins.Before receipt of vaccine, such persons should be referred to a physician with expertise in the management of allergic conditions for further risk assessment (Figure 2). 3.All vaccines should be administered in settings in which personnel and equipment for rapid recognition and treatment of anaphylaxis are available.ACIP recommends that all vaccination providers should be familiar with the office emergency plan (11).4.Some persons who report allergy to egg might not be eggallergic.Those who are able to eat lightly cooked egg (e.g., scrambled egg) without reaction are unlikely to be allergic.Egg-allergic persons might tolerate egg in baked products (e.g., bread or cake).Tolerance to egg-containing foods does not exclude the possibility of egg allergy (23).Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs and egg-containing foods, plus skin and/ or blood testing for immunoglobulin E antibodies to egg proteins.5.A previous severe allergic reaction to influenza vaccine, regardless of the component suspected to be responsible for the reaction, is a contraindication to future receipt of the vaccine. # Quadrivalent Influenza Vaccines All currently available influenza vaccines are trivalent and contain A(H1N1), A(H3N2), and B viral antigens.There are two antigenically distinct lineages of influenza B viruses referred to as Victoria and Yamagata lineages (24).Immunization against B virus strains of one lineage provides limited cross-protection against strains in the other lineage (25).Because of this and the difficulty of predicting which B virus lineage will predominate during a given season, inclusion of a second influenza B vaccine virus strain in seasonal influenza vaccines has been proposed.A recent analysis indicates that the impact of such a quadrivalent vaccine could result in a modest reduction in influenza-associated outcomes, depending upon adequate vaccine supply, coverage, effectiveness, and incidence of influenza associated with the two B lineages (26). In February 2012, FDA approved a new seasonal quadrivalent LAIV, FluMist Quadrivalent (MedImmune).
This vaccine currently is not anticipated to be available until the 2013-14 influenza season, at which time it is expected to replace the currently available seasonal trivalent FluMist formulation (Table ).Inactivated quadrivalent influenza vaccines currently are in development.These vaccines will be addressed in the ACIP influenza statement as they are approved and become available commercially. -Respiratory distress (e.g., wheezing)? - Gastrointestinal (e.g., nausea/vomiting)? - Reaction requiring epinephrine? - Reaction requiring emergency medical attention? ? # Reported by Lisa Grohskopf
# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR INORGANIC LEAD recommends that employee exposure to inorganic lead in the workplace be controlled by adherence to the following sections.The standard is designed to protect the health and safety of workers for an 8-hour day, 40-hour week over a working lifetime; compliance with the standard should therefore prevent adverse effects of lead 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 criteria and standard will be subject to review and revision as necessary. "Inorganic lead" means lead oxides, metallic lead, and lead salts (Including organic salts such as lead soaps but excluding lead arsenate). "Exposure to Inorganic lead" is defined as exposure above half the recommended workroom environmental standard.Exposures at lower environmental concentrations will not require adherence to the following sections, except for Section 7(a). # Section 1 -Environmental (workplace air) (a) Concentration Occupational exposure to Inorganic lead shall be controlled so that workers shall not be exposed to inorganic lead at a concentration greater that 0.15 mg Pb/m^ determined as a time-weighted average (TWA) exposure for an 8-hour workday. (b) Sampling, Collection, and Analysis Procedures for collection of environmental samples shall be as provided in Appendix I, or by an equivalent method.Analysis of samples shall be as provided in Appendix II, or by any method shown to be equivalent in precision and accuracy to the method specified in Appendix II. # Section 2 -Medical Medical monitoring (biologic monitoring and medical examinations) shall be made available to workers as outlined below. (a) Biologic monitoring Biologic monitoring shall be made available to all workers subject to "exposure to inorganic lead."It consists of sampling and analysis of whole blood, or alternatively, of urine for lead content.Such monitoring shall be performed to ensure that no worker absorbs an unacceptable amount of lead.Unacceptable absorption of lead posing a risk of lead poisoning is demonstrated at levels of 0.080 mg Pb/100 g of whole blood or greater, or at levels of 0.20 mg Pb/liter of urine (with urine specific gravity corrected to 1.024) or greater. Procedures for sampling and analysis of blood or urine for lead shall be as described in Appendix II, or by any method shown to be equivalent in precision and accuracy.In the case of urine, "spot" urine specimens of about 100 ml shall be collected during a workday, and urine specimens with a specific gravity less than 1.010 shall be discarded and another sample obtained. Half of all workers subject to "exposure to inorganic lead" shall be offered biologic monitoring every 6 months, so that each worker 1-2 shall have blood sampling and analysis made available to him yearly. If urine sampling and analysis are chosen instead of blood lead sampling and analysis to satisfy the biologic monitoring requirement, every worker shall have urine sampling and analysis made available to him at 6 month intervals.The schedule of biologic monitoring, above, may be altered if indicated by a professional industrial hygiene survey.If environmental sampling and analysis show that environmental levels are at or greater than the environmental limit, the interval of biologic monitoring shall be halved, i.e. blood analysis shall be conducted quarterly, with each worker sampled semi annually, or urinalysis shall be conducted quarterly on every worker. This increased frequency shall be continued for at least 6 months after the high environmental level has been shown. If a worker's urine lead level is found to be 0.20 mg/liter or greater, calculated to a specific gravity of 1.024, a blood sample shall be obtained and analyzed within two weeks.If a blood lead level of 0.080 mg Pb/100 g or greater is found, and confirmed by a second sample to be taken within two weeks, steps to reduce his absorption of lead shall be taken as soon as the high levels are confirmed. Steps to be considered should include improvement of environmental controls, of personal protection or personal hygiene, and use of administrative controls.A medical examination for possible lead poisoning shall be made available, and the OSHA area industrial hyglenist shall be informed of the results of the biologic 1-3 sampling of those workers with confirmed, high biologic levels of lead. Biologic monitoring shall also be made available where the OSHA area Industrial hygienlst has reason to believe operations produce unusual exposure excursions or that environmental samples do not adequately describe worker exposure. (b) Medical examination Medical examinations shall be available when a variance has been granted permitting administrative controls or use of respiratory protection, for workers with unacceptable absorption of lead as judged by biologic monitoring, or when environmental levels are at or above the environmental standard. These examinations should be made available prior to employee placement and annually thereafter.They should include a physical examination, complete blood counts, blood lead determinations, routine urinalysis (specific gravity, sugar and protein determinations, and microscopic examination), and should record any signs or symptoms of plumbism, if present.Where urine is selected instead of blood for biologic monitoring, the preplacement examination should also include a urinary lead determination.Each employee who absorbs unacceptable amounts of lead as indicated by biologic monitoring shall be examined as soon as practicable after such absorption is demonstrated and confirmed, and at least every 3 months thereafter until his blood or urine lead levels have returned to normal, i.e. below 0.080 mg/100 g of blood or 0.20 mg/liter of urine.If clinical evidence of plumbism 1-4 is developed from these medical examinations, the worker shall be kept under a physician's care, in accordance with applicable Workman's Compensation provisions, until the worker has completely recovered or maximal improvement has occurred. Medical records shall include information on all biologic determinations and on all required medical examinations.These records shall be available to the medical representatives of the employer, of the Secretary of Labor, of the Secretary of Health, Education, and Welfare, and, at the employee's request, to the employee's physician.These records shall be kept for at least five years after the last occupational exposure to inorganic lead. # Section 3 -Labeling (Posting) Areas where exposure to lead at levels over one-half the workroom air standard is likely to occur shall be posted with a sign reading: LEAD (Pb) DANGER! High concentrations of fume or dust may be hazardous to health. Provide adequate ventilation. If environmental levels are at or greater than the environmental limit, or if a variance permitting use of respiratory controls has been granted, add information to the label or placard describing the location of the respirators.Engineering controls shall be used wherever feasible to maintain lead dust and fume concentrations below the prescribed limits. Appropriate respirators shall be provided and used when a variance has been granted to allow respirators as a means of control of exposure to routine operations and while the application is pending. Administrative controls should also be used to reduce exposure. Respirators shall also be provided and used for nonroutine operations (occasional brief exposures above the TWA of 0.15 mg/n?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 class of respirator to be used, the employer shall measure the atmospheric concentration of inorganic lead in the workplace when the initial application for variance Is made and thereafter whenever process, worksite, climate or control changes occur which are likely to affect the lead concentration.The employer shall test for respirator fit and/or make lead measurements within the respiratory inlet covering to ensure that no worker is being exposed to inorganic lead in excess of the standard either because of improper respirator selection or fit, (4) The employer shall provide respirators in accordance with the Table below and shall assure that the employee uses the respirator provided. (5) If both fume and dust are present, the recommended usage is that for fume. (6) Respiratory protective devices described in the following (2) Work clothing should be vacuumed before removal. Clothes shall not be cleaned by blowing or shaking. (3) Work clothing should be changed at least twice a week and more frequent changes, especially in high exposure areas, are suggested. (4) Adequate shower facilities should be available and used. (5) When in the judgment of the OSHA area industrial hygienist contamination of clothing or exposed body surfaces can produce significant secondary exposures, items (1), ( 2), (3), and (4) above shall be mandatory. (2) Respirators shall be available for wearing during evacuation procedures if long distances need to be traversed; supplied air respirators shall be available for employee use where equipment or operations cannot be abandoned. # (b) Exhaust Systems Where a local exhaust ventilation and collection system is used, it shall be designed and maintained to prevent the accumulation of lead dust and fume. (1) Hazardous types of exposure should not be scattered throughout a plant but, rather, concentrated in a single area where special control procedures can be utilized. (2) Air from the exhaust ventilation systems shall not be recirculated into the workroom, and should not be discharged outside the plant so as to create an air pollution problem. (c) General Housekeeping (1) Vacuuming shall be used wherever practicable and no dry sweeping or blowing shall be performed. (2) Emphasis shall be placed upon cleanup of spills, periodic repair of equipment and leaks, proper storage of material«, and collection of lead-containing dust.Records of these surveys, including the basis for concluding th?f f,,r levels are below half the environmental standard, shall be k®pt. # T--7 2 Requirements set forth below apply to inorganic lead exposures, (a) Employers shall monitor environmental levels of lead at least every 6 months, except as otherwise indicated by a professional industrial hygiene survey.If environmental levels are at or above the standard, environmental levels shall be monitored every 3 months. This increased frequency of monitoring shall be continued at least 6 months (i.e. two more quarterly monitoring periods) after the last sampling that demonstrated levels at or above the environmental limit. Periodic environmental sampling shall be performed to coincide with periodic biologic sampling, i.e. shall be performed within 2 weeks of biologic sampling.Metal products and miscellaneous categories account for the bulk of lead consumption.The refining and processing necessary to form these products include heating, grinding, and volatilization and therefore produce potentially hazardous industrial atmospheres.The impression should not be left that all workers in these industries are jeopardized, but rather that such uses of lead places them at risk of lead absorption. # Historical Lead has been used for thousands of years because of its availability and desirable properties.Its low melting point (327 C), ductility, malleability, and weathering resistance enabled its use without the need for the more complex equipment that, in modern times, has enabled the use of other metals such as steel that have more desirable properties for many applications. In the 1800's, there was an increasing recognition of hazards to health associated with lead.It was found that lead could be absorbed by inhalation and ingestion, and that lead absorption was responsible for loss of movement in printers' fingers exposed to heated lead type and for "dry grippes" in pottery and glass workers.In 1839, Tanquerel des Planches^ published a treatise on lead diseases, to which Dana later added notes on the effects of using lead pipes.Progress in recognizing signs of lead absorption was made during the 19th Century also.Burton,^ described in 1840 the "Burtonian Line", a blue line on the gums, as a sign of lead absorption, and chemical methods for detection of lead in blood or urine were developed. The prevalence of lead poisoning in ancient times is speculated upon, and it has been suggested that Rome fell because of the prevalence of lead III-2 poisoning (plumbism) in its citizens.It seems likely that, with the ignorance that existed on the hazards of lead and on methods of limiting exposure, there was a significant incidence of plumbism until its recognition in recent times generated preventive procedures. # Effects on Humans A description of effects of lead absorption can be graphic if based 8 on effects seen in industries earlier in this century.Thus, Mayers can describe effects of lead poisoning, from studies of many years ago, such as loss of appetite, metallic taste in the mouth, constipation and obstipation, anemia, pallor, malaise, weakness, insomnia, headache, nervous irritability, muscle and joint pains, fine tremors, encephalopathy, and colic.In lead colic, there may be severe abdominal pain, such that abdominal surgery has occasionally been performed.In workers, as pointed 8 out by Mayers, who have had repeated attacks of lead colic over many years, there is a tendency towards the occurrence of weakness of extensor muscle groups.This weakness may progress to palsy, often observed as a characteristic "wrist drop" or "foot drop." The important routes of absorption of lead by man and animals are ingestion and inhalation.Eating of lead-bearing paint by children and drinking of lead-contaminated, illicitly distilled whiskey are important sources of non-industrial poisoning.Other sources include exposure to buring battery casings, drinking of liquids from improperly fired, leadglazed containers, and high levels of airborne lead.But man absorbs lead in small amounts not normally leading to poisoning from his food and water, and from the air.These sources lead to the "normal" body burden III-3 of lead.Thus, the lead absorbed in the course of occupational exposure Is superimposed on lead abosrbed from other means. Descriptions of lead poisoning appear in many texts and reviews, for example Airborne Lead in Perspective, a report of the National Epidemiologic Studies L a n e^ examined the causes of death of storage battery workers, including retired workers, and compared data from this group with data from all English and Welsh males of similar ages during the same period of time. Among the retirees who had been exposed to lead, there were found to be greater numbers of deaths than would have been expected, for their ages, from data on the population as a whole.Most of this excess in expected mortality was accounted for by vascular lesions in the central nervous system.Lead workers who died during employment also showed an excess of deaths from this cause. Another study of electric storage battery workers was conducted by the Public Health Service over 30 years a g o .^ In this study, the incidence of various disease states was studied in relation to lead exposure of 766 workers, most of whom (75%) had worked in storage battery plants for more than five years and some of whom (12%) had worked there for twenty years or more.The incidence of disease (other than plumbism) in men exposed at 3 levels of 0.15 mg/m and higher (high exposure group) was compared to the 3 incidence in men exposed below 0.15 mg/m (low exposure group).Special attention was given to cardiovascular disease because of the common belief that chronic plumbism results in arteriosclerosis; however, the data developed by the PHS team did not show that more severe exposure to lead is associated with a significantly higher incidence of vascular disease. The incidence of arteriosclerotic-hypertensive disease was not significantly different in the high and low exposure groups.The responses to a standard III-6 exercise, in terms of return to pre-exercise pulse rates and to systolic and diastolic blood pressure, were also compared, and again the two groups were found not to be significantly different from each other.These lead workers were also found not to be significantly different from other, non-lead, workers in terms of blood pressure.From this, it was concluded that exposure to lead in the storage battery industry does not cause cardiovascular effects. A contrary conclusion was reached by Dingwall-Fordyce and Lane ^ in a study of British battery workers.A significant excess of deaths from cerebro vascular accidents was found in pensioners who had had exposure to lead of sufficient degree to have caused mean urinary lead levels of 0.25 mg/liter during many years of lead work.They compared three groups of workers-those with no occupational lead exposure, those with negligible exposure, and those occupationally exposed to leadwith the general population of English and Welsh males of similar ages.They found a significant excess of death, over that predictable from the population at large, among retirees in the highest exposure group, and this was largely attributable to cerebrovascular accidents.They also examined records of deaths due to cancer in lead workers, both employed and retired, and concluded that there was no association between malignant disease and lead absorption. While they found an excess of deaths from cancer in the negligible exposure group (in the last decade of the 35-year figures only), there was *Urinary lead levels in this group averaged between 0.10 and 0.25 mg/liter for a 20-year period.III-7 a slight decrease in deaths, from that expected from statistics on the whole population, among workers absorbing more than negligible amounts of lead, hence their conclusion that malignant disease is not related to lead absorption.As improved working conditions decreased lead exposure, the excess of cerebrovascular deaths diminished.13 Malcolm recently conducted similar investigations of past and present employees exposed to lead.Since 1927, airborne lead to which these men 3 had been exposed had been limited to 0.15 mg/m , according to Malcolm. He divided the workers into three groups: (A) no exposure, (B) mild exposure, 'ft and (C) severe exposure.Average blood lead in group (C) workers, since 1961, has been 0.065 mg/100 g, from which it may be inferred that the 3 0.15 mg/m air concentration was sometimes exceeded.
Urinary leads in subgroups averaged 0.09 to 0.180 mg/liter, and averaged 0.119 mg/liter for the entire group of workers. Based on comparison of blood pressures of the two exposed groups (B and C) with the control group (A), it was concluded that there was no occupationally induced hypertension (although there might have been leadinduced hypertension before improved hygienic measures were instituted). There was a non-significant increase in chest disease among older retired workers, attributed to other causes, since most of these pensioners lived in an urban area with a higher rate of death from chest disease than that in the country as a whole. "Concentrations of lead in blood are expressed as weight units (such as mg) per 100 ml or 100 g of whole blood.European workers more commonly express blood lead as weight units per 100 ml of blood, while American workers more commonly express blood lead as weight units per 100 g of blood.This document will follow the American custom except in referring to studies reporting blood lead in weight units per 100 ml.The difference between the two expressions is small, about 5% or less.Thus, a blood lead concentration of 0.080 mg/100 g would be equivalent to about 0.084 mg/100 ml. III-8 Unlike the findings of earlier investigators (Dingwall-Fordyce and Lane, and Lane ^ Malcolm found no evidence of increased frequency of cerebrovascular death in his study, which included deaths occurring between 1963 and 1967, while data from the two earlier reports included deaths from 1926 to 1960.Thus, if all three reports are correct in their conclusions, it would seem that improving hygiene has diminished leadinduced cerebrovascular disease. For years, chronic nephritis was thought to be a consequence of plumbism, and an analysis of death rates in the U.K. in 1921 ^a n d in 13 1931 shows a considerable excess in plumbers and painters due to nephritis and to cerebrovascular disease.The question of nephropathy 14 from lead has also been raised by Henderson and Inglis, who showed a relationship between chronic nephritis and excessive lead absorption as indicated by elevated lead levels in bone. L a n e^ described 9 deaths from renal failure in lead workers, men 3 who had been exposed for long periods at lead concentrations around 0.5 mg/m .Terminally, they all had evidence of chronic azotemic nephritis.These men, all of whom worked in storage battery industries for over 20 years, died between the ages of 42 and 52 (average age at death was 48.4).Other than two episodes of colic, there had been no previous history of lead intoxication. In the United States, there have been few reports of renal disease in 13 lead workers, though the PHS survey of storage battery workers discovered an increased incidence of albuminuria in affected workers. # III-9 Animal Toxicity Unlike toxicologic studies of many industrial substances, experimental animal studies of either inorganic or organic lead have contributed far less to an understanding of the toxicology of lead and its compounds than studies on man, and hence have directly contributed very little to the criteria for the standard for lead.The reason is that until recently, much of the investigative effort was directed to the effects of lead on the red blood cell, its urinary intermediates and lead content of blood and urine, all readily investigated in man.Moreover, many of the studies in man or animals relate to detecting changes in biologic constituents of the blood and urine, and hence are relevant more to criteria for biologic standards than to air standards.Thus, the experimental studies discussed herein will be confined to those that confirm or extend the findings in man in these areas and which are related, even if only indirectly, to the criteria for the air standard. In recent years, research investigations have broadened to include biologic systems other than the erythropoietic, and in this way may ultimately provide new criteria for standards.Lead intoxication has been studied for its effects on the rat thyroid, comparative changes in kidneys of rat and man, and the effect of certain trace metal deficiencies on the toxicity of lead.But only a beginning has been made in our understanding of the action of lead on the nervous system; behavioral effects have been A distinct relationship has been found between lead poisoning and the metabolism of nicotinic acid^®; animals poisoned by lead showed a marked decrease in the nicotinic acid content of blood (and urine), indicating an increased utilization of this constituent by lead, and suggesting that lead exerts serious effects on the pyridine nucleotides, either by blocking *This is not to detract from the major recommendation of the PHS conference on lead ° to search for ever-more sensitive indicators of response, because much of value on the mechanism of lead in the biosynthesis of heme has resulted, but it does clearly point out 1) that ultra-sensitive methods may not always have practical utility in estimating and controlling workers exposure, and 2) that, inasmuch as highly sensitive methods are used as the criteria for many, if not most, of the air standards in the U.S.S.R., these standards must be carefully reexamined in the light of their appropriate' ness and suitability. their synthesis or by accelerating the degradation of nicotinic acid. These changes have been suggested as a means of assessing the severity of lead poisoning. In line with the general opinion that toxic substances adversely affect the body's resistance to disease by interfering with natural 31 immunologic processes, Fonzi et al. showed that lead-treated and actively immunized animals developed lesser amounts of gamma globulin than did immunized controls.Similarly, lysozyme, another part of the defense mechanisms of the body, was progressively reduced in the blood serum of 32 dogs administered lead salts for a prolonged period. Although shifts in the body's inorganic elements (copper, calcium 33 phosphorus, sodium and potassium ) from lead poisoning have been 34 reported, their significance in over-all body metabolism is yet to be clearly demonstrated. e. Endocrine Changes.The effects of lead exposure on some aspects of endocrine function have been studied in animals, as well as in man.The excretion of steroids was studied in the urine under different conditions of lead exposure in the hope of finding some evidence of their relation to lead absorption.Adrenal steroids were reported at first to decrease, then to 35 increase considerably during advanced stages of lead intoxication. Vitamin C content of the adrenal gland was decreased in the guinea pig following exposure to l e a d .R elatively little use has been made of animals in the study of other 37 endocrine functions, these functions being readily studied in man.Sandstead has, however, reported that lead, like other heavy metals, impairs the uptake of iodine by the thyroid, and that the conversion of iodine to proteinbound iodine is retarded; females were more affected than males. f. Renal Changes, Goyer has recently reviewed the current state of knowledge of the effects of lead on the kidney; his review is based in large part on his investigations and those of his associates.Prominent among their findings of acute lead poisoning in animals were 1) formation of intranuclear inclusion bodies, 2) mitochondrial swelling with impairment of oxidative and phosphorylative processes, and 3) ami noaciduria (apart from the long-recognized delta-aminolevulinic aciduria); the intranuclear inclusion bodies were a lead-protein complex that may have adaptive function in excessive lead exposure.The acute renal changes progress to a diffuse nephropathy with tubular atrophy and dilation.Rats developed hyperuricemia and in chronic lead poisoning, renal adenocarcinoma.In all but the last, the findings made in rats paralleled those seen in man. g. Trace Metal Interactions.In recognition that lead poisoning is often associated with an iron-deficiency anemia, the interaction of lead on 39 iron deficiency was studied in the rat. An enhancement of lead retention and toxicity was found in the iron-deficient animals as measured by elevated ALA excretion. To control urinary coproporphyrin to normal levels (below 50 pg/liter), 3 they recommended a TLV of about 0.12 mg/m for daily 8-to 10-hour exposures. However, the workers studied by these investigators worked 48 to 60 hours a week.With the increased lead absorption from these working hours, a lower standard than that suitable for a 40-hour week would be indicated. If other criteria were chosen on which to base an air limit, other limits O would have been selected; 0.10 mg/m would have been recommended to keep q urinary lead levels below 0.15 mg/liter, 0.14 mg/m to keep basophilic 3 stippling at 0.3 per thousand, and 0.14 to 0.15 mg/m to prevent anemia. They did not use blood lead as a criterion of effect. The study of Williams, King, and Walford was based on observations of storage battery workers who worked a 40-hour week, and were stable in their exposure.They had worked without job change for a year, there was no recent absence for sickness or vacation, and no change in overtime or productivity for 6 months. Workers in the plastics department were exposed to airborne lead levels of about 0.01 mg/m , while workers in lead handling departments were exposed q to higher levels, up to about 0.3 mg/m .Specific gravities of urine samples averaged 1.020 in the morning and 1.022 at lunch time.They concluded that air levels of 0.20 or 0.15 would result in the blood and urinary lead levels given in Table X-5 (urinary lead levels were corrected for a specific gravity of 1.024; it should be noted that a urinary level of 0.20 mg/liter corrected to a specific gravity of 1.024 would be 0.133 mg/liter corrected to 1.016). These investigators also showed a very low correlation (r = 0.09) between airborne lead and blood hemoglobin levels. Selander and Cramer compared blood lead, urinary lead, and urinary ALA in lead workers.They found several workers with high urinary lead and ALA values in relation to blood lead and attributed this to a metabolic influence of lead; ALA excretion in these workers had seldom fallen to normal values. They recommended that workers removed from lead overexposure not be allowed to return until ALA excretion was normal.Blood lead: 0.08 mg/100 ml Urinary lead: 0.15 mg/liter Urinary coproporphyrin: 0.50 mg/liter Urinary ALA: 20 mg/liter They point out that these values may not be applicable when there are low hemoglobin levels or where chelating agents have been used. Stankovic^ reported on blood and urine lead concentrations, urinary coproporphyrin, and urinary ALA in workmen exposed to lead at various « 1 concentrations of lead in air.In workmen exposed to 0.15 mg/m-and below, the highest Individual blood lead found was 0.06 mg/100 g, the highest urine lead 0.12 mg/liter, the highest urinary coproporphyrin 0.186 mg/liter, and the highest urinary ALA 11.85 mg/liter.There were 48 workers exposed to air lead levels of 0.025 to 0.15 mg/m , whose mean blood lead level was 0.05 mg/100 g (range of 0.03 to 0.06).However, the number of workers exposed to or near 0.15 mg/m was not stated. Zielhuis^ has reviewed and analyzed the data of several other investi gators of human absorption of lead, In terms of the.relationships between, blood lead, ALA, and copToporphyrin.He concluded from analysis of these data that a combination of blood lead greater than 0.08 mg/100 g with values of urinary lead greater than 0.15 mg/liter or urinary ALA greater than 20 mg/llter or urinary coproporphyrin greater than 0.80 mg/liter is evidence of an unacceptable degree of occupational exposure to lead.He did not review the relationships between airborne lead and the several Indices of biological effect of absorbed lead. The selection of 0.08 mg Pb/100 g of whole blood has been described by 52 # Kehoe as the critical concentration of lead in blood below which no case of even olid poisoning has been induced by lead.The higher the concentration of blood lead above 0.08f the greater the likelihood of lead poisoning, though higher concentrations did not mean lead poisoning in all Individuals. The scientific consensus supports the view of Kehoe as it applies to adults. However, even in the hands of the best analyst, there may be a 10% error in a specific lead determination.Thus, an analysis showing a blood level of 0.08 mg/100 g may have a true value of almost 0.09.This may account for the recommendation of some authorities^® that blood lead levels be kept below 0.07 mg/100 g. IV. ENVIRONMENTAL DATA Information presented in this section was selected to satisfy two purposes: (1) link measured environmental and biological levels to specific lead using industries, and (2) to link exposure levels to clinical lead intoxication.Table X- Leaded steel production sometimes generates hazardous occupational exposures to lead.Ruhf^® reported that the highest atmospheric lead concentra tions prevailed during the steel pouring operation in which the lead is added. Other elevated exposures were measured in processes such as the rolling mills. However, because of the intermittent nature of the operations the time weighted average exposure was below the then current limit of 0.20 mg/m^. Ruhf further described control measures and manufacturing techniques whereby lead exposure can be minimized. # IV-4 V. DEVELOPMENT OF STANDARD # Basis for Previous Standards The American Conference of Governmental Industrial Hygienists (ACGIH) ^ has reviewed previous standards for lead in the work environment, and has commented that there are few meaningful data relating to the threshold limit value, probably because most authorities rely primarily on other tests for estimating lead hazards, such as urinary and blood leads, urinary coproporphyrin and ALA, as well as examination of the blood for stippled cells. Nevertheless, attempts were made to control occupational lead poisoning by establishing acceptable air levels to guide engineering control measures.Although the point is not documented, it seems that 3 at one time an air limit value of 0.This ANSI standard provided no basis for its recommendation. # Basis for Recommended Environmental Standard and Biologic Monitoring Earlier in this century, efforts to reduce occupational lead poisoning were based on adherence to hygienic workroom air guides.As more knowledge developed, increasing attention was given to blood and urinary lead levels as guides to reduction of occupational poisoning.Concomitantly, there was increasing attention to better lead analyses.There was also an increasing knowledge of the relationship between levels and rates of absorption and excretion, blood lead levels, and health status. The PHS study by Dreessen et al.^was undertaken during the period q that the workroom air guide of 0.15 mg/m was accepted, but failure to achieve eontrol of airborne lead to this level was common, so findings of slight effects among workers in lead-using industries by Dreessen and co-workers did not invalidate the guide.Though not documented, it appears that many industries have rotated their workers to various jobs to keep blood lead levels below 0.08 mg/100 g; thus, exposure to unsafe workplace air levels did not result in adverse effects on health. # V-2 Consequently, there is a little definitive information from experience in the United States and other countries on the suitability of 0.15 or O 0.20 mg/m as an air-lead level to which workers can be safely exposed over a working lifetime. However, much experience has accrued to show that absorption of lead in amounts resulting in blood lead concentrations of 0.08 mg/100 g or less will not lead to adverse effects on health, and there is information from studies in other countries relating airborne lead levels to blood lead. # It was previously concluded (III.Biologic Effects of Exposure; Correlation of Exposure and Effect) that a blood lead level of 0.08 mg/100 g is useful for delineating acceptable from nonacceptable lead absorption. While levels below 0.08 mg/100 g are indicative of acceptable occupational lead absorption and, if also representative of past absorption of lead by an individual person, also indicative of insignificant risk of lead poisoning, it should not be concluded that lead poisoning will occur if blood lead levels exceed 0.08 mg/100 g. However, there is an increasing risk of poisoning as levels increase above 0.08 mg/100 g, so absorption of lead should be held to amounts that will result in blood lead levels less than 0.08 mg/100 g. As K e h o e^ has stated, "...lead poisoning occurs in man only when certain well-defined conditions have been fulfilled" and that this is quantitatively applied by "...the relationship between the current rate and the extent of the absorption of the inorganic compounds of lead, and the concentration of lead in an accessible tissue of the living body, namely, the blood."Thus, a biologic standard of 0.08 mg of lead per 100 g of whole blood is recommended; it provides a margin of safety in adults, but probably not in children.The extent of this margin of safety is not known, but it seems likely that there will be few, if any, cases of lead poisoning below 0.09 mg/100 g. Kehoe^"- also pointed out the usefulness of urinary lead as an index of current absorption of lead, but added that it was a quantitatively less certain index than blood lead.It may be consistent with this view that 47 Williams, King, and Walford found that the best correlation between air borne lead and biochemical index of effect was with blood lead (r = 0.90) and less correlation with urinary lead (r = 0.82).The study of Williams and # co-workers Indicates that blood levels of 0.08 mg/100 ml is associated (Urinary lead levels of 0.20 mg/liter, adjusted to a specific gravity of 1.024, would be 0.133 mg/liter if the specific gravity were calculated to 1.016.)Thus, the conclusion of Zielhuis"^ that urinary lead greater than 0.15 mg/liter, uncorrected for specific gravity, represents unacceptable absorption of lead is consistent with the selection of a biologic standard for urinary lead of 0.20 mg/liter, so long as the specific gravity correction is used.
ALA and coproporphyrin assays, and blood examinations for hemoglobin, reticulocytes, and stippled cells are useful in the assessment of worker health, but are less useful than blood lead as a single criterion for week. The study most directly relevant to the development of a recommended 47 workplace air standard is the study of Williams, King, and Walford. Their data (Table X-5), from studies of storage battery workers stable in their employment (40-hour work week, no job change in the past year, no recent absence or sickness, no change in overtime or productivity), showed that 3 exposure at 0.15 mg/m resulted in a mean blood lead of 0.060 mg/100 ml. Were mean blood lead the criterion of effect, an air standard much higher 3 than 0.15 mg/m could be recommended, but in order to keep most or all workers' blood lead below 0.084 mg/100 ml (0.080 mg/100 g), it is believed that a mean of about 0.060 mg/100 ml should be achieved.The data of 47 Williams and associates does not provide a basis for interpreting the 3 percentage of workers exposed at 0.15 mg/m that will have blood levels above 0.084 mg/100 ml.However, it is believed that a small percentage will have blood lead levels at or above 0.084 mg/100 ml or 0.080 mg/100 g, so it Is recommended that workers be monitored biologically, by periodic assays of blood lead, or of blood and urinary lead. # V-6 Stankovic^ also compared airborne lead with blood and urinary lead, 3 and in workmen exposed to lead at 0.15 mg/m and below, the highest individual blood lead found was 0.06 mg/100 g, and the highest urinary lead 0.12 mg/liter.However, the number of workers exposed at or near 0.15 mg/m was not stated, so his finding of 0.06 mg/100 g as the highest individual blood lead is not believed to contradict the previously stated inference that some workers The recommended method of sampling air involves collection of 100 liters of air or more, use of breathing zone samplers with sampling at a rate of 2 liters/min.,and collection on 0.45y cellulose membrane filters.Other sampling rates and other collection media (filter paper, nitric acid impinger, electrostatic precipitation) are capable of giving equivalent results.The recommended procedure is described in Appendix I. For analysis of lead in blood, atomic absorption spectrophotometry^ 7 2 7â nd dithizone colorimetry - were considered.Appreciable consonance can be demonstrated between results obtained with atomic absorption and dithizone methods.Both methods have been used for analysis of air samples, and both are concluded to be capable of giving accurate results.After a review of the several procedures involving atomic absorption spectrophotometry, it was concluded that no one of these procedures has been sufficiently standardized. Individual laboratories get excellent results with a specific procedure, but these procedures have not been compared in a number of laboratories. Dithizone colorimetry, on the other hand, has been used for a long time and has been thoroughly studied.The procedures, interferences, sensitivity, and replicability have been studied and are described by Keenan, Byers, Saltzman, and Hyslop.^ The recommended procedure is described in Appendix II. Dithizone colorimetry is a wet chemical method requiring equipment found in most chemical laboratories, but requires meticulous attention to detail and to the prevention of loss and the exclusion of contamination. V-8 Results of lead analysis by this method obtained by well trained technicians are often superior to results obtained by other methods of analysis. # Basis for Biologic Analytical Method Blood lead was selected as the best method, and urinary lead as an accept able method, for judging lead absorption, for reasons discussed in earlier sections (see "Basis for Recommended Environmental Standard and Biologic Monitoring"). Specific details for collection of biologic specimens for lead have described some of the results, from which it is apparent that lead analysis is subject to significant error unless a very high degree of care is used. Methods for the collection of blood and urine are described by Additional methods, such as cell stippling, porphobilinogen determinations, and examination of intranuclear Inclusion bodies have received less acceptance.These biochemical indices are not recommended at this time. They can be sensitive, perhaps too sensitive, but they are not specific for lead, and are judged to be less useful than blood and urinary lead deter minations for estimating the absorption of lead.However, future develop ments may resolve some of the present objections to the routine use of these indices of alterations of heme synthesis in the assessment of lead absorption. The dithizone procedure is recommended for analysis of lead in blood and urine.As discussed in the previous section (Basis for Environmental Sampling Method), the method is capable of good results if meticulous attention is given to details, including sources of contamination and loss.Additional information on the reproducibility and accuracy of the method is given in other portions of the report. # REAGENTS Analytical grade reagents are used.Purification is essential when analyzing biological tissues and fluids because of the very low levels of lead in these materials; purification of reagents may not be required for air samples containing quantities of lead sufficiently greater than that present in the reagent blank.A reagent blank sample is carried through the entire procedure with each set of unknown samples (air, biological, or other type) and its analyzed lead content is subtracted from each analytical result to calculate the net quantity of lead in each unknown sample. A boiling rod is used to prevent bumping in the flasks when distilling reagents.This is prepared by cutting 3 or A mm O.D. glass tubing to a length which is one cm greater than the height of the flask.The tubing is sealed at a spot about one cm above the bottom end which is fire- Use an electric heating jacket on the boiling flask to minimize danger of its breakage, and a boiling rod to prevent bumping, which otherwise would be severe.Discard the first 50 ml of distillate; this may be combined with the acid allowed to remain in the flask at the end of the distillation and used for washing glassware.The reagent is conveniently dispensed from a small automatic burette.No grease should be used on the stopcock.Nitric Acid, 1:99 -Dilute 10 ml of the redistilled, concentrated acid to one liter with doubled-distilled water.Ammonium Hydroxide, Concentrated -Distill in an all borosilicateglass still 3 liters of the ACS reagent grade, 28.0% minimum specific gravity 0.8957 at 60 F, into 1.5 liters of double-distilled water, VIII-2 contained in a 2-liter reagent bottle which is chilled in an ice bath. Continue the distillation until the bottle is filled up to the pre viously marked 2-liter level.Submerge the condenser tube deeply in the water in the receiver, but withdraw it before discontinuing the heat to avoid siphoning back of distillate.This reagent may be pre pared more conveniently from tank ammonia, using a small wash bottle to scrub the gas and a sintered glass delivery tube which extends to the bottom of the reagent bottle.The ammonia gas is absorbed in double-distilled water until the solution reaches the desired specific gravity. Chloroform -Use a brand with a statement on the label that the chloroform passes the American Chemical Society test for suitability for use in dithizone procedures.In addition, each batch of chloroform should be purchased in glass containers only and should be tested as follows in the laboratory to make sure that it is satisfactory for preparing the dithizone solutions: add a minute quantity of dithizone to a portion of the chloroform in a test tube, shake gently, then stopper with a cork.The faint green color should be stable for one day.Our experience has indicated that the procedures for reclaiming Store in a brown bottle in the refrigerator but allow to warm to room temperature before using.Age for at least one day, then standardize as described in the procedure.Restandardize every few months. Sodium Citrate -Dissolve 125 g of the 2 Na^C^H^-O^-11 H2O salt in sufficient distilled water to provide a solution nearly 500 ml in volume. Adjust the pH to 9-10, using a very small quantity of phenol red indi cator solution (strong red color) and fresh, pHydrion test paper to check the pH. Extract in a large separatory funnel with a 100 mg per liter solution of dithizone and finally with the extraction dithizone reagent until a green extract is obtained with the latter reagent.Add a small volume of lead-free citric acid until an orange color (pH 7) appears.Extract the excess dithizone repeatedly with chloroform until a colorless extract is obtained.Remove the last traces of chloroform. Hydroxylamine Hydrochloride -Dissolve 20 g of the salt in distilled water to provide a volume of 65 ml.Add a few drops of m-cresol purple indicator, then add ammonia until the indicator turns yellow (pH 3). Add a sufficient quantity of a 4% solution of sodium diethyldithiocarbamate to combine with metallic impurities, then mix.After a few minutes extract repeatedly with chloroform until the excess carbamate reagent has been removed, as indicated by the absence of a yellow color in the final chloroform extract tested with a dilute copper solution. # VITT-4 To the aqueous solution of the hydroxylamine hydrochloride add redistilled, 6N hydrochloric acid until the indicator turns pink, and adjust the volume to 100 ml with double-distilled water. Potassium Cyanide -(Danger!Highly poisonous!I) To 50 g of potassi um cyanide in a beaker, add sufficient distilled water to make a sludge. Transfer the sludge to a separatory funnel previously marked to Bhow 100-ml volume.Add a small amount of distilled water to the beaker and warm. (Potassium cyanide cools the solution as it dissolves, thus retarding the solution process.)Add this warm water to the separatory funnel but do not permit contents to exceed the 100-ml mark.Shake, then let stand until the contents come to room temperature.A practically saturated solution results. Extract the lead by shaking repeatedly with portions of the extrac tion dithizone solution until the lead has been removed.Part of the dithizone dissolves in the aqueous phase but enough remains in the chloroform to color it.A green extract indicates that all the lead has been completely extracted.Most of the dithizone in the aqueous phase is then removed by repeated extractions with pure chloroform. Dilute the concentrated solution of potassium cyanide with double-distilled water to 500 ml.It should not be necessary to filter the solution, if the directions are followed precisely.Extraction is carried out before dilution because the higher pH of the dilute solution is less favorable. V I I I -5 (NOTE: A colorless solution usually results if above directions are followed.Occasionally aging results in a brown color or precipitate due to polymerization of hydrogen cyanide.This does not interfere with use of the reagent if it is carefully decanted.Old potassium cyanide reagent may lose enough strength to cause insufficient complexing of large amounts of zinc.)Ammonia-cyanide Mixture -Mix 200 ml of the purified 10% potassium cyanide reagent with 150 ml of distilled ammonium hydroxide (specific gravity 0.9, corresponding to 28.4% NH^) and dilute to one liter with double-distilled water.If the measured specific gravity of the ammonia is not 0.9, use the equivalent volume as calculated from a table of specific gravity vs. percentage ammonia. Standard Lead Solution -Dissolve 1.5984 g of pure lead nitrate in one liter of 1:99 nitric acid to provide a strong stock solution containing one mg Pb per ml.Pipet exactly 20 ml into a 500-ml volumetric flask and make to mark with 1:99 nitric acid to give a dilute stock solution containing 40 y g Pb per ml. (A standard lead solution, 10 yg Pb/ml, was stable in 1:99 nitric acid for three years.)Prepare a working solution, containing 2 y g Pb per ml, just before it is needed by pipetting 5 ml of the dilute stock solution into a 100-ml volumetric flask and making to mark with 1:99 nitric acid. Phenol Red -0.1% aqueous solution. Ashing Aid Acid -Dissolve 25 g potassium sulfate in sufficient redistilled concentrated nitric acid to make 100 ml. # VIII-6 White Petrolatum -Supplied in a glass jar, for greasing stopcocks. To check on the purity, put a pinch of this petrolatum in a beaker, add a few milliliters of the standard dithizone and swirl.If the dithizone is no longer green after a few minutes, the material is unsatisfactory for greasing stopcocks. (This wash nitric acid may be used repeatedly until it loses its strength.) # APPARATUS Then rinse successively with three or four portions each of tap water, distilled and double-distilled water.Set the beakers upright on the bench and cover with a clean dust-case or a large piece of filter paper (or otherwise protect from dust).Under no circumstances is glassware turned upside down to drain on a towel or cheesecloth placed on a laboratory bench.Use an oven operating at 105 C if dry glassware is required. # VIII-8 Separatory funnels are rinsed with tap water immediately after use.If a high lead sample was present or if a visible precipitate remains on the inside, it is rinsed with a small portion of 1 : 1 wash nitric acid (which is discarded), followed by tap water.The stoppered funnels are stored in double-deck racks. Immediately before use, stopcocks are regreased if necessary.. Then the funnels are rinsed with wash acid, four times with tap water, and four times with dis tilled water.Each rinse is accomplished by shaking with the stopper, then draining through the stopcock with two or three turns. Spectrophotometer tubes are rinsed four times each with tap and distilled water immediately after use.They are placed upright in a large beaker and dried in an oven at 105 C, then stored under a dust-cover.Occasionally they are cleaned with dichromate-sulfuric acid and nitric acid as described above. (NOTE: With this method of cleaning glassware we have never encountered cross-contamination from chromium, lead, or from any other trace element being determined routinely in this laboratory.) ANALYTICAL PROCEDURE 1.Warm the sample ash (prepared as described in the following sections) with 2 ml of concentrated nitric acid for a few minutes, then add 25 ml of distilled water, heating on the hotplate until a clear solution is obtained. 2.Cool to room temperature.Add to the solution in the beaker one ml of hydroxylamine hydrochloride, 4 ml of sodium citrate (10 ml is required for a urine sample), one drop of phenol red indicator, and titrate to a strong red color with concentrated ammonia reagent.Add a few drops excess of ammonia to make sure that the pH is between 9 and 10, using fresh pHydrion test paper to check the pH. (NOTE: Phenol red has a weak orange-red color in strong acid, yellow in weak acid, and a red color in alkaline solution.Do not mistake the VIII-9 first color for that produced in alkaline medium!) 3.Transfer the sample quantitatively with double-distilled water rinsings to a 125-ml Squibb separatory funnel containing 5 ml of the potassium cyanide reagent. 4.Add 5 ml of the extraction dithizone and shake two minutes, after releasing the initial pressure by momentarily opening the stopcock of the inverted separatory funnel.Allow the chloroform layer to settle. 5.Draw off most of the extraction dithizone into a second funnel containing exactly 30 ml of 1:99 nitric acid. 11.Set the spectrophotometer at a wavelength of 510 nm. 12.Set the instrument at zero absorbance using the zero lead standard solution. 13.Read the absorbances of the samples and of the reagent blank.Finally, the residue will remain pale yellow or light brown (due to iron con tent) after heating for 5-10 minutes at the high temperature.Avoid excess baking at this stage as the ash will become decomposed to a difficultly soluble form.It is now ready for solution and analysis.Report results as milligrams of lead per 100 grams of whole blood. # COLLECTING AND ASHING URINE SAMPLES Use lead-free, narrow-mouthed, reagent-type, borosilicate, 250-ml bottles provided with standard taper glass stoppers to collect grab samples of VIII-14 urine.Add 2.0 ml of a 37% formalin solution as a preservative, shaking the bottle 10-12 times after the contribution of the urine to mix the specimen with the formalin thoroughly. Alternatively, urine specimens may be collected in 125-ml polyethylene bottles containing as a preservative 100-200 mg of EDTA (acid form) per bottle.This is convenient and economical for shipping samples considerable distances. If the urine sample is clear and only one or two days old, measure a 50 ml portion into a graduated cylinder.However, if the sample is older, much of the lead may be in a sediment or on the walls of the bottle and must be dissolved before aliquoting.Transfer the entire specimen to a glassstoppered graduated cylinder, record the volume, rinse the sample bottle with three small portions of concentrated nitric acid and add these rinsings to the cylinder.Mix thoroughly (Caution!Old samples may foam over.)Note the total volume and remove an aliquot equivalent to 50 ml of urine for analysis.Transfer the aliquot portion to a lead-free, 250-ml borosilicate Phillips beaker and add 5 ml of redistilled concentrated nitric acid. Evaporate just to dryness on a hotplate operating at about 130 C. Cool, add sufficient nitric acid to moisten the residue and cover the beaker with a lead-free watchglass.Heat on the 130 C hotplate and then alternately bake for a few minutes and digest with minimal amounts of nitric acid (as des cribed in the ashing method for blood) until a white residue remains after the final heating for 5-10 minutes at the high temperature.The sample is now ready for solution and analysis.Report results as milligrams of lead per liter of urine.
# VIII-15 PROCEDURE FOR AIR SAMPLES It is convenient to wash out samples in electrostatic precipitator tubes with redistilled ethanol, using a special policeman made with a rubber disc cut to fit the tube like a piston, and transferring the sample through a short stem funnel into a 250-ml Phillips beaker; gently evaporate just to dryness. (Ethanol is helpful in removing greasy deposits on the walls of the precipitator tube.Some chemists may prefer hot 1 to 5% nitric acid to transfer the sample.)Transfer impinger samples or membraine filter samples to Phillips beakers.If little ash is expected (usually for impinger or membrane filter samples), add 2 ml of ashing aid acid reagent. (The presence of this salt will prevent loss of lead by glazing onto the surface of the beaker during ashing.)Otherwise add 1-2 ml nitric acid.Evaporate to dryness.Continue ashing with nitric acid at a moderate heat until organics are destroyed. Dissolve the ash in 2 ml of concentrated nitric acid and distilled water and then transfer quantitatively to a 100-ml volumetric flask and make to mark.Pipet a suitable aliquot into a separatory funnel, contain ing about 5 ml of double-distilled water, add sufficient additional double-distilled water to make the total volume about 25 ml, and apply the Analytical Procedure, starting with step 2.In step 3, as the sample is already in a separatory funnel, merely add the cyanide. The amount of lead present in the aliquot may be estimated as described in step 6.If it is less than a few micrograms, an additional aliquot may be added to the same funnel, and the pH readjusted with ammonia. The extraction is then continued, and extracts combined with those collected previously in the second funnel.If the estimated amount of lead exceeds the range of the method (25 micrograms), take an aliquot as described in Note 2, step 8. When calculating the results, make allowance for the total number of aliquots.If convenient, aliquot the reagent blank in the same manner so that the correction represents the same amounts of ashing and extraction reagents as are present in the sample.However, the blank correction is usually small for air samples.Report results as milligrams of lead per cubic meter of air. This may be indicated as a range of maximum amount, i.e., 10-20% V; 10% max.W. From reference SB V
This manual introduces the reader to the principles and practical tools of crisis and emergency risk communication (CERC).Principles in this manual adapt (1) writings of classical rhetoricians; (2) a wealth of modern crisis, issues management, communication theory, and psychological theory; and (3) lessons learned from the real and often painful world of experience, old-fashioned trial and error.CERC addresses a number of topics critical to successful public, partner, and stakeholder communication during crises and emergencies.This is not intended to be an in-depth manual on risk communication, issues management, crisis communication, or disaster communication.It is an amalgamation of all of these, incorporated from theory and practical applications.CERC draws on the work of many experts including Drs.Peter Sandman and Vincent Covello; therefore, no single chapter is a complete source for a specific discipline.The chapters are meant to help those who are charged with these responsibilities, but who may not be steeped in these subjects, to manage the task of planning and implementing CERC activities.When possible, we have provided resource sites that offer more in-depth materials on a particular subject.CERC is the attempt by public health professionals to provide information that allows individuals, stakeholders, and entire communities to make the best possible decisions for their well-being during a crisis or emergency.CERC includes communicating to these groups regarding decisions made by response organizations within nearly impossible time constraints.CERC principles teach us to accept the imperfect nature of choices as the situation evolves.Communication in a Crisis is Different 29 1.We simplify messages.29 2.We hold on to current beliefs.29 3.We look for additional information and opinions.30 4.We believe the first message.The Perception of Risk 32 1.Accept and involve the public as a legitimate partner.33 3.Be honest, frank, and open.33 4.Coordinate and collaborate with other credible sources.34 5.Meet the needs of the media.35 6.Speak clearly and with compassion.35 7.Plan carefully and evaluate performance.CERC in Action 36 1.Don't Dismiss Outrage.36 2.Be careful with risk comparisons.37 3.Don't over-reassure.37 4.Put the good news in secondary clauses.37 5.Acknowledge uncertainty.38 6.Give people meaningful things to do.#Dear Reader, In 2002, the Centers for Disease Control and Prevention (CDC) decided to fill a critical training gap and resource need and developed the Crisis and Emergency Risk Communication manual.When it was written, the central role of crisis communication in public health responses to crises was beginning to be recognized.Since that time, thousands, perhaps tens of thousands, of health, emergency management, and government professionals have been trained using the original CERC Manual and associated materials in the United States, Canada, Europe, and many other locations. While CERC principles are timeless, new information has been developed, new examples have emerged, and new understandings have been created.Crisis communication is by definition a very dynamic field, and for any work to maintain its state-of-the art relevance, revisions and updates are required.Risk Communication 7 # Table of Contents Issues Management Communication 7 Crisis and Emergency Risk Communication 8 Emergencies, Disasters, and Crises The Communication Lifecycle 10The Pre-crisis Phase 11 The Initial Phase 12 The Maintenance Phase 13 The Resolution Phase 14 The Evaluation Phase 14 The Role of CERC Tables Table 1-1 "CERC is a way to talk to people, a set of principles that allow us, in the heat of a crisis when the unthinkable happens, to be able to get a message through to people in a way that they can actually understand it and act on it." Dr. Barbara Reynolds, Centers for Disease Control and Prevention "We will always be giving people the best information we have and the best recommendation based on what we know the best information is right now.That's one of the ways you can be first and be credible, because it sets the expectation that things will change and we are working to learn more.That's always a challenge, but I think it is our best practice." # Dr. Marsha Vanderford, Centers for Disease Control and Prevention Throughout this book, six principles 1 of effective crisis and risk communication are emphasized: 1.Be First: Crises are time-sensitive.Communicating information quickly is almost always important.For members of the public, the first source of information often becomes the preferred source. 2.Be Right: Accuracy establishes credibility.Information can include what is known, what is not known, and what is being done to fill in the gaps. 3.Be Credible: Honesty and truthfulness should not be compromised during crises. 4.Express Empathy: Crises create harm, and the suffering should be acknowledged in words. Addressing what people are feeling, and the challenges they face, builds trust and rapport. 5.Promote Action: Giving people meaningful things to do calms anxiety, helps restore order, and promotes a restored sense of control. 6.Show Respect: Respectful communication is particularly important when people feel vulnerable.Respectful communication promotes cooperation and rapport. Well-planned and well-executed CERC, fully integrated into every stage of the crisis response, helps ensure that limited resources are managed well and can do the most good. # Types of Disasters The most common disasters 2 are natural disasters, but the line between natural and manmade often blurs, as it did with Hurricane Katrina.Based on the disaster, both CDC and the Federal Emergency Management Agency (FEMA) have grouped them by type (see lists of specific types extracted from publications by both agencies in Table 1-1 and Table 1-2 at the end of this chapter). While there are many types of disasters, most planners try to take an all-hazards approach.Most planners create general plans that are designed such that they can be adapted to specific situations, rather than trying to plan separately for every possible type of disaster.In addition, all disasters are managed locally until local resources are overwhelmed, at which point state, regional, national, and international resources are deployed.While an all-hazards approach works in operational response, there will be important distinctions in the way communication is executed by type of disaster and these differences require consideration during planning.3 # A Changing World Disasters test emergency response capabilities.The ability to deal effectively with disasters is becoming more relevant, because the factors that tend to increase risks are also increasing. Infectious diseases remain a danger to all people, no matter their age, gender, lifestyle, ethnic background, or economic status.They remain among the most common causes of suffering and death.These infections impose a huge cost to society.Since it is never certain when or where new diseases will arise, we must always be prepared. # Emerging Infectious Diseases and Antibiotic Resistance In the years following World War II, it was widely believed that humans were winning the war against infections.We learned antibiotics could treat life-threatening bacterial diseases.Dreaded childhood diseases, such as polio, could be prevented through vaccinations.However, this hopefulness was premature.Listed are just a few events over the last 60 years that demonstrate that infections are here to stay: As early as the 1950s, penicillin began losing its ability to cure Staphylococcus aureus infections, also known as staph.12 In the 1970s, there was a resurgence of sexually transmitted diseases.12 Also during the 1970s, new diseases were identified, such as Legionnaires' disease, toxic shock syndrome, and Ebola.12 At the same time, antibiotic-resistant bacteria became more common in hospitals, spreading to patients and into communities.12,13 In 1981, AIDS was first reported by CDC.14 Flu season remains a yearly threat.Experts say it is possible that a new pandemic strain might emerge that could span the globe and reduce the world's population.15 In 1997, the avian influenza, H5N1, scare in Hong Kong raised the specter of a possible global pandemic and jolted the world.16 The emergence of H1N1 in 2009 was yet another sign that a deadly pandemic is possible.16 # Increased International Travel International travel and trade play a role in the rapid spread of disease and the resistance to antibiotics.A microbe originating in Africa or Southeast Asia can arrive on North American shores within 24 hours.In the U.S., published reports show that the majority of multidrug-resistant typhoid cases originated in six developing countries. The exact number varies, depending on population criteria and how city limits are defined, but according to one source, 17 as of January 2012, 26 cities worldwide had populations above 10 million.While there are many heavily populated cities in developed countries, experts suggest that future growth in urban areas will occur mainly in developing countries.These are where we are likely to see the following problems: # Poverty Population density # Lack of sanitation Bacteria and viruses growing and rapidly spreading The threat from terrorism is real, ongoing, and evolving.State-sponsored terrorism appears to have declined recently, but transnational groups are emerging.They tend to have dispersed networks and decentralized leadership that is harder to disrupt.Increasingly, terrorists' acts are initiated and executed at lower levels and decentralized units. # Increased Terrorism 18 Terrorists are increasingly adept and technically savvy in their ability to defeat counter-terrorism measures.As security around government and military facilities improves, terrorists are seeking out vulnerable targets for mass casualties.They do this according to well-conceived plans, such as: Employing advanced tools, such as improvised explosive devices Using strategies such as simultaneous attacks, which kill or injure many people at once An act of biological or chemical terrorism may range from the dissemination of anthrax spores to intentional food product contamination.Accurately predicting when and how such an attack may occur is impossible.The probability of biological or chemical terrorism cannot be ignored.The possibility of mass causalities plus widespread social and economic disruption means threats must be taken seriously. study and practice can fulfill a basic need for public health professionals as they react to a public health emergency.This book reflects the special combination of "crisis and emergency risk communication."Together, they help us create effective strategies. # Crisis Communication The term "crisis communication" is generally used in two ways: 1.It describes the communication activities of an organization or agency facing a crisis.They need to communicate about that crisis to their organization, various partners, and the public.Typically, a crisis: y Occurs unexpectedly y May not be in the organization's control y Requires an immediate response y May cause harm to the organization's reputation, image, or viability As an example, the 1984 Bhopal gas leak in India 19 was a crisis confronted by an organization that faced blame for the situation.The company faced legal challenges and negative public reactions for many years after the crisis.This organization faced some legal or ethical responsibility for the crisis (unlike a disaster, where, for example, a tornado does the damage). The public and many stakeholders judged the organization based on their actions throughout the response. For example, leaders might need to evacuate a community in advance of a hurricane.In this definition, the organization is not facing a threat to its reputation or image.The effort to inform and warn the public is universally recognized as important.Many public alert systems, like the old Emergency Broadcast System and the new Commercial Mobile Alert System are based on this form of crisis communication. The underlying thread in both forms of crisis communication is that an unexpected and threatening event requires an immediate response.The content, form, and timing of the communication can help reduce and contain the harm or make the situation worse.Crisis may also imply lack of control by the involved organizations based on the timing of the incident. # Risk Communication The field of environmental health elevated the prominence of risk communication.Through risk communication, the communicator hopes to provide the audience with information about the expected type (good or bad) and magnitude (weak or strong) of an outcome from a behavior or exposure.Typically, risk communication involves a discussion about adverse outcomes, including the probabilities of those outcomes occurring.In some instances, risk communication has been used to help an individual make a decision in response to many questions, including the following: Should I undergo a medical treatment? What are the risks of living next to a nuclear power plant?Do I elect to vaccinate a healthy baby against whooping cough? In some cases, risk communication is used to help individuals adjust to something that has already occurred, such as exposure to harmful carcinogens, possibly putting them at greater risk for cancer.Risk communication would prepare people for that possibility.If warranted, the communication would offer steps to take to lower their chance of dying from cancer, such as screenings. # Issues Management Communication Issues management communication can be similar to crisis communication.An issue is a public question that has generated some interest by stakeholders.Questions about vaccine safety, for example, have generated concern among some groups.Their worry has sparked a great deal of public debate.Issues management involves using communication to influence how the organization responds to the issue and how it is potentially resolved.In some cases, an issue can become a crisis.Issues managers have forewarning that an issue is developing.Issues may develop more slowly and continue over extended periods.Managers typically have more time to respond to issues than they would to a crisis.Again, the organization or agency is central to the event. # Crisis and Emergency Risk Communication CERC combines the elements of crisis communication and risk communication as they are used during an emergency response.CERC involves experts who provide information allowing individuals or an entire community to make the best possible decisions about their well-being.Communicators must also help people accept the imperfect nature of choices during the crisis.CERC also differs from pure risk communication in that a decision must be made within a narrow time constraint.The decision may be irreversible, the outcome of the decision may be uncertain, and the decision may need to be made with imperfect or incomplete information. Communicators must inform and persuade the public in the hope that they will plan for and respond appropriately to risks and threats.The work presented here shows that your organization should follow CERC principles when responding to a crisis.If you fail to use CERC, you may fail to effectively communicate key information that could save lives. # Emergencies, Disasters, and Crises What do emergencies, disasters, and crises have in common?Simply that something bad has happened or is happening, that it is surprising on some level, and that an immediate response is required.When something bad or unexpected happens, it may be called an emergency, a disaster, or a crisis depending on who is involved, the magnitude, and the current phase of the event. A crisis involves many players and, depending on the location and the nature of the event, different agencies and groups take different roles.Government agencies that may be involved in the response at some level include the following: # Businesses It is important to remember that at the center of any crisis are those individuals, groups, and communities most directly affected.All disasters are local.The community is the first and most important responder. The role of government agencies is outlined by a set of federal guidelines called the National Incident Management System (NIMS).20 NIMS is a national standard for organizing agencies and improving coordination of incident management operations.Communication is a key part of NIMS.It applies to creating systems where agencies can communicate with each other, what is called interoperability.It also ensures that good communication occurs with the public. "Numerous after-action reports from major incidents throughout the history of emergency management in our nation have cited communications difficulties among the many responding agencies as a major failing and challenge to policymakers." The National Emergency Communications Plan The Communication Lifecycle Understanding the pattern of a crisis can help communicators anticipate problems and appropriately respond.For communicators, it's vital to know that every emergency, disaster, or crisis evolves in phases.The communication, too, must evolve through these changes.By dividing the crisis into the following phases, the communicator can anticipate the information needs of the media, agencies, organizations, and the general public.For each of these phases, specific types of information need to be created and delivered to your audience. # Figure 1-1.Crisis and Emergency Risk Communication (CERC) Lifecycle Be prepared. Foster alliances. # Develop consensus recommendations. Test messages.
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# acute renal failure, acute respiratory distress syndrome, and disseminated intravascular coagulation.He required hemodialysis and mechanical ventilation and underwent bilateral foot amputations subsequently because of ischemia.After a 6-week ICU stay, he recovered and was discharged to a long-term-care rehabilitation facility. Case 2.On November 3, the wife, aged 47 years, of patient 1 also became ill.On November 5, she sought medical care for fever, fatigue, myalgias, and unilateral inguinal swelling.A physical examination noted tender right inguinal and femoral adenopathy with overlying erythema and induration.Her temperature was 102.2 º F (39.0 º C), blood pressure was 120/72 mm Hg, and oxygen saturation was 98% on room air.WBC was 9,500/µL, and platelet count was 189,000/µL. Aspiration of the inguinal lymph nodes did not yield any material.The patient received a presumptive diagnosis of bubonic plague because of her clinical signs and symptoms and the recovery of Y. pestis from her husband's blood culture.She was hospitalized and treated with gentamicin, doxycycline, and ticarcillin-clavulanic acid, followed by a 14-day course of oral Epidemiology - Plague is usually transmitted to humans by the bite of an infected rodent flea. -Incubation period is 1-7 days for bubonic plague and 1-4 days for pneumonic plague. -Case-fatality rate for untreated bubonic plague is >50%. - Domestic pets (i.e., cats and dogs) can carry plagueinfected fleas. -Risks include hunting, trapping, cat ownership, and rural residence in areas where plague is endemic. -Person-to-person transmission can occur after contact with a suppurating lesion (bubonic plague) or via respiratory droplets (pneumonic plague). -Naturally acquired plague typically begins as bubonic plague; intentional release (i.e., terrorism) would manifest chiefly as pneumonic plague.Clinical findings - Signs and symptoms include fever, chills, malaise, sore throat, and headache. -A lymphadenitis (bubo) commonly develops; inguinal lymph nodes are affected in 90% of cases. -Infection can progress to shock (septicemic plague) and pneumonia (pneumonic plague).Laboratory testing - Bipolar staining, "safety pin" ovoid, gram-negative organisms are suggestive of plague infection. -Direct fluorescent antibody testing or antigen capture enzyme-linked immunosorbent assay are specific tests. -Confirmatory testing includes culture or a fourfold or greater change in antibody titer.Recommended treatment - Primary therapy: streptomycin; alternatively use gentamicin, tetracyclines, or chloramphenicol. -Mortality from bubonic plague is reduced markedly by appropriate therapy. -Patients with primary pneumonic plague are not likely to survive if they do not receive adequate therapy within 18 hours after onset of respiratory symptoms.Prevention and reporting - Educate the public about plague symptoms, mode of transmission, and prevention methods. -Use insect repellents. - Rodent-proof buildings. - Avoid handling rodents or camping near rodent burrows. - Treat dogs and cats in rural areas where plague is endemic with insecticides. -Report plague cases and sick or dead animals to health authorities. 80% of these exposures occurred in peridomestic environments, particularly those that provided abundant food and harborage for flea-infested, plague-susceptible rodents.Travelers can acquire plague in one area and become ill in another area where plague is not endemic (i.e., peripatetic plague) (3)(4)(5)(6)(7).Although rare, peripatetic plague is more likely to result in fatal outcomes because of delays in seeking treatment or misdiagnosis in areas where health-care providers might be less familiar with the disease (3)(4)(5)(6)(7).In the current state of heightened awareness of possible terrorism, peripatetic cases also might be confused with those arising from an intentional release of plague bacteria.The two cases described in this report did not cause such confusion because the initial history provided a plausible exposure.In addition, both patients had inguinal adenopathy, indicating that transmission was from bites of infectious fleas rather than inhalation of airborne materials, the route considered more likely for terrorism (8).However, intentional release should be considered as a cause of cases occurring outside an area where plague is endemic, particularly for patients with primary pneumonic or primary septicemic plague. Plague prevention depends on the timely implementation of preventive measures, including public education, applying insecticides to kill fleas, using various personal protective measures (e.g., common insect repellents), and avoidance of sick or dead animals (2) (Box).A vaccine is not available in the United States.The rapid identification of peripatetic cases depends on public health surveillance systems that include the availability of laboratory expertise and facilities to provide rapid presumptive evidence and laboratory confirmation of Y. pestis infection.Because NMDOH had identified plague previously on the patients' property, the patients were able to alert clinicians of their potential plague exposure, which enabled early diagnosis and prompt treatment.NYCPHL, which had received training and reagents for diagnosis of Y. pestis as part of a nationwide effort to enhance terrorism response capabilities (9), also performed DFA and PCR analyses that presumptively identified Y. pestis as the bacterium cultured from patient 1.This was later confirmed by phage-lysis and other analyses.Genotyping at CDC indicated that the isolate was indistinguishable from (by PFGE) or highly similar to (by MLVA) an isolate obtained earlier in the year from wood rat fleas collected on the patients' property (10). The findings in this report highlight how clinical, epidemiologic, and laboratory programs can act in a coordinated manner to diagnose peripatetic plague cases rapidly and identify probable exposure sites and sources of infection.Communication between public health and law enforcement agencies remains paramount in the effective diagnosis, treatment, and investigation of infections with potential terrorism agents.These capabilities have been enhanced, particularly in areas such as NYC, where plague is not endemic by a series of efforts undertaken by local, state, and federal agencies to prepare for the possibility of terrorist attacks.for 2002 † , which indicate a marked nationwide increase in coverage with >1 dose of varicella vaccine (VAR), substantial uptake for >3 doses of pneumococcal conjugate vaccine (PCV), generally steady coverage levels for other vaccines nationwide, and continued wide variability in coverage among the states and selected urban areas. To collect vaccination data for all age-eligible children, NIS uses a quarterly random-digit-dialing sample of telephone numbers for each of the 78 survey areas.NIS methodology, including how the responses are weighted to represent the population of children aged 19-35 months, has been described previously (1,2).During 2002, health-care provider vaccination records were obtained for 21,317 children.The overall response rate for eligible households in 2002 was 62.3%. National vaccination coverage with >1 dose of VAR increased from 76.3% (95% confidence interval = ±0.8%) in 2001 to 80.6% (95% CI = ±0.9%) in 2002.Coverage for >3 doses of PCV, reported for the first time, was 40.9% (95% CI = ±1.1%).For all other vaccines, coverage levels remained steady during .For all combined vaccine series reported previously, coverage remained steady (Table 1).In 2002, coverage was reported for the 4:3:1:3:3:1 § series, which includes >1 dose of VAR.Coverage in 2002 for the 4:3:1:3:3:1 series was 65.5% (95% CI = ±1.1%), compared with 2000 and 2001, when coverage for this series was 54.1% (95% CI = ±1.0%) and 61.3% (95% CI = ±1.0%), respectively (Table 1). In 2002, substantial differences remained in estimated vaccination coverage among the states.The estimated coverage with the 4:3:1:3:3 ¶ series ranged from 86.2% in Massachusetts to 62.7% in Colorado (Table 2).Variability among the 28 selected urban areas was slightly less than that among the states.Among the 28 selected urban areas, the highest estimated coverage for the 4:3:1:3:3 series ranged from 81.1% in Santa Clara County, California, to 57.5% in Newark, New Jersey (Table 2).Changes in national level coverage from 2001 to 2002 with all vaccines other than VAR and PCV were so small that they are unlikely to have a major public health impact.Although coverage with recommended vaccines for each new birth cohort remains high, vigilance is needed to maintain these high levels.Eliminating the coverage disparity between states and urban areas with the highest and lowest coverage remains a priority.If vaccine-preventable disease is introduced in an area with low coverage, groups of susceptible children might serve as a reservoir to transmit disease. Because coverage with >1 dose of VAR attained a level approximately equal to that of >4 doses of DTaP, coverage for the 4:3:1:3:3:1 series, which includes VAR, was assessed and presented for the first time in this report.From 2000 to 2002, steady increases were observed.The 2002 NIS cohort was the first entire NIS birth cohort to be eligible for PCV.Coverage with >3 doses of PCV (40.9%) was similar to coverage for VAR in 1998 (43.2%), the first year for which the entire NIS birth cohort was eligible for that vaccine.Uptake for >3 doses of PCV showed steady quarterly increases (Q1 = 24.5%; Q2 = 35.3%; Q3 = 48.8%; Q4 = 56.3%), with a similar trend for >4 doses. The findings in this report are subject to at least three limitations.First, NIS is a telephone survey; although statistical weights adjust for nonresponse and households without telephones, some bias might remain.Second, although NIS relies on provider-verified vaccination histories, incomplete records and reporting could result in underestimates of coverage.The estimation procedure assumes that coverage among children whose providers do not respond is similar to that among children whose providers respond.Finally, although national level estimates are precise, estimates for states and urban areas should be interpreted with caution (3); CIs are wider for state and selected urban areas compared with national estimates. During the time that children in the 2002 cohort were to be vaccinated, vaccines in short supply included DTaP; measles, mumps, and rubella (MMR); VAR; and PCV (4-7).When DTaP was in short supply, approximately 86% of the NIS cohort needed >1 dose of the vaccine to stay on schedule.For MMR, VAR, and PCV, the percentages were approximately 6%, 21%, and 37%, respectively.NIS has sufficient power to detect a moderate (e.g., 15%) decrease in coverage even among the 6% of children due to receive a dose of MMR during the period it was in short supply; no effect on coverage was noted for any vaccine or series.These shortages affected children, their parents, and health-care providers; however, many aspects of vaccine delivery are not reflected by coverage attained among children aged 19-35 months.For example, if vaccine was unavailable at a health-care provider visit, another visit could have been made at a later time when vaccine was † For the January-December 2002 reporting period, NIS included children born during February 1999-June 2001. §Comprises >4 doses of diphtheria and tetanus toxoids and pertussis vaccine, diphtheria and tetanus toxoids, and diphtheria and tetanus toxoids and acellular pertussis vaccine (DTP/DT/DTaP); >3 doses of poliovirus vaccine; >1 dose of measles-containing vaccine (MCV); >3 doses of Haemophilus influenzae type b vaccine (Hib); >3 doses of hepatitis B vaccine (hep B); and >1 dose of VAR vaccine. ¶Comprises >4 doses of DTP vaccine, >3 doses of poliovirus vaccine, >1 dose of MCV, >3 doses of Hib vaccine, and >3 doses of hepB vaccine. # Vaccination Services in Postwar Iraq, May 2003 In the aftermath of the war in Iraq, widespread looting and intentional damage to government facilities resulted in the interruption of public services and utilities.Basic communications were disrupted nationally.Public health headquarters, clinics, and laboratories were damaged, records were ruined, and equipment was stolen.Because travel often was difficult and dangerous, Coalition forces received numerous requests from hospital directors for armed security, and many healthcare workers reportedly feared either to commute to their worksites or to remain after dark (D. Simpson, M.D., Coalition Provisional Authority 's Ministry of Health Team, personal correspondence, 2003).Public health employees who were able to continue their work went unpaid for several weeks.As a result, throughout Iraq, core public health services (e.g., vaccination services, vectorborne disease control, and the Tuberculosis Directly Observed Therapy program) were disrupted.In addition, severe health hazards caused by damaged water and sanitation systems were added to an already compromised and deteriorating health-care system (1,2).This report assesses the cumulative impact of these conditions on vaccination services in postwar Iraq, including the subsequent loss of staff, facilities, and equipment.Because vaccinations in Iraq are available only through the national system of primary health-care centers (PHCCs), this assessment can help address comparable problems experienced by other programs offered through Iraq's PHCCs, guide subsequent emergency responses to vaccine shortages, and provide a preliminary gauge of the status of preventive health-care infrastructure and services to children in Iraq. By late March 2003, public health officials thought that routine childhood vaccinations were unavailable at the majority of public health clinics.In mid-May, with assistance from CPA and the United Nations Children's Fund (UNICEF), the Iraqi Ministry of Health (IMoH) sent teams to assess the damage that hampered the efforts of the Expanded Program on Immunization (EPI).During May 17-22, six teams traveled to all of Iraq's 18 governorates and visited major vaccine-storage sites and some primary health-care centers.Each team visited three to four governorates and used a standard form to collect information on clinic staff availability, remaining vaccine supplies at the major storage sites, and the status of cold-chain equipment.Karkh and Rusafa, the two districts comprising the governorate of Baghdad, were assessed separately because of the size of their populations and the number of public health facilities (Table ). At the time of the survey, 893 (61%) PHCCs in Iraq had equipment and staff sufficient to provide vaccinations daily.On the basis of the amount of equipment known to have existed immediately before the war, the assessment found that 532 (33%) of the 1,628 refrigerators, 18 (46%) of the 39 cold rooms, and 81 (13%) of the 642 generators needed to provide electricity to some equipment were damaged.Four of the 18 governorates maintained >80% of their prewar cold- chain equipment.The overall loss for the entire Baghdad governorate was 24%, with the Karkh district losing substantially less equipment (12%) than Rusafa (40%).Total vaccine stocks- were assessed at the major storage sites but not at the clinic level.Only Sulaimaniyah had BCG vaccine, and stocks of HBV were low in all governorates except Najaf.However, tens of thousands of doses of both OPV and DTP vaccine were counted in all but five governorates.Although rabies is endemic in Iraq, stocks of rabies immunoglobulin were reported in only three governorates.Nine (50%) of the governorates had stocks of hepatitis B immunoglobulin.The presence of working cold-chain equipment was recorded, but levels of vaccine maintained constantly under proper environmental conditions at the surveyed sites were not determined.Editorial Note: This assessment found that the Iraqi vaccination program had lost necessary cold-chain equipment throughout the country and that the supply of properly maintained vaccine and immunoglobulin had been disrupted.Despite the brief duration of the war in Iraq and the intent to spare hospitals and clinics from direct attack, resulting disruptions in civil order and public services affected public health programs severely.Of urgent concern to public health officials were the temporary disruption of routine childhood vaccination activities and the lack of potable water.Vaccination services were especially susceptible to disruption because the effectiveness of the vaccination program depended on continuous provision of services in all parts of the country, easy accessibility by vulnerable women and children, and working cold-chain equipment.Before the war, EPI typically provided approximately 750,000 doses of routine vaccines † monthly to children aged 12 months (IMoH, unpublished data, 2003). Results of this survey are being used to revise distribution methods until damaged or looted cold-chain equipment can be replaced.Vaccines at central sites are being packaged into cold boxes and transported to clinics without refrigerators so vaccines will be available at least a few times each week in each PHCC.However, the provision of vaccines, medicines, supplies, and equipment is not alone sufficient to restore public health services interrupted in the aftermath of the war.A safe and secure work environment, a fair and reliable salary for public health staff, and accessible transportation also should be re-established. CPA and IMoH, with the assistance of the Coalition forces, UNICEF, the World Health Organization, and many nongovernment organizations, are working to ensure security, rehabilitate clinics and laboratories, and restore public health programs.Early results of these combined efforts include 1) an increasing number of adequately chlorinated public water supplies, 2) a rapid assessment of the nutritional status of young children in Baghdad, and 3) the distribution of routine childhood vaccines throughout Iraq by the third week of June. Despite these gains and the re-establishment of many services, substantial work remains for the Iraqi public health system to prevent resurgence of endemic diseases (e.g., visceral leishmaniasis, typhoid fever, and cholera) and the emergence of drug-resistant TB and malaria.The efforts of public health workers and the continued support of partner organizations will be critical to meeting these concerns in the coming months. # Update: Adverse Event Data and Revised American Thoracic Society/CDC Recommendations Against the Use of Rifampin and Pyrazinamide for Treatment of Latent Tuberculosis Infection-United States, 2003 CDC has reported previously surveillance data of severe liver injury in patients treated for latent tuberculosis infection (LTBI) with a daily and twice-weekly 2-month- regimen of rifampin with pyrazinamide (RZ).On the basis of these initial reports, CDC cautioned clinicians in the use of this therapy with advised additional monitoring (1-4).To estimate the incidence of RZ-associated severe liver injury and provide more precise data to guide treatment for LTBI, CDC collected data from cohorts of patients in the United States who received RZ for the treatment of LTBI during January 2000-June 2002 and for whom data were reported to CDC through June 6, 2003.This report summarizes the analysis, which found high rates of hospitalization and death from liver injury associated with the use of RZ.
On the basis of these findings, the American Thoracic Society (ATS) and CDC now recommend that this regimen should generally not be offered to persons with LTBI.The revised ATS/CDC recommendations described in this report have been endorsed by the Infectious Diseases Society of America (IDSA).Clinicians are advised to use the recommended alternative regimens for the treatment of LTBI (Table ).Rifampin and pyrazinamide (PZA) should continue to be administered in multidrug regimens for the treatment of persons with active tuberculosis (TB) disease (5). For surveillance purposes, a case of severe liver injury was defined as one leading to the hospitalization or death of a patient being treated for LTBI with RZ (2).During October 2000-June 2003, CDC received reports of 48 patients who had confirmed cases; 33 (69%) cases occurred in the second month of treatment.A total of 11 (23%) patients died † , including two persons known to be infected with human immunodeficiency virus (HIV). †Of the 11 deaths, eight were reported previously (1-3). # TABLE.Revised drug regimens for treatment of latent tuberculosis infection (LTBI) in adults- Rating § (Evidence) ¶ HIV-HIV-Drug Interval and duration Comments † negative infected A. Both strong evidence of efficacy and substantial clinical benefit support recommendation for use.Should always be offered.B. Moderate evidence for efficacy or strong evidence for efficacy but only limited clinical benefit supports recommendation for use.Should generally be offered.C. Evidence for efficacy is insufficient to support a recommendation for or against use, or evidence for efficacy might not outweigh adverse consequences (e.g., drug toxicity, drug interactions) or cost of the treatment or alternative approaches.Optional.D. Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use.Should generally not be offered.E. Good evidence for lack of efficacy or for adverse outcome support a recommendation against use.Should never be offered. ¶Quality of evidence supporting the recommendation: I. Evidence from at least one properly randomized controlled trial.II.Evidence from at least one well-designed clinical trial without randomization from cohort or case-controlled analytic studies (preferably from more than one center), from multiple time-series studies, or from dramatic results from uncontrolled experiments.III.Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. Recommended regimen for persons aged <18 years. † †Recommended regimens for pregnant women. § §The substitution of rifapentine for rifampin is not recommended because rifapentine's safety and effectiveness have not been established for patients with LTBI. # Isoniazid In HIV-infected persons, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Directly observed therapy (DOT) must be used with twice-weekly dosing. Not indicated for HIV-infected persons, those with fibrotic lesions on chest radiographs, or children. DOT must be used with twice-weekly dosing. Used for persons who are contacts of patients with isoniazid-resistant, rifampin-susceptible TB. In HIV-infected persons, most protease inhibitors or delavirdine should not be administered concurrently with rifampin.Rifabutin with appropriate dose adjustments can be used with protease inhibitors (saquinavir should be augmented with ritonavir) and NNRTIs (except delavirdine).Clinicians should consult web-based updates for the latest specific recommendations.RZ generally should not be offered for treatment of LTBI for HIVinfected or HIV-negative persons. A two-phase retrospective survey was conducted to estimate the incidence of severe liver injury among persons receiving RZ for treatment of LTBI.In December 2001 (phase I), CDC sent a questionnaire by e-mail to TB-control programs in 12 large cities and all 50 states, asking them to identify programs and health-care providers prescribing RZ for treatment of LTBI.All controllers responded, and in February 2002, CDC staff called the programs and health-care providers identified as prescribing RZ for LTBI to confirm its use.In September 2002 (phase II), CDC mailed a second questionnaire to the 150 health-care providers identified during the first phase, requesting aggregate cohort data for January 2000-June 2002; 109 (78%) health-care providers responded by June 6, 2003. Of 7,737 patients who were reported to have started RZ for treatment of LTBI during the survey period, 5,980 (77%) received daily doses, and 1,757 (23%) received twice-weekly doses.A total of 204 patients discontinued using RZ because of aspartate aminotransferase (AST) concentrations greater than five times the upper limit of normal (rate: 26.4 per 1,000 treatment initiations; 95% confidence interval (CI) = 22.8-30.0).An additional 146 patients discontinued using RZ because of symptoms of hepatitis (rate: 18.9 per 1,000 treatment initiations; 95% CI = 17.4-20.4). Of the 48 cases of severe liver injury reported to CDC through passive surveillance, 30 also were detected in the second phase of the survey.Of the 18 patients whose cases were not detected, six patients had liver injuries outside the survey period, five patients' health-care providers did not respond to the questionnaire, and seven (six of whom were in private practice) were not identified in the first phase of the survey.Of the 30 patients whose cases were detected, 23 (77%) recovered, and seven (23%) died.On the basis of these 30 cases, the estimated rates of hospitalization and death during the survey period were 3.0 (95% CI = 1.8-4.2) and 0.9 (95% CI = 0.2-1.6) per 1,000 treatment initiations, respectively. # Reported by: State and territorial health depts.Div of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, CDC. Editorial Note: The CDC cohort analysis found that the rates of severe liver injury and death related to the use of RZ are higher than the rates for isoniazid (INH)-associated liver injury in the treatment of LTBI.Although initial studies attributed hospitalization rates as high as 5.0 per 1,000 treatment initiations and mortality rates as high as 1.0 per 1,000 to INH (6,7), studies conducted since 1991 involving more than one million persons treated with INH have reported hospitalization rates of 0.1-0.2 (median: 0.15) and mortality rates of 0-0.3 per 1,000 (median: 0.04) (4,8,9).This decrease from earlier studies might reflect careful selection of patients and active monitoring for early signs of adverse events.In addi-tion to the survey on the use of RZ described in this report, recent studies have reported episodes of liver injury and hospitalization associated with RZ for treatment of LTBI (10,11), including the need for transplantation in one patient (12).Among first-line agents in the treatment of active TB disease, pyrazinamide (PZA) might be the most hepatotoxic (13). These data and other recent studies (4,10,11,14-16) were reviewed by TB experts § at a meeting held during the 99th International ATS Conference in Seattle, Washington, on May 12, 2003, to discuss proposed revisions to guidelines for the treatment of LTBI.ATS and CDC now recommend that this regimen should generally not be offered to persons with LTBI for either HIV-negative or HIV-infected persons.On the basis of the investigation of potential cofactors in the 48 patients with serious liver injury, this regimen should never be offered to patients who 1) are concurrently taking other medications associated with liver injury; 2) drink excessive amounts of alcohol, even if alcohol use is discontinued during treatment; 3) have underlying liver disease; or 4) have a history of INH-associated liver injury. If the potential benefits of this regimen outweigh the risk for severe liver injury and death associated with it, use of RZ might be considered in carefully selected patients, but only if 1) the preferred or alternative regimens (i.e., 9 months of daily or biweekly INH, 6 months of daily or biweekly INH, or 4 months of daily rifampin) are judged not likely to be completed and 2) oversight by a clinician with expertise in the treatment of LTBI can be provided.A TB/LTBI expert should be consulted before RZ is offered.In addition, patients should be asked whether they have had liver disease or adverse effects from taking INH or other drugs, informed of potential hepatotoxicity of the RZ regimen, and advised against the concurrent use of potentially hepatotoxic drugs, including over-the-counter drugs such as acetaminophen. To instruct the patient to stop taking RZ immediately and seek medical consultation if abdominal pain, emesis, jaundice, or other symptoms of hepatitis develop.Provider continuity is recommended for optimal monitoring.For persons taking this regimen, serum aminotransaminases (AT) and bilirubin should be measured at baseline and at 2, 4, 6, and 8 ¶ weeks of treatment.Because the majority of these patients had onset of symptoms of liver injury after the fourth week of therapy (Figure ), patients should be monitored throughout the entire course of treatment.Use of RZ should be discontinued immediately and not resumed for any of the following findings: 1) AT greater than five times the upper limit of normal range in an asymptomatic person, 2) AT greater than normal range when accompanied by symptoms of hepatitis, or 3) a serum bilirubin concentration greater than the normal range, whether or not symptoms are present. The risk for progression from LTBI to active TB is increased substantially in persons with HIV infection (4).Therefore, as recommended previously for the treatment of all persons in whom LTBI is diagnosed, voluntary HIV counseling and testing should be offered routinely. For progression to TB disease to be prevented, persons with LTBI should be identified in contact investigations and targeted screening programs and should complete treatment with safe and effective regimens.The successful treatment of LTBI is an essential component of the TB elimination strategy in the United States (4).In addition to this report, CDC and its partners are sending a letter to TB-control programs in 12 large cities and all 50 states and organizations active in TB control (e.g., the National Coalition to Eliminate Tuberculosis).To reach clinicians who are treating patients with LTBI, primary care medical associations (e.g., the American Medical Association and the American College of Physicians) are distributing this report to their members.This report and the letter are available at .The letter is being added to the April 2000 CDC Targeted Tuberculin Testing and Treatment of Latent TB Infection Guidelines, and existing provider educational materials are being revised. The recommendations against the use of RZ for treatment of LTBI described in this report do not apply to the appropriate use of rifampin and PZA in multidrug regimens for the treatment of persons with active TB disease.In these circumstances, the risk for morbidity and mortality from TB disease is substantially greater than with LTBI.Rifampin and PZA are essential components of recommended ATS/CDC/IDSA regimens that render patients noninfectious rapidly and are effective in curing patients with drug-susceptible M. tuberculosis strains within 6 months (5). CDC continues to collect reports of severe liver injury leading to hospital admission or death in persons receiving any treatment for LTBI.Health-care providers are encouraged to report such events to CDC's Division of Tuberculosis Elimination, telephone 404-639-8442.Details of the RZ survey analysis and the case series will be described in a separate publication. # Pneumococcal Vaccination for Cochlear Implant Candidates and Recipients: Updated Recommendations of the Advisory Committee on Immunization Practices On July 31, this report was posted on the MMWR website (). In October 2002, CDC recommended that all persons with cochlear implants receive age-appropriate pneumococcal vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) (Prevnar ® ), 23-valent pneumococcal polysaccharide vaccine (PPV23) (Pneumovax ® ), or both according to the Advisory Committee on Immunization Practices (ACIP) schedules for persons at high risk (1).CDC issued these recommendations on the basis of preliminary data suggesting an increased risk for pneumococcal meningitis in persons with cochlear implants.Findings of a recent investigation by CDC, the Food and Drug Administration (FDA), and state health departments support this recommendation.Children aged <6 years with a cochlear implant had a substantially greater risk for having pneumococcal meningitis, compared with children in the general U.S. population of the same age (2).Some children who are candidates for cochlear implants have preexisting anatomic factors that might contribute to an increased risk for meningitis; however, the recent study was not designed to assess this association (2).August 8, 2003 Because the rate for pneumococcal meningitis is higher in children with cochlear implants and Streptococcus pneumoniae is the most common pathogen causing bacterial meningitis in cochlear implant recipients of all ages with meningitis of known etiology (2,3) During the reporting week of July 31-August 6, a total of 109 human cases of WNV infection were reported from 13 states (Colorado, Iowa, Kansas, Kentucky, Louisiana, Minnesota, Mississippi, Nebraska, New Mexico, North Dakota, Ohio, South Dakota, and Texas), including four fatal cases from three states (Alabama, Colorado, and Texas).During the same period, WNV infections were reported in 622 dead birds, 191 horses, one dog, four unidentified animal species, and 359 mosquito pools. During 2003, a total of 153 human cases of WNV infection have been reported from Colorado (n = 72), Texas (n = 19), Louisiana (n = 15), South Dakota (n = eight), Ohio (n = seven), Alabama (n = six), Nebraska (n= six), Florida (n = four), Minnesota (n = four), Mississippi (n = four), Iowa (n = two), New Mexico (n = two), Kansas (n = one), Kentucky (n = one), North Dakota (n = one), and South Carolina (n = one) (Figure ).Among 150 (98%) cases for which demographic data were available, 81 (54%) occurred among men; the median age was 45 years (range: 17 months-87 years).Of the 153 cases, four fatal cases were reported from Alabama (n = one), Colorado (n = one), and Texas (n = two).In addition, 1,770 dead birds with WNV infection were reported from 36 states and New York City; 282 WNV infections in horses have been reported from 22 states (Alabama, Arkansas, Colorado, Florida, Georgia, Kansas, Kentucky, Minnesota, -- MOUNTAIN - - - - - 2 Mont. - - - - - - Idaho - - - - - - W y o . - - - - - - -Colo. N N - - - - - N .M e x . - - - - - - -A r i z . - - - - -2 Utah - - - - - - - N e v . - - - - - - -PACIFIC 1 - - - - - - Wash. - - - - - - - Oreg. - - - - - - -Calif. 1 - - - - - - Alaska - - - - - - - H a w a i i - - - - - - - Guam - - - - - - - P.R. N N - - - - - V .I . - - - - - - -Amer.Somoa - - - - - - - C.N. - - - - 184 W y o . - -1 8 - 5 - - 1 0 7 Colo. - 1 59 - 2 - - 607 N .M e x .131 - 125 - - 1,074 La. - - - - - 1 - 792 Okla. - N 126 - 111 - - 527 Tex.N 6 1,038 - 13 2 - 2,325 MOUNTAIN 1 5 311 - 15 - - 2,558 Mont. - - 19 - 1 - - 91 Idaho - 2 38
# I. RECOMMENDATIONS FOR A STANDARD FOR WORK IN HOT ENVIRONMENTS The National Institute for Occupational Safety and Health (NIOSH) recommends that employee exposure to heat in the workplace be controlled by requiring compliance with the work practice standard set forth in the following sections.Adherence to the precautionary procedures prescribed will prevent acute or chronic heat disorders and illnesses and heat induced unsafe acts, and will reduce the risk of harmful effects due to the interactions between excessive heat and toxic chemicals and physical agents.The standard is amenable to techniques that are valid, reproducible, and presently available.It will be reviewed and revised as necessary. Section 1 -Definitions (a) Acclimatization to heat means a series of physiological and psychological adjustments that occur in an individual during his first week of exposure to a hot environment so that thereafter the individual is capable of working in a hot environment without excessive strain. (b) Unimpaired mental performance means the ability of an employee to cope with conditions where safety and health depend on constant alertness because he has to make critical decisions, fine discriminations, or fast and skillful actions. (c) Intermittent heat exposure means exposure to hot environmental 1-1 conditions which continues no longer than fifteen minutes without an interrupting interval spent either spontaneously or according to a prescribed schedule in a cooler environment. (d) Continuous heat exposure means any exposure to hot environ mental conditions which is not an intermittent exposure. (e) Hot environmental condition means any combination of air temperature, humidity, radiation and wind speed that exceeds a Wet Bulb Globe Temperature (WBGT) of 79°F. # Section 2 -Applicability The provisions of this standard are applicable to all places of employment, indoors and outdoors, and to all employees except those who are required to wear impermeable protective clothing. (c) When exposure of an employee is continuous for one hour or intermittent for a period of two hours and the time-weighted average WBGT exceeds 79°F for men or 76°F for women, then any one or combination of the following practices shall be initiated to insure that the employee's body care temperature does not exceed 100.4°F: 1-2 FIGURE 1 -1 . # UPPER LIMITS OF EXPOSURE FOR UNIMPAIRED MENTAL PERFORMANCE (i) Acclimatization (1) Unacclimatized employees shall be acclimatized over a period of 6 days.The acclimatization schedule shall begin with 50 percent of the anticipated total work load and time exposure on the first day, followed by daily 10 percent increments building up 100 percent total exposure on the sixth day. (2) Regular acclimatized employees who return from nine or more consecutive calendar days of leave, shall undergo a four day acclimatization period.The acclimatization schedule shall begin with 50 percent of the anticipated total exposure on the first day, followed by daily 20 percent increments building up to 100 percent total exposure on the fourth day. (3) Regular acclimatized employees who return from four consecutive days of illness should have medical permission to return to the job, and should undergo a four day re-acclimatization period as defined in (2) above. (ii) A work and rest regimen shall be implemented to reduce the peaks of physiological strain and to improve recovery during rest periods. (iii) The total work load shall be evenly distributed over the entire work day when possible. # (iv) When possible hot jobs shall be scheduled for the coolest part of the work shift. # 1-3 (v) Regular breaks, consisting as a minimum of one every hour, shall be prescribed for employees to get water and replacement salt. The employer shall provide a minimum of 8 quarts of cool potable 0.1 percent salted drinking water or a minimum of 8 quarts of cool potable water and salt tablets per man per shift.The water supply shall be located as near as possible to the position where the employee is regularly engaged in work, but never further than 200 feet- therefrom. (vi) Appropriate protective clothing and equipment shall be provided and used. (vii) Engineering controls to reduce the environmental heat load shall be utilized. (i) Where exposure to environmental conditions is continuous for several hours or the entire work day, the WBGT shall be calculated as an hourly time-weighted-average. (ii) Where exposure is intermittent, the WBGT shall be calculated as a two-hour time-weighted average. Section 5 -Medical (a) All employees who are 45 years of age and older and who have not had previous occupational exposure to heat shall not be assigned to jobs where the environmental conditions equal or exceed 79°F WBGT for men and 76°F WBGT for women, until they are acclimatized. (b) All personnel who are to be assigned to hot jobs for the first time shall be evaluated by a physician prior to assignment to assure that the individual can cope with the hot environment.In the examination special emphasis should be on the cardiovascular, renal, hepatic, endocrine, and respiratory system and the skin.The examination should 1-5 also include a complete medical history of the worker with specific emphasis on previous heat-related disorders or illnesses. (c) All employees exposed to hot environmental conditions should be given a periodic physical examination every 2 years for employees under age 45, and every year for employees 45 years of age or older, that should include all components of the preplacement examination. (a) Information as to water intake for replacement purposes. (b) Information as to salt replacement. (c) Importance of weighing each day before and after the day's work. (d) Instruction on how to recognize the symptoms of heat disorders and illnesses, including dehydration, exhaustion, heat syncope, heat cramps, salt deficiency exhaustion, prickly heat, and heat stroke. (e) Information as to special caution that shall be exercised in situations where employees are exposed to toxic agents and/or other stressful physical agents which may be present in addition to and simultaneously with heat. (f) Information concerning heat acclimatization.The information shall be kept on file and readily accessible to the worker at all places of employment where he may be exposed to excessive heat. # Section 7 -Warning Sign The following warning sign shall be appropriately located at one or more places to be noticed by any one entering an area where environmental conditions are 86°F WBGT or above. (ii) Records of acclimatization as required by Section 3(c)(i). (iii) Records of the WBGT for each work area as specified in Section 8. (b) Records required by provisions (i) and (ii) above shall be maintained for a period of the employee's employment and for one year thereafter. (c) Records of the WBGT as specified in (iii) above shall be maintained for a period determined by the Secretary of Labor with consultation with the Secretary of Health, Education, and Welfare. The pertinent results of these field studies are summarized below. The workers in hot jobs are a highly select population.Workers who feel that they cannot cope with the prevailing heat stress change their job for a less demanding one.As a result of this natural selection process, the majority of the workers in hot jobs have high levels of physical performance and capacity and are highly adaptable to work in heat. Heat disorders are more likely to occur at times when the workers are unacclimatized as during the first hot spell in the summer or when physical fitness is diminished as on Mondays after a leisurely weekend or the first day after a vacation, or return to work after an illness. Because jobs in hot environments may be better paid than other jobs, it often happens that workers try to stay with the hot job even after their health or fitness becomes inadequate for the job.Since there is no obligatory standard for physical fitness for these jobs and since periodic III-l medical examinations have been haphazardly done in many industries, if done at all, these workers stay on the job and run a high health risk. Oral temperatures in excess of 99.6°F (corresponding to a deep body temperature of 100.4°F) or first-minute recovery heart rates in excess of 110 have been very seldom observed.They occurred mainly in jobs where the environmental conditions exceeded the upper limit prescriptive zone (ULPZ), (see part V) particularly if the workers worked overtime or worked two shifts in sequence. There are many work practices in industry which are unofficial and are aimed at ameliorating the workers heat strain on excessively hot days. # Such practices are: 1.Only the unavoidable operations are performed.Other less important jobs are postponed. 2.Workers involved in auxiliary jobs are reassigned to help out those who work in the hot areas. 3.The younger and more fit take over some of the work from the older and less fit.These practices, if not recognized, may give the wrong impression that the old and less fit worker tolerates the work in heat as well as the younger and more fit. Most workers in hot jobs drink less water than they lose by sweating. According to many laboratory and field studies, this affects physical fitness adversely, particularly if the water loss is more than 1.5% of total body weight.6 Such dehydration could be prevented by: Making drinking water of good quality easily accessible to the worker. III-2 2.Providing a 0.1 percent salt solution as drinking water, available from drinking fountains which cool the water. 3.Providing salt tablets for salt supplementation to the workers. Advising the worker about the significance of drinking water often in small installments and using much salt on food when he is exposed to hot working conditions. In many jobs the workers' heat exposure could be substantially reduced by relatively simple measures, such as wearing certain protective clothing, turning on all available fans and opening all windows, distribu ting the job more evenly during the workday and breaking up the work cycles into shorter work-rest cycles.Unfortunately, either because of ignorance or carelessness, the workers often expose themselves to greater heat stress than would be necessary. Often with little expense the climatic conditions could be ameliorated or the work load diminished. # Early Historical Reports Nearly 70 years ago concern for the health of the Cornish Tin Miners lead to one of the first studies of the effects of heat on the health of workers and stimulated the search for a method of expressing in simple terms the impact of a hot working environment.Except for the studies of Bedford,^ on the effects of atmospheric conditions on the indus trial worker, little progress was made until shortly before and during During the past 25 years much effort has centered around the problem of expressing in relatively simple terms the total impact of the hot working environment upon the worker.Several attempts have been made to < formulate a predictive scheme which would translate the heat load into biologically meaningful values.These predictive schemes can be roughly grouped into: (a) those that sought a device which would respond to the major environmental factors in a manner similar to man's, (b) those based upon measured human responses which could be used to evaluate combinations of environmental conditions, and (c) those based on calculations to determine whether it is possible to maintain thermal balance under any combinations of the climatic factors and work intensity and if so, how much physiological strain is involved.Each approach has its logic as well as its failings. A detailed discussion of the more important of the indices for estimating the biologic impact of a hot environment is presented later in the text. # 111-4 Epidemiological Studies Neither prospective nor retrospective epidemiological studies have been made in which the health experiences of workers have been correlated with the length and intensity of heat exposure at the work site during the working life of the individuals.Health data for retrospective studies could probably be found in the health and medical records of some insurance companies and larger industries.Particularly lacking in most of the morbidity and mortality reports, however, are measurements of the level of heat exposure and the time spent on the hot jobs. Health experience statistics for some hot industries have been reported over the past 50 years.1^»1^»1®>19, 20,21,22 in a study of 23,000 coal miners,!® lost time due to sickness was 63 percent higher in miners working at temperatures above 80°F.than in those working at temperatures of 70°F.or less.Death rate increase of about 35 percent was reported in 193720fOr miners working hotter mines.In another study, Britten and Thompson,21 found organic heart defects were more frequent in foundry workers.Enlarged hearts and arteriosclerosis were found more often among steel and glass workers.The frequency of industrial accidents increases in higher temperatures but the increase is mostly in minor accidents.It is not possible to generalize these reports of heat experience in chronic heat exposure in industry several decades ago to present-day industry.However, personal communications and experiences of medical and scientific personnel suggest that chronic exposure in hot working environments can have serious health and safety consequences. # III-5 The acute effects of heat on health and safety have been documented by literally hundreds of carefully controlled laboratory and field studies. The incidence of heat illness in young men in industry and military service who were not acclimatized to heat has been reported in several studies to be between 1.5 and 3.Mechanically, the heat may tend to promote accidents due to slipperyness of sweaty palms or interfering with vision through fogging of safety glasses.Beyond these obvious effects, accidents have been documented 18 to increase in hot jobs (e.g., Vernon et al. ).A striking demon stration of environmental effect on accident rates was compiled from records of a steel mill over a four-year period (Figure 1).^ There is a definite parallelism between weather and accident frequency.The accident peaks, however, exhibit a downward trend over the years, most likely reflecting the efforts of intensive safety programs.Belding et al.have suggested the weather effect may be due to reduced general tonus of bodily activities and alertness related to high environmental temperatures.Again, increased bodily temperature and discomfort III-9 increase irritation, anger, and other emotional states which may induce 42 workers to commit rash acts or divert attention from hazardous tasks. In extreme heat, emotions may spill over into fights^ or other manifesta-43 tions of emotional crises, e.g. At lesser stresses, more subtle disturbances in emotional state, e.g., depression, may be evident.Extensive folklore has been generated around the deleterious effects of the "Foehn" of Europe, the "Sharav" 44 of Israel, and other warm "ill winds". While the correlation between these climatic changes and illness seems real, the aetiology remains 45 controversial. Intuitively, disturbed emotional states should reduce 46 alertness on the job, setting the stage for accidents. Effects of stresses in the occupational environment have been the subject of many quantitative studies.From these, threshold limit values (TLV) were derived, values which have served well as guides to reduce occupational exposures. In general, the TLV's were established from experiments with single stress exposures.Often, however, more than one stress will occur and, in fact, it will be the rare case where only one stress obtains.There has been an increasing awareness of the alteration in physiological response to a stress where other stresses are present.Because of the ubiquitous nature of heat stress, it has received attention as a potentiator or mediator of response to other physical and toxic agents; and it certainly influences the course of diseases. In combination, heat (85°F, ET) and carbon monoxide (100 ppm) have been shown to have a greater deleterious effect than either stress 47 alone. It is difficult to quantitate the effect; manifestations included 111-10 inability to complete the four-hour exposure, irritability, and, occasionally, syncope.The effects were more pronounced in women than in men.The subjects reported persistent headaches, anorexia, irritability, depression, and general malaise.These postexposure symptoms were markedly more severe after exposure to heat and CO than after exposure to either alone.It is interesting to note that these were physiological disturbances and that the more Renshaw "^investigated the effects of noise (41, 80, 90, and 100 dBA) and heat (72,78,84, and 90°F ET) on performance on a 5-Choice Serial Reaction Task.The effect of heat on "gaps" was statistically significant. Subjects committed 18 percent more gaps at 90°ET than at 72°ET at the same noise level. # III-ll It has been a common observation that mortality increases during 51 prolonged hot spells, e.g., St. Louis, 1966.Similarly, the frequency of illinesses seems to be dependent on the heat load.There are numerous instances cited in the literature where increases in dispensary visits, etc.,accompany hot weather, even as do accidents (as noted above).While somewhat afield from the problem under review here, the implications are that there are many subtle little understood physiological adjustments to heat stress whose role in rendering a worker on hot jobs more or less resistant to bacterial invasion is unknown. # Correlation of Exposure and Effects The physiological and medical consequences of exposure to heat are not directly proportional to the intensity throughout the entire range of heat stress.Over a rather large range of temperatures, physiological functions are independent of the temperature.In the environment driven zone (EDZ See Part V) the physiological strain increases exponentially so that at high levels of heat stress a small incremental increase in stress 111-12 results in a large increase in strain.The safety factor becomes progressively smaller as the total heat-work stress is increased.Consequently, as the heat stress becomes higher, more care and precaution must be exercised to insure the health and safety of the worker. Many factors, which can exist in limitless combinations, interact to determine relationships between exposure and effects.The more important of these factors include the Environmental Factors, the Human Factors, and the Task Factors (Table I).
The impact of some of these factors on performance and heat tolerance has recently been 33 reviewed. It is emphasized that for any specific environment-worker-job situation the total stress and health and safety consequences can be brought to acceptable and desirable levels by adequate control of one or more of the factors. One of the most dramatic and successful physiological mechanisms possessed by man is his ability to increase his tolerance to work in heat. The physiological and psychological processes involved in acclimatization to heat have been described in many technical papers and several comprehensive reviews»^ »^^»54 Acclimatization to heat is a series of physiological adjustments that occur when one who is accustomed to working in a temperate environment is suddenly placed in a hot environment.These physiological adjustments which occur over a period of one to two weeks reduce the strain experienced on the initial exposure to heat.The physiological changes during acclimatization which are most easily observed are the responses of the body temperature and pulse rate, both of which increase during the first day of heat exposure and then progressively decrease with each In four groupings of cases surviving long enough to be admitted to a hospital for treatment and reported in the medical literature, the mortality rate increased in direct ratio with the increased temperature on admission (Minard and Copman, 1963 if hyperthermia is prolonged.By the same token, survival with complete recovery is possible at extreme hyperthermia; e. g., 108 or above, if cooling is prompt and effective. Malamud, Haymaker, and Custer who described a wide range of premortem brain disorders in 125 fatal cases of heat stroke occurring in military trainees in World War II, state that "damage to the central nervous system was manifest from the onset and persisted to the end.In cases of longer duration, dementia, asphasia, or hemiplegia indicated that the effect on the central nervous system was probably lasting and irreversible. A direct relationship between the nervous manifestations and the degree and duration of hyperthermia was always evident."trainees, the primary underlying factor in heat stroke is lack of accli matization often associated with poor physical fitness and/or obesity. Precipitating factors are prolonged exertion under heat stress with inadequate time allowances for rest and recovery.Recent alcoholic overindulgence in otherwise seasoned workers has been identified as a probable factor in some cases.In elderly individuals living in poorly ventilated housing, the risk of heat stroke during prolonged heat waves in northern cities is greates in those with a history of chronic cardio-51 vascular or cardiorespiratory disease. In such cases impaired circulatory capacity to transport heat from body core to the skin is the underlying cause of hyperthermia and thermoregulatory failure rather than elevated metabolic heat production during work.The underlying disorder in heat exhaustion is depletion of body water due either to restricted water intake, or to deficient salt intake, or more often to both.In the water restriction type, urine is highly concentrated and small in volume; thirst is a prominent symptom.In the salt deficiency type, circulatory insufficiency is more extreme, urine is more dilute, larger in volume, but chlorides are absent « 1 gm/liter).Thirst is less evident.Blood electrolytes may be slightly elevated with hemoconcentration in the water restriction type and somewhat below normal in the salt defi ciency type.Laboratory facilities are often not available to differentiate the two types.Results of blood analysis, however, are not essential in making a diagnosis of heat exhaustion as this can be determined on the basis of the clinical signs and symptoms noted above.is the best method for supplementing salt intake.Also, lack of accli matization in men losing up to several liters of sweat per day often leads to voluntary dehydration, a term indicating that the thirst mechanism fails to provide an adequate stimulus to drink water in sufficient quantities to balance the losses in sweat.Workers should be instructed to drink more than necessary to satisfy thirst.Failure of supervisors to provide ready access to water, or to provide breaks at frequent intervals, may lead to degrees of dehydration which cannot readily be compensated because the volume of water necessary to be ingested causes gastric distention and distress. The objectives of a preventive program are to prevent clinical disorders from heat stress and also to prevent aggravation of existing impairments by heat and to maintain optimum health and work efficiency. The objectives can be accomplished through the following procedures: pre-placement and periodic medical examination, acclimatization of workers to heat, and monitoring of oral temperature and heart rate. The approach toward control may involve modification of one or more of these determinants of heat stress.The challenge is to select specific methods for attack which will be both feasible and effective.Serious errors can result from resorting to some single pet engineering solution. IV-2 Consider the consequences of ducting outside air to the task site.This air usually is blown at the worker at a temperature as warm as the upper reaches of the shed where the ducts have been installed.This will enhance cooling by evaporation of sweat, but if the air is warmer than the skin (35°C, 95°F), it will increase the convective heat load.Consideration of the trade off between needed heat loss and increased heat gain is essential.The same goal might be achieved less expensively with portable fans. In some situations the real mistake may be the failure to recognize that the heat problem derives from radiant load from a furnace which is not decreased by air movement.This mistake has been made less frequently in recent years, but elaborate ducting across the ceilings of older plants exist as testimony to use in the part of this inappropriate action. Effectiveness of means used to control the five listed determinants of heat stress can be compared. First to be discussed is decreasing the physical work of the task. Metabolic heat, M, can comprise a large fraction of the total heat load. However, the amount by which this factor may be reduced by control often is quite limited.This is because an average sized man who is simply standing quietly while pushing buttons will produce heat at a rate of 100 Kcal/hr whereas one who is manually transferring fairly heavy materials at a steady pace will seldom have a metabolic rate higher than 300 Kcal/hr and usually not more than 250 K c a l / h r .Obviously, control measures, such as partial mechanization, can only reduce the M component of these steady types of work by 100 to 200 Kcal/hr; nevertheless, mechanization can also IV-3 help by making it possible for the worker to be more isolated from the heat source, perhaps in an air conditioned booth. Tasks such as shovelling which involve metabolic heat production at rates as high as 500 or 600 Kcal/hr require that rest be taken one-half to two-thirds of the time simply because of the physical demands of the labor.Thus, the hourly contribution of M to heat load will seldom exceed 300 Kcal/hr.It is obvious that mechanization of such work can increase worker productivity by making possible a decrease in the time needed for rest. The second modifier warranting discussion is modifying the number and duration of exposures.When the task in a hot environment involves work that is a regularly scheduled part of the job, the combined experience of workers and management will have resulted in an arrangement which makes the work tolerable most of the time for most of the workers.For example, the relief schedule for a task which involves manual transfer of hot materials may involve two workers only; because of the heat and depending on the duress, these two workers alternate at intervals from five minutes up to an hour, which have been determined empirically.Under such conditions overall strain for the individual will be less if the cycles are short.66 Where there is a standardized quota of hot work for each man, it is some times lumped at the beginning of the shift.This arrangement may be pre ferred by workers in cooler weather; however, there is evidence that the strain of such an arrangement may become excessive on hot days.The total strain will be less, evidenced by fewer heart beats, if the work is spread out.Significantly large variations in work site temperature usually occur during the work day.A typical continuous recording is shown in Figure 4. # IV-4 The stress of hot jobs is also dependent on vagaries of weather.A hot spell or an unusual rise in humidity may create overly stressful condi tions for a few hours or days in the summer.Non-essential tasks should be postponed during such emergency periods, in accordance with a prearranged plan.Also, assignment of an extra helper can importantly reduce heat exposure of members of a working team.However, there is danger in this practice when novices are utilized. Many of the critically hot exposures to heat faced by employees in industry are incurred irregularly, as in furnace repair or emergencies, where levels of heat stress and physical effort are high and largely unpredictable, and values for the components of the stress are not readily assessable.Usually such exposures will force progressive rise in body temperature.Ideally, such physiologic measurements as body temperature and heart rate would be monitored and used as criteria for limiting such exposures on an ad hoc basis.Practically, however, the tolerance limits have been based on experience of the worker as well as of his supervisor. Fortunately, for most workers, perception of fatigue, faintness, or breath lessness may be relied upon most of the time for bringing individual ex posures to a safe ending. The highly motivated individual, particularly the novice who desires acceptance, is at greater risk.In the same spirit, foremen should respect the opinion of an employee when he reports that he does not feel up to work in the heat at a particular time.Non-job personal factors such as low grade infection, a sleepless night, or diarrhea (dehydration affects sweating) which would not affect performance on most jobs, may adversely affect heat tolearance. # IV-5 Perhaps the best advice that can be offered for control of irregular exposures is (a) that formal training and indoctrination on effects of heat be provided both supervisors and workers, and (b) that these include directions to the effect that each exposure should be terminated before physical distress is manifest.There is abundant evidence that the physiological strain of an exposure which raises body temperature above 38°C is such as to contraindicate further exposures during the same day; it may take hours for complete recovery.More work can be achieved during several shorter exposures and with less overall strain. The third modification to be discussed is modifying the thermal environment.The environmental engineer will usually identify important sources of heat stress in a qualitative sense, without resort to elaborate measurements.Thus, his experience will suggest that when air is static and the clothes of the workers become wet with sweat, it will help to provide a fan. Nevertheless, we reiterate the advantages in making a quantitative analysis of the heat stress (and where possible the resulting strains) on workers.The effects of various approaches to control can be predicted, and improvements in thermal conditions at the workplace can be documented for higher levels of management based on measurements made before and after action has been taken. We cite concrete examples to illustrate how the quantitative analytic approach may be used. Case I. A case which is encountered frequently under ordinary conditions of hot weather. # IV-6 Let us assume a laundry where the humidity is high (Pa = 30 mm Hg) despite the operation of a small exhaust fan on the wall.There is no high level heat source so the temperature of the solid surround (reflected in Tg) is about the same as that of the air. In the simplest situation we take Ta and Tg equal to the temperature of the skin, which may be assumed to be 35°C (95°F A more effective permanent approach would be to replace the small exhaust fan with exhaust hoods opening over the moisture source.Adequate make-up air would have to be provided. If outside high humidity rather than a large inside source of hot water were creating inside conditions similar to those of this case, the obvious solution would be installation of mechanical air conditioning.This would be an expensive solution for Case I. It is obvious from the deficiency of evaporation and the enormous load that the workers, despite full clothing and a face shield, were able to perform this task only for a few minutes at a time.Heat exhaustion was not uncommon (and might partly be attributable to the difficult hot conditions prevailing in the nearby rest area). Engineers undertook control of this heat exposure by interposing finished aluminum sheeting between the heat source and the worker.Infra red reflecting glass at face level permitted seeing the task and space was left for access of the arms in using the ladle.As a result of these measures it was recorded that both Tg and Ta were reduced to 43°C (110°F). The same air speed was present as before and if we assume the same Pa By this action to reduce R, the heat load was brought to a level that is reasonable for prolonged work, but did not completely eliminate the heat stress.The predicted requirement for sweating to maintain heat balance was reduced to about 0.7 liter/hr from the previously impossible-to-sustain level of 2.1 liters/hr. (The before and after average levels actually observed for two workers were not far from these predictions, namely 1.1 and 2.1 liters/hr.The same two subjects also showed a marked reduction in heart rate, as a result of the changes, from an average of 146 to 108 bears/min.) The percent reduction of the radiant load can be taken as a measure of the effectiveness of the reflective shielding, and in this instance approximates 85%.Large errors in the stimate of R are possible at extremely high globe temperatures, but in this case it appears that the IV-11 maximum relief that could be expected from shielding was achieved.Haines and Hatch reported smaller reductions in R of 51 to 74% from interposing a sheet of aluminum at eleven different work sites in a glass factory. Others have shown reduction of 90% or more under ideal conditions not likely to prevail on the plant floor. While in Case III we have dealt with some aspects of control of R by shielding, the two other classical approaches of industrial hygiene engineering, namely, control at the source and control at the man, offer possibilities which must be considered. Application of insulation on a furnace wall can reduce its surface temperature and thereby the level of R. A by-product of such treatment is a saving in fuel needed to maintain internal furnace temperatures. Application of a polished metallic surface to a furnace wall will also reduce R. However, a polished metallic surface will not maintain its low emissivity if it is allowed to become dirty.A layer of grease or oil one molecule thick can change the emissivity of a polished surface from 0.1 to 0.9.And the emissivity of aluminum or gold paints for infrared is not necessarily indicated by their sheen.If the particles are smaller than about one micron they emit almost like a black body. (The same is true for fabrics coated with very fine metallic particles.) Equal or even more effective reduction of R is achievable with nonreflective barriers through which cool water is circulated. The engineer is frequently baffled in shielding by the fact that access to the heat source is required for performance of the task.We have seen various solutions to this problem.One is a curtain of metal chains which can be parted as required and which otherwise reduces IV-12 emission like a fireplace screen.Another is a mechanically activated door which is opened only during ejection or manipulation of the product. And finally, remotely operated tongs may be provided, taking advantage of the fact that radiant heating from an open portal is limited to line of sight and falls off as the reciprocal of the square of the distance from the source. The fourth modification to be discussed is that of thermal conditions of the rest area.Brouha66 states "it is undeniable that the possibility of rest in cool surroundings reduces considerably the total cost of work in the heat."There is no solid information on the optimum thermal conditions for such areas but there are laboratory data which support setting the temperature near 25°C (77°F).This feels chilly upon first entry from the heat, but adaptation is rapid. The placement of these areas is of some importance.The farther they are from the workplace, the more likely that they will be used infrequently or that individual work periods will be lengthened in favor of prolonged rest periods. Incidentally, the same principle applies for positioning of water fountains.When they are remote from the worker, substantial dehydration is more apt to occur.The proper temperature for drinks under hot conditions is often asked.There is no scientific answer, but most men will not willingly drink fluids that are close to body temperature.They welcome chilled water and recognize that frequent small drinks are better than large draughts. # IV-13 The final modification to be discussed is clothing.Heat stress usually may be altered substantially through selective wearing of clothing. In the heat, as in the cold, the thermal function of clothing is to reduce heat transfer between the individual and his environment.14 Clothing may reduce transfer by radiation, by convection, and by evaporation of sweat.
Whether clothing will represent an advantage depends not only on its design but on the characteristics of the particular thermal environment in which the work is being performed. # Conventional work clothing: We first examine what is known about the effects of ordinary work clothing consisting of work shirt and trousers.These will be of flame retardant material if fire or sparks are in the working area. Other items normally will include cotton underwear, socks (which in hot weather are better if of medium to heavy weight), perhaps gloves, and perhaps a hard hat.The wearing of long underwear, woolen or cotton, represents a special case which is dealt with later. The effect of such clothing in interfering with heat loss by R+C is substantial and can be illustrated.For a man doing moderately hard physical work (1200 Btu/hr) and wearing only shorts, comfort temperature would be about 70°F.In work clothing comfort temperature might well be 55°F.If the environmental temperature actually was 70°F, the cost of wearing clothing, in terms of heat stress, would be equivalent to an added sweat rate of at least one-half pint per hour. Laboratory studies clearly indicate that ordinary work clothing will reduce radiant heat transfer by 30 to 40 percent.70 Theory yields a similar reduction for transfer by convection.And recent studies demonstrate that this clothing will reduce the potential for evaporating sweat by about 40 percent. There are two important implications of these findings.Only the first is common experience.In warm environments, below skin temperature, wearing of clothing decreases heat loss and comfort.This is particularly true when humidity is high or the air is static.This disadvantage may become an advantage when air temperature and/or radiant temperature exceeds skin temperature.Then clothing reduces heat gain to the body.For example, on a 95°F day the radiation from the sun under a clear sky can represent the equivalent of a 20°F increase in air temperature for the seminude body.14 This load can be reduced to the equivalent of 8°F by conventional work clothing (to even less with near-white clothes).Heavier clothing would reduce R even more, but this advantage is nulified at the point such clothing interferes with evaporation of sweat.In arid climates adequate evaporation seldom is a problem, particularly with good air movement, but in an industrial plant with the high radiant heat from a furnace the limits on evaporation may preclude heavy clothing for prolonged tasks. The implication of the above is that radiant heat which was tolerable for a worker wearing shirt and trousers would be excessive for a man in shorts.This has been demonstrated in the laboratory.70 A mean radiant temperature of 205°F was used in simulation of a task involving fourminute exposures interspersed with two-minute relief periods.This was tolerable when clothes, but intolerable when nude.The radiant load became just tolerable when reduced in intensity by about 30 percent.As mentioned in the preceding section, the color of skin or of clothing is immaterial in these exposures; they are black to infrared heat. The highest local skin temperatures readily tolerable under such conditions depends on the amount of body surface area affected.For large areas such as the back it is about 105°F; for smaller areas such as a hand it may be 110°F.As an average for the whole body of an individual at work for prolonged periods, 95°F is about the limit; with higher average skin temperatures, a rise in internal body temperature may be expected.Additional information on time-tolerance relationships appears.71 Long winter-weight underwear has been adopted by many workers who move in and out of very hot environments.This makes sense to the extent that the extra layer provides a substantial buffer against extremes of heat gain (and loss, which is a factor in open sheds in wintertime).In humid slimmer weather the practice is less justified, unless there is ready access to air conditioned areas for recovery, because the underwear interferes with evaporation of sweat from the skin.The ounce-by-ounce efficiency of evaporation of sweat from clothing is considerably less than from the skin, more sweat must be produced to maintain heat balance and little or no more can be evaporated. # IV-16 It is obvious that ordinary work clothing itself moderates extremes of transient heat exposures, but this is to a lesser extent than when long underwear is worn. # Special Clothing: This may take various forms.For example, the wearing of infra red reflecting face shields may be indicated when radiant heat is high. In frequent handling of hot materials, it is good practice to provide several pairs of oversize insulative gloves, these having wide gauntlets for easy entry without using both hands. For very hot exposures, as in relining furnaces, thick insulative clothing is appropriate.This acts as a heat "sponge."This sponge may be more effective if made of high density materials (asbestos in the recent past) because of the higher heat capacity, but insulation with minimum weight is best imparted by a thickness of trapped, still air. It is obvious that for relatively longer intervals of exposure, high density and highest feasible thickness should be sought.The protective value of such clothing is enhanced by aluminizing its surface and sometimes interlining foil between insulative layers. # Aluminized Reflecting Clothing: When shielding against radiant heat loads cannot be accomplished by fixed barriers, aluminized clothing components may often be used to advantage.The aluminum is vacuum deposited on the surface of the fabric. Interposition of such coated fabrics between a 600° to 1100°F source and a black globe has resulted in reflection of 90% of incident energy.60 # IV-17 However, in a study using reflective clothing items while working in the 205°F radiant heat mentioned above, efficiency was found to be much less. Ordinary work clothing yielded 40 percent protection, an aluminized apron about 50 percent and a full aluminized suit about 60 percent.In inter mittent work at high humidities the full suit proved a handicap because of its interference with evaporation of sweat.The use of full reflective clothing can sometimes be avoided.For example, fixed shielding to waist level may make possible use of only an aluminized jacket.Or a worker who faces the heat source may resort to a long metallic apron.When the coverage with reflective clothing is only partial, there is much more opportunity for evaporation of sweat. It is obvious that an aluminum finish, as on the palmar surface of an insulative glove, will be of little use in handling materials. # Thermally Conditioned Clothing: Numerous ideas have been incorporated in special clothing for maintaining comfort in extreme heat (or cold).Some systems supply appropriately cool air from a mechanical refrigerator to points under a jacket or coveralls.When air from a remote source is used, there are two problems.One is the gain of heat through the walls of the supply tubing.This problem has been solved in some cases by using porous tubing which will leak an appropriate amount of supply air to keep the walls suitably cool.The other problem is distribution of the air through the suit.With a simple, single orifice it is difficult to cool a sufficient area of skin and the area cooled may be too cold.Provision of several orifices, though better, will create bulk and restrict mobility. # IV-18 In fact, the restriction of movement resulting from tethering the worker to a supply line will often contraindicate this type of system.When such a line is used, there should always be a simple quick disconnect for use in emergency. The vortex tube source of cool air has been used successfully in some situations.62 The device is carried on the belt.Air introduced tangentially at high velocity is forced into a vortex, which results in two separable streams of air, one cold which is distributed under the suit, the other hot which is discarded.Compressed air requirements to operate the vortex system are large. Self-contained sources of conditioned air which can be backpacked have also been developed.One involves a liquid refrigerant which is sealed into a finned container.After being cooled in a deep freeze, the container is placed in the pack.A small battery-driven fan circulates air across the fins and into the suit.A single charging of this device may extend tolerance for relining furnace walls from several minutes to 30 or 60 minutes. More sophisticated devices employ a closed system with liquid as the coolant and a fairly elaborate network of small tubes for distribution. The nuisance factor must be considered for all such devices.Men will not go to the trouble of donning them unless they recognize more than a marginal advantage.On the other hand, with such devices, it has sometimes been possible to change hot tasks which required long rest pauses and multiple workers into single worker, continuous duty operations. IV-19 All of these indices include the four climatic factors: air temperature, humidity, radiant heat, and wind velocity.However, the work load is not included in the ET and WBGT. This fact weighs in favor of HSI and P4SR.On the other hand, the calculation of these latter two indices is much more complicated than that of ET and WGBT, even when the available monograms are used.Between ET and WBGT, the latter one wins out in simplicity of calculation.Another aspect which makes WBGT more desirable is that while wind velocity must be measured for the other three indices, for WBGT this is not required.This is a very important consideration in view of the difficulty NIOSH has experienced in field studies^" in establishing an hourly time-weighted average value for this factor.One important reason for this is that as man moves around while performing his job, he is exposed to wind velocities which vary con siderably and often suddenly. As far as the fourth criterion is concerned, all four indices have some shortcomings, as pointed out in the previous section.Thus, from this point of view, none of the four indices has an advantage over the other. The HSI has many advantages from the point of view of the fifth criterion, the greatest one being that it makes it possible to calculate the allowable exposure time as well as the minimum recovery time for a QO given heat stress condition. # V-5 The studies performed by Lind on the prescriptive zone (PZ) were used as a basis for the determination of the environmental conditions (including different combinations of climatic and work load), which can be tolerated by 95% of the worker population with body temperatures not in excess of 38° C. The essence of this principle is shown in Figure 5.Each point on the graph represents the result of an experiment lasting until the rectal temperature of the observed subject reached a steady state.This took about 30-to-60 minutes depending on the intensity of the combined heatwork exposure.It becomes apparent from the graph that up to a certain level of effective temperature (ET) the equilibrium rectal temperatures follow a straight horizontal line, i.e., they do not increase, no matter how much the ET is increased in the heat chamber.However, the rectal temperature is higher when the work rate is higher.Thus, in this range of environmental heat the rectal temperature is determined only by the work intensity.This range is called the prescriptive zone (PZ). Over a certain level of environmental heat each of the three curves in the graph show a sudden turn upward, indicating that over this level the equilibrium rectal temperatures increased each time the climatic conditions became hotter.Thus, in this range of environmental heat the deep body temperature becomes sensitive to changes in climatic conditions and man can easily lose his ability to maintain an equilibrium temperature, thus leading to heat disorders.This range of climatic conditions is called the environment driven zone (E D Z ).The environmental temperatures at the border between the PZ and EDZ are called the upper limit of prescriptive zone (U LPZ). # V-6 The value of the ULPZ varies for different individuals.It is higher for men who are acclimatized to heat, by approximately 4.0°F ET, and is lower the more clothing an individual wears. To make sure that 95% of a heat acclimatized population wearing worker uniforms will not have a rectal temperature in excess of 38°C, it must be established at what level of environmental heat will the 5 percentile man reach his ULPZ, and this value has to be corrected for the level of acclimatization and clothing.This ULPZ was found in a paper of Lind and Liddell®^ in which they tested the ULPZ of a group of 128 men of average physical fitness.Figure 6 shows that about 95% of the men could reach an equilibrium deep body temperature in the 3-hour exercise test if the climatic conditions did not exceed 80.5°F.Thus, at a work load of 300 Kcal/hr the 5 percentile man's ULPZ lies about 1.0°C lower than that of the subjects' observed by Lind in his first study of the PZ.®® This result was adopted as a guideline to correct the ULPZ values orginally recommended by Lind as shown in Figure 7.As can be seen, it was assumed that a larger correction is required at higher levels of work load when the rectal temperature in the PZ is already very close to 38°C and no correction was applied at the lowest level of work load where the rectal temperature in the PZ is much lower than 38°C.Another justification for applying this upward adjustment for heavy work and downward adjustment for light work comes from the study of Kraning et al.®^ this study evidence was presented that the heat generated by work metabolism causes about twice as much strain on the cardiovascular system as the same amount of heat taken up from the environment.Studies performed by NIOSH V-7 have confirmed these findings. Corrections would also be needed for clothing because Lind's subjects were tested wearing shorts and sneakers only whereas the workers in hot industries wear underwear and work uniforms as well as boots. This would require a lowering of the ULPZ value.However, an increase would be permitted because it is assumed that the workers in hot jobs will be acclimatized.These two factors then cancel out each other. The ULPZ values read from the abscissa in Figure 7 are expressed in 86 terms of basic ET.They were converted by using Minard's graph showing the correlation between ET and WBGT.In this graph, however, the normal ET is stated for semi-nude men.Thus the ULPZ values read from Figure 7 were first converted to normal ET values, then to WBGT values. Justification for using time-weighted average hourly work-load 87 values for intermittent work comes from another study by Lind.The results showed that from the point of view of the ULPZ it does not matter whether a certain hourly amount of work is performed at a lower rate continuously or at a higher rate but interrupted with rest periods. The permissible exposure limits for heat stress cannot be based on 8-hour average values because if excessive exposure persists for longer than 1 hour, the worker may accumulate enough heat in his body to cause him to suffer an acute heat disorder or heat illness; thus in continuous heat exposure, hourly averages are necessary.However, if the exposure is intermittent the accumulation of heat will be slowed down; thus, it is permissible to average the exposure every 2 hours. V-8 The ULPZ was found to be the same for men of different ages, 88 thus no correction for age is required according to Lind et al.However, when older men are exposed to strenuous heat load an increased caution is advisable because of their lowered physiological capacities and increased susceptibility to diseases. A sex difference in the pattern and magnitude of physiological responses to work in heat has been demonstrated.Whether the observed differences in the responses reflect real differences in heat tolerance or in work performance is not fully proven (see references 33, 43, and 89 thru 96). In resting-in-heat studies the young female subjects had a higher body temperature and a lower sweat production than did the young males 89 for the same heat exposure.The onset of sweating occurred at a higher body temperature in the females, which resulted in a time delay in the onset of sweating during both severe and mild heat stress.Actual tolerance time in the severe heat was shorter in the females even though the maximum endurable body temperature was the same in both sexes.The symptoms present when an individual collasped from the heat stress were comparable even though the females found the stress intolerable sooner with work-in-stress. Women started to sweat at a higher skin temperature and had a lower sweat production for any specific heat load.Calculated skin temperatures at the onset of sweating were about 4°F higher in female than male subjects and for equal sweat rates the skin temperature was 1.8°F lower in the males. # V-9 In spite of the greater strain in women, they are capable of effective heat acclimatization.However, even after acclimatization the sweat rate is lower in the females, and they may have more subjective distress.Resistance to naturally occurring heat waves seems to be lower in women.Apparently there is no real difference in the degree of acclimatization that can be reached in men and women, but they may achieve equal acclimatization in different ways using different configurations of components of the regulating process. The question arises whether the lower sweat production in females may be due to fewer active sweat glands during the heat exposure. Both the total number of sweat glands and the number per unit area of skin surface are greater in females.
In lean females one hundred sweat glands per square centimeter of skin were counted while fifty-nine per square centimeter were found in males.In obese females there were seventy-five per square centimeter and in obese males, forty-seven per square centimeter.A recent WHO report questions this difference in sweat QAq rates after acclimatization. Differences in pulse rate responses to a standard work-in-heat test between both young and old men and women have been found.^ At the lower levels of work the women had pulse rates ten to twelve beats per minute higher than the men.For the high levels of work the differences were twenty to thirty beats per minute higher in the females.The higher pulse rates in the women reflect both the heat stress and the physical work and are higher in the women mainly because the work is relatively harder for them.Oxygen consumption expressed as V-10 milliliters per kilogram of body weight was about 15 to 20% higher in women than in men.The highest level of physical work used in the test required about 43% of the predicted maximum aerobic capacity for the older men, 30% for the young men, 66% for the older women, and 44% for the younger women.W i n g 9 ?reviewed the results of 15 studies performed in different laboratories on the effect thermal stress has on mental performance.It is quite apparent from these studies that thermal stress is an important factor where the worker has to make critical decisions, make fine discriminations, or has to perform fast and skillful actions because safety will depend on constant alertness.The number of errors made will increase if the worker is exposed to heat even before body temperature or pulse rate reaches critical levels. Figure 1-1 in the recommended standard is adapted from Wing's97 review paper.Although Wing recommended these limits only as tentative upper performance limits, they are considered to be the best presently available.Since Wing's values were expressed in ET, they were converted by using Walters'9® graph on correlation between ET and WBGT. As shown in Figure 1-1 of the recommended standard, unimpaired mental performance can be maintained below 86°F WBGT for 4 hours and probably even longer, although this needs experimental confirmation.Since environmental conditions above 86°F WBGT are permissible only for jobs with a work load below 200 Kcal/hr for men and below 150 Kcal/hr for women, Figure 1-1 of the recommended standard has to be taken into consideration only in sedentary jobs. # V-ll It is impossible that for unimpaired mental performance as work loads above 200 Kcal/hr, the 86°F WBGT may be too high.However, there are no data available either supporting or contradicting this assumption. Since then this problem was investigated in several studies and discussed at two Workshop sessions at the University of Pittsburgh. At these workshops the leading experts in problems of industrial heat stress agreed that the Brouha method should be used as a means of monitoring cardiovascular strain in industry. Figure 8 shows data obtained in PHS field studies on the dehydration of workers exposed to hot environments.There is a correlation between daily sweat loss and dehydration: the higher the sweat loss the more dehydrated the worker will be at the end of the work shift.However, this correlation was quite different in the four plants.The heavy equipment operators sweated the least, but dehydrated most.At about the same level of daily sweat loss, the foundry men and chemical plant workers dehydrated significantly less.Finally, the aluminum reduction workers whose daily sweat loss was the highest did not dehydrate more than workers of the chemical plant. # V-12 When analyzing for causes of the differences in the extent of dehydration, it was discovered that aluminum reduction plant workers were supplied from their drinking fountains a 0.1% salt solution.Thus, it was made sure that the salt they lost by sweating was replaced each work day.For the chemical plant workers and the foundry men salt tablets were available at the drinking fountains.The heavy equipment operators were not supplied with any additional salt, except that salt ingested with their midday lunch. These results suggest that salt supplementation may play an important role in preventing dehydration. Another difference between the working condition of the heavy equip ment operators and the workers of the other three plants was in the avail ability of drinking water.Whereas the heavy equipment operators had to go out of their regular path and disembark from their vehicles to have a drink of water, all the workers in the rest of the plants had to do was to go a few steps to the nearest drinking fountain.This circumstance may have also contributed to the higher level of dehydration of the heavy equipment operators.Indeed, it was observed that the workers were not drinking as often as necessary to replace their water loss if they had to make some effort to reach the source of water.These results indicate the importance of making drinking water available close to the job site and recovery places where the workers- daily sweat loss exceeds 2 liters. In Figure 8 a horizontal broken line is drawn at the 1.5% dehydration level.This is done because the results of earlier NIOSH studies suggested that if the level of dehydration exceeds 1.5% of body weight the V-13 physiological responses, such as the body temperature and heart rate, start to increase, indicating an increase of strain.In this respect it may be worth mentioning that among the heavy equipment operators the accident frequency was double that observed at other locations where the same operations were performed, but in comfortable climatic conditions. It may be assumed that the dehydrated heavy equipment operators, unaware of their diminished performance capacity, may have been unable to react fast enough and correctly in situations where sudden action would have been necessary to prevent an accident.This again may be interpreted as a warning as to the importance of proper fluid and salt replacement in hot jobs. # Summary of the Basis for the Work Practices Standard The work of L i n d e , 84 £n the development of the prescriptive zone (PZ) is undoubtedly the basis for the best approach for the development of an environmental standard for heat stress because it combines both the climatic and work load conditions that are imposed upon the worker in hot industries.There are, however, a number of practical shortcomings and unresolved questions related to this approach. These unresolved questions which will require additional research to validate the hypotheses presently proposed as the best technique for evaluation of heat stress conditions dictates the necessity for the development of the work practices standard as outlined in this document as opposed to an environmental standard.The additional research is such that it would be impossible to utilize an environmental standard at this time without stringent limitations being placed upon both the worker and management.Such an approach would be unrealistic. V-14 The This must also be considered in relationship to the normal work clothes of the industrial worker, as well as any other protective clothing that such a worker may be wearing. # V-15 All of the above factors can have a significant impact upon the level of heat stress to which a worker might be permitted to be exposed without adverse affects.At this time, such factors without sufficient validation would result in severe limitations on any environmental levels that might be proposed.The information does exist, however, to allow for environmental measurements that can be utilized to initiate work practices that will protect the industrial worker. Additional research is being conducted with regard to how the questions, indicated above, might be resolved. # Environmental Measurements The climatic conditions are expressed in wet-bulb globe temperature (WBGT) on both the Fahrenheit and Centigrade scales. Assessment of the WBGT Index The numerical value of the WBGT Index is calculated by the following equations: 1.Indoors or outdoors with no solar load WBGT = 0.7 WB + 0.3 GT # Instrumentation The instruments required for determining the WBGT Index are a natural wet-bulb thermometer, a globe thermometer, and when outdoors in sunshine, a dry-bulb thermometer. A satisfactory wet-bulb thermometer may be constructed using a mercury-in-glass thermometer having a range of 30 to 120°F with 0.5°F graduations, and guaranteed to be accurate within + 0.5°F throughout its range.A centigrade thermometer of comparable accuracy may also be used.A highly absorbent woven cotton wick shall cover the thermo meter bulb and at least 1-1/4 inches of the thermometer stem above the bulb.The lower end of the wick shall be immersed in a reservoir of V-17 distilled water.There shall be one inch of wetted wick exposed to the air between the top of the reservoir and the bottom of the bulb. The wick should be wet to the top at all times.Under unusually hot or dry conditions this may be difficult to achieve, and special pro visions may be necessary, such as an auxiliary water supply or manual wetting. The globe thermometer should consist of a 6-inch diameter thin copper sphere, the outside of which is painted a matte black.Either Krylon No.1602 Ultra Flat Black Enamel or 3 M No.101-C10 Nextel Black Velvet coating is available in spray cans and will provide an satisfactory surface.A mercury-in-glass thermometer, having a range of 30 to 220°F with 1°F graduations and guaranteed to be accurate to + 1°F, should be inserted through the shell with the thermometer bulb located at the center of the globe.The thermometer mounting and the globe support may be arranged in several ways.One convenient method is to use a globe having a spud with a 1/A inch pipe tapping.The thermometer can be inserted through a hole drilled through the spud and supported at the proper height by a ring of rubber tubing, and the complete assembly can be supported by a clamp around a 1/A inch nipple screwed into the spud.Another satisfactory method is to insert the thermometer through a rubber stopper in a hole in the top of the globe.The globe is then supported from the bottom by a 3/16 inch rod threaded into a matching spud.The globe thermometer should be allowed 20 minutes to reach equilibrium. # V-18 When a dry-bulb temperature is necessary it may be obtained with a mercury-in-glass thermometer as specified above for the wet-bulb thermo meter.The dry-bulb thermometer should be shielded from solar radiation, but shielding must be applied in such a manner that air circulation over the thermometer bulb is not restricted. Mercury-in-glass thermometers have been indicated as the sensing elements in the above described instruments.Thermocouples, thermistors, or any other sensors which will provide the same accuracy are equally acceptable.In some cases these may have an advantage over the ordinary thermometer in that the signals from such sensors may be readily recorded. A suggested arrangement of the instruments is given in Figure 9. Further instrument details and techniques for their use may be found in references.99'100'101 In addition to the above described instrumentation which requires the calculation of the WBGT index value, there are instruments described in Qo in9 ihq the literature ' ' or available on the market which sense the required temperatures and automatically integrate them to give a readout in WBGT- Another such instrument is currently (March, 1972) being developed by NIOSH. Instrumentation for the determination of the WBGT Index should always be located so that the readings obtained will be truly representative of the environmental conditions to which the workman is exposed.Sensors should be at about the mean height of the worker, and due consideration should be given to the location of radiation sources and the direction of air movement.A record shall be maintained of the WBGT Index observed at each of the various hot work sites. V-19 # Medical The purpose of the pre-placement examination of persons applying for hot jobs is the same as for evaluating the health status of a prospective employee for any job, namely, to determine his mental, physical and emotional qualifications to perform his job assignment with reasonable efficiency and without risk to his own health and safety or to that of his fellow employees.10T he examining physician, however, will recognize the particular requirements for persons whose jobs involve significant heat exposure. He should be probing in taking the employees' history, both medical and occupational, in order to discern possible evidence of intolerance co heat either occupational or off the job. By the same token, a history of successful adaptation to heat exposure on previous jobs is perhaps the best criterion on which to predict effectiveness of a worker's future performance under heat stress, assuming that levels of work demands and heat exposure are equivalent and that no significant alteration has occurred in his health status since his previous employment. For new employees without previous occupational exposure to heat, they should not be assigned to hot jobs where the environmental conditions exceed 79°F WBGT for men and 76°F WBGT for women until they are acclimatized.It has been established that both heat tolerance and also physical work capacity decline with age.10^'10D uring both the history taking and the physical examination, the examiner should direct careful attention particularly to detect evidence of chronic functional or organic impairments not only of the cardiovascular system V-20 but also of the kidneys, liver, endocrines, lungs, and skin.Significant disease of any of these systems should be disqualifying for new employement on jobs involving severe heat exposure, or for those previously employed on such jobs if the disease is progressive despite treatment. Careful inquiry should be made on use of drugs, particularly hypotensive agents, diuretics, antispasmodics, sedatives, tranquilizers, and anti depressants as well as the abuse of drugs, particularly amphetamines, hard narcotics, and alcohol.Many of these drugs impair normal responses to heat stress and others alter behaviour, thus, exposing the employee or fellow workers to health and safety hazards.Evidence of therapeutic use of one or more of these categories of drugs or personal abuse of alcohol and other drugs should be disqualifying. Other qualifications depend on the job demands independently from heat exposure, for example, statutory requirements to qualify as a vehicle operator, craneman, locomotive engineer, etc.,would obviously need to be met as well as nonstatutory requirements for jobs in a particular industry. A glucose tolerance test, renal clearance studies, X-ray examination of the renal pelvis and biliary system with contrast media, pulmonary function tests and other special tests are recommended when indicated in addition to routine 12-lead ECG 14" x 17" chest X-ray, and the usual blood and urine analyses. Workers employed on jobs which regularly expose them to levels of heat stress which have been determined to approach or equal permissible limits prescribed by the heat standard should be examined periodically on an annual basis or more frequently if indicated.The examination should be conducted during the summer season.In employees after the age of V-21 forty-five, physical and laboratory examinations should be designed to detect conset of chronic impairments of the cardiocirculatory and cardio respiratory systems and also to detect metabolic, skin, and renal disease. In cases of older employees who had not undergone the pre-placement examination, and whose health records indicated pre-existing chronic diseases of the systems referred to in the section on pre-employment examination, the examination should determine the extent to which such impairments have progressed.For all employees on hot jobs undergoing periodic examination, any history of acute illness or injury, either occupational or nonoccupational, during the interval between examinations, should be carefully evaluated.Repeated accidental injuries on the job or frequent sick absence should alert the physician to possible heat intolerance of the employee or the possibility of an aggravating stress with heat in combination, such as CO.Nutritional status should be noted and advice offered to correct overweight. In industrial establishments in which heat stress approaches or equals permissible limits only during the summer season, periodic examin ations should be administered during the summer.In establishments in which heat stress at the permissible level occurs throughout the year, the periodic examination can be administered at any time regardless of season.The first periodic examination of workers already employed on hot jobs who had not undergone the pre-placement examination required for new employees should be conducted within a year.Guidelines for qualifications should be the same as for new employees but with due allowance made for successful performance on the job, which as indicated earlier is perhaps the most important criterion in evaluating a worker's capacity to adapt to heat stress on the job. # V-22 In cases of those previously employed but with a record of health impairment or significant impairments found first on periodic examinations, the examiner should determine whether pre-existing impairments had been effectively controlled by treatment.If progressive, despite treatment, these findings should disqualify the employee from continuing on the same job.In case of impairments detected for the first time, the examiner should evaluate these in light of possible aggravation by heat stress. If such a likelihood exists, the employee should be reevaluated periodically at intervals shorter than those recommended for routine periodic examinations. For a new employee undergoing his first periodic examination, the examiner should note evidence of heat intolerance, including a history of repeated accidental injury on the job, episodes of heat disorder, or frequent sick absence.In such cases, the examiner should assess the employees capacity to continue on the same job and consider recommending his transfer if indicated. The supervisor and selected personnel should be trained in recognizing the signs and symptoms of heat disorder and in administering first aid.
As described earlier, the most serious emergency is heat stroke signaled by the signs of dry, hot, red, or mottled skin, mental confusion, delirium, convulsions, or coma, and a high and rising rectal temperature, usually 106°F and above but occasionally lower, between 104 and 106°F. First aid treatment requires immediate removal to a cooler area, soaking the clothing in cold water, and fanning vigorously.The final treatment is conducted in a medical facility but first aid must not be delayed. # V-23 In severe heat exhaustion, the victim may faint on standing, but unlike heat stroke the skin is wet and cool.He should be given water by mouth if conscious, and transported to the medical facility without delay.It is essential that water intake during the workday should about equal the amount of sweat produced.Work in a hot environment may result in sweat productions of 1 to 3 gallons a day.If this water lost in the sweat is not replaced, dehydration with its debiliating effects will result. Thirst is an inadequate drive to stimulate one to drink that much more water.An ample supply of cool water readily available to the workers is required and the worker should be encouraged to take a drink of water each 15 to 20 minutes preferably using disposable paper cups rather than drinking directly from the fountain. Large amounts of salt may be lost in the sweat particularly by the individual not acclimatized to heat.The salt must be replaced daily to prevent heat induced salt deficiency heat illness. The acclimatized individual looses much less salt in his sweat.Salt V-25 can be replaced by liberally salting ones food or by using a 0.1% salt solution drinking water.About 1 level tablespoon of table salt to fifteen quarts of water will make a 0.1% salt solution.Enteric coated salt tablets may also be used; however, they must be taken with ample water to prevent gastric irritation.It is particularly important that salt depletion is prevented by supplemental salt intake during the first few days of heat exposure when the worker is not yet acclimatized. Each employee exposed to heat should weigh himself at the beginning and end of the workday to insure that fluid intake has been sufficient to prevent serious dehydration.Weight loss at the end of the workday should not exceed 1.5% of the worker's body weight. Each employee should be instructed on how to recognize the symptoms of heat disorders and illnesses including dehydration exhaustion, heat syncope, heat cramps, salt deficiency exhaustion, prickly heat and heat stroke.Recognition of early warning signs so that corrective or evasive action can be taken is one of the best means of preventing health damage. The major heat disorders are shown in Figure 3 and have been discussed in the section on Medical Considerations. The most prevalent of the heat disorders is undoubtedly heat syncope (possibly along with heat edema) which is seldom a debilitating disorder. (over many days), the end result is the same.In extreme examples, as for men lost in a desert with no water to drink to replace sweat losses, 16 death can occur in 12 hours and is usually inevitable within 48 hours. Even for individuals in a temperate climate, such as castaways at sea, water deprivation will usually result in death in 7-10 days.Death from water depletion will occur if 9-10 liters (18-20 pints) is lost from the body, and loss of 4 liters (8 pints) without replacement leads to intense thirst, a rapid heart rate, and a high body temperature.Water intake must equal the water loss by sweat if this disorder is to be avoided; workers exposed to hot climates must be encouraged to drink an ample supply of water or flavored drinks which must be readily available to them.Again, there is no specific environmental condition above which this disorder occurs, since it depends simply on the replacement of the fluid loss which occurs even in comfortable conditions; however, the hotter the environment is, the greater is the fluid loss by sweating and the worker will thereby come closer to water depletion. Salt is also lost in the sweat.The concentration of salt in the sweat is higher in unacclimatized men than in acclimatized men, but the concentration also depends on the dietary salt intake, which is usually in excess of the body's needs.If salt lost in the sweat exceeds the dietary intake, a salt depletion occurs.If this is not corrected, a vicious cycle can occur, since salt depletion can lead to loss of appetite and nausea, leading in turn to a further salt depletion; moderately severe salt depletion results in vomiting and diarrhea, with further loss of salt.If this cycle is not inter rupted, death inevitably follows.Those who suffer salt depletion complain of weariness and weakness and may suffer muscle cramps; headaches, giddiness, V-28 and other symptoms are common.While those who are not acclimatized are at greatest risk, the disorder can occur in any individual who sweats a lot and whose dietary salt intake is low.Supplementary salt of 5 to 15g daily may be required by unacclimatized men to avoid salt depletion, though this may be reduced by half or more after 10 days of work in the heat.While at least some of this supplementary salt can be obtained by the additional salting of food, it may be necessary to supply salted drinks or salt tablets to be taken with drinking water. The most severe heat disorder is heatstroke, the mortality rate for 16 which has been found to be between 25% and 75%. The variability in mortality depends on the length of time elapsing between the onset of the disorder and the start of treatment and the highest body temperature attained during the episode.Heatstroke always constitutes an urgent medical emergency, in which the basic requirement is to cool the patient rapidly. Heatstroke is a state of thermoregulatory failure usually of sudden onset, following exposure to hot environments, and is characterized by a disturbance of the central nervous system (often expressed as convulsions), by a failure of sweating (so that the skin is hot and dry), and by a high deep body temper ature.The body temperature at the time of onset of the disorder is usually in excess of 40.5°C (105°F) although cases have been reported at 39.5°C (103°F). The treatment of heatstroke must be vigorous and immediate, under the careful control of a physician. The environmental conditions in which heatstroke has been reported have been plotted on a psychrometric chart (Figure 10) and are surprisingly low. # V-29 But the values reported do not include the degree of radiant heat load, nor do they disclose the rate of work of the victims prior to the onset of the disorder; both of these contributions to the total heat load were probably high in many cases.Nevertheless, heatstroke has been known to occur in environmental conditions that are not particularly severe.Additional contributory causes can be of many origins -heavy clothing, water depletion, age
Scopolamine Poisoning -Continued Heroin is mixed ("cut") frequently with other substances primarily to increase its weight for retail sale (e.g., mannitol and starch) and to add pharmacologic effects (e.g., dextromethorphan and lidocaine).During 1995 and 1996, health departments and poison-control centers in New York City (NYC); Newark, New Jersey; Philadelphia; and Baltimore reported at least 325 cases of drug overdoses requiring medical treatment in persons who had used "street drugs" sold as heroin that probably also contained scopolamine, an anticholinergic drug.This report summarizes the clinical and epidemiologic features of these cases, which represent a new type of drug overdose.On March 16, 1995, eight persons were treated in the emergency department (ED) of a Bronx hospital for acute onset of agitation and hallucinations approximately 1 hour after "snorting" heroin.On physical examination, all these persons had clinical manifestations of anticholinergic toxicity (i.e., tachycardia, mild hypertension, dilated pupils, dry skin and mucous membranes, and diminished or absent bowel sounds); five had urinary retention.All were initially lethargic and became agitated and combative after emergency medical service (EMS) personnel treated them with parenteral naloxone, which is routinely used for suspected heroin overdose to reverse the toxic effects of opioids (e.g., coma and respiratory depression).All patients received diazepam or lorazepam for sedation, and signs and symptoms resolved during the next 12-24 hours.During March 17-April 5, 1995, a total of 10 persons who reported using heroin presented with similar clinical findings to hospital EDs in the Bronx and Manhattan.Seven patients reported having used heroin with the street names "Point on Point" or "Sting."Specimens of "Sting" heroin obtained from two patients on April 5 and analyzed by gas chromatography-mass spectrophotometry (GC-MS) by the Bureau of Laboratories, New York City Department of Health (NYCDOH), contained heroin and scopolamine.The GC-MS patterns of the scopolamine suggested it was synthetic rather than derived from a plant source.As a result of this finding, these patients were treated for suspected scopolamine poisoning with physostigmine (an antidote for anticholinergic toxicity).While receiving physostigmine intravenously for 5-10 minutes, their paranoia, hallucinations, and agitation resolved (1 ).During March 17-April 10, 1995, NYCDOH issued press releases warning of scopolamine-adulterated heroin sold under the street names "Point on Point" and# "Sting."During March 16, 1995-May 27, 1996, the New York City Poison Control Center (NYPCC) recorded 121 cases that met a case definition of both historical or clinical evidence of heroin use and clinical manifestations consistent with anticholinergic toxicity.NYPCC continues to receive several reports each week of presumed combined heroin/scopolamine overdoses that respond to physostigmine treatment. # Newark During a 24-hour period on December 28-29, 1995, a Newark hospital ED treated 22 persons who, approximately 30 minutes after using heroin with the street name "Polo," developed clinical manifestations of anticholinergic toxicity.Naloxone treatment increased agitation and hallucinations, and physostigmine treatment resolved the signs of toxicity. On December 29, the New Jersey Poison Center (NJPC) informed all EDs in the state about the syndrome of severe anticholinergic toxicity associated with the use of "Polo" heroin.Later that day, after GC-MS testing of a sample of heroin obtained from a patient identified both heroin and scopolamine, the New Jersey Department of Health (NJDOH) held an emergency press conference to alert the public to this drug combination. NJDOH and NJPC identified a total of 61 persons with 1) recent histories of snorting or ingesting heroin with the street name "Polo" and 2) clinical manifestations of anticholinergic toxicity for which treatment had been provided at 13 EDs in the Newark metropolitan area during December 28-30, 1995.During December 31, 1995-June 1, 1996, NJPC was consulted 2-3 times each week about patients with similar conditions. # Philadelphia During February 19-21, 1996, a total of 12 patients who had injected or snorted heroin and had clinical manifestations of anticholinergic toxicity were treated in EDs at four hospitals in northeastern Philadelphia and reported to the Delaware Valley Poison Control Center (DVPCC).DVPCC estimated that in the Philadelphia area, during February 19-21, a total of 35 persons were treated for apparent combined scopolamine/ heroin overdose, and during March 15-May 5, six persons were treated. On May 9, a total of 27 persons presented to one Philadelphia hospital ED between 4:30 p.m. and 11 p.m. because of drug overdoses after taking heroin (mostly by injection).Of these, 16 were admitted to the hospital for observation because of tachycardia, hallucinations, or semi-coma.In addition to these cases, DVPCC was consulted about apparent anticholinergic toxicity among 72 heroin users during May 9-11, and among 12 during May 22-23. # Baltimore During May 10-12, 1996, a total of 22 persons presented to one hospital ED with clinical manifestations of anticholinergic toxicity.Although these persons reported taking heroin with street names of "Homicide" and "Super Buick," GC-MS testing of a specimen identified scopolamine, quinine, and dextromethorphan but no heroin. # Testing of Heroin by the Drug Enforcement Administration The Drug Enforcement Administration monitors the purity of and adulterants in heroin through "street" purchases of heroin (i.e., the "Domestic Monitor Program" ) and testing of heroin obtained during criminal justice operations.From June 1979 through February 1996, DMP did not detect scopolamine in specimens sold as heroin.During 1995, DMP made a total of 806 purchases, including 195 from Maryland, New Jersey, New York, and Pennsylvania; none contained scopolamine.During 1996, of the 147 DMP purchases, including 46 from Maryland, New Jersey, New York, and Pennsylvania, only two (made in March 1996 in Elizabeth and Passaic, New Jersey) contained scopolamine.In addition, four of 23,288 non-DMP specimens believed to be heroin and obtained through criminal justice operations contained scopolamine.The earliest was obtained in October 1995 in Bohemia, New York; two in March 1996 in Philadelphia; and one in March 1996 in NYC. -bscure the classical effects and differences.Although some of these patients improve dramatically with intravenous physostigmine therapy, such treatment should be administered only by experienced staff and with appropriate patient monitoring because of the potential for serious side effects, including seizures, bronchospasm, and bradycardia.For many patients, treatment may be restricted to sedation and observation, and manifestations may resolve over a period of hours.Naloxone remains the treatment of choice for coma and severe respiratory distress associated with possible drug overdose.Because of the complexities of both the diagnosis and treatment of patients with mental status changes and possible drug overdose, practitioners caring for such patients should consult their local poison-control center. Surveillance based on data from the system of poison-control centers in the Northeast was critical in recognizing the cause of this new type of drug overdose among heroin users and alerting health departments.The impact of the effects of these drug overdoses was limited further by timely recognition of the combined heroin and anticholinergic toxicity, use of sedation or physostigmine to treat the patients, and prompt investigation and reporting by state and local health departments.The continued occurrence of drug overdoses associated with use of scopolamine-containing heroin indicates the need for clinicians, public health programs, and organizations working with drug users to be aware of this problem; new cases should be reported promptly to the local poison-control center and health department. # Scopolamine Poisoning -Continued # Trends in Rates of Homicide -United States, 1985-1994 Homicide -Continued During 1993, a total of 26,009 homicides were reported in the United States; 71% were firearm-related, and one third of all homicides occurred among persons aged 15-24 years (1 ).Since 1985, national homicide rates have increased sharply, especially firearm-related homicides and homicides among persons aged 15-24 years.However, based on data from the Supplementary Homicide Report compiled by the Federal Bureau of Investigation and reports from some cities, homicide rates have been stable or declining since 1993.To examine this trend and to assess the relative contributions of firearm-and nonfirearm-related homicide to these recent changes, CDC analyzed national vital statistics data for 1985-1994.This report summarizes this analysis, which indicates that overall rates of homicide increased from 1985 to 1991 and decreased from 1992 to 1994, and that during these two periods, rates for total firearm-related homicides and homicide among persons aged 15-24 years increased then stabilized but remained at record-high levels. Data for 1985-1993 (the most recent year for which complete data are available) were from final mortality statistics (FMS), and data for 1994 were from the Current Mortality Sample (CMS).FMS are based on information from death certificates submitted by all 50 states and the District of Columbia, and CMS data provide national estimates based on a 10% systematic sample of death certificates received monthly by the vital statistics offices in the 50 states, the District of Columbia, and New York City.A homicide was defined as death resulting from injury purposefully inflicted by another person (including those caused by law enforcement officers or legal intervention), for which the underlying cause listed on the death certificate was International Classification of Diseases, Ninth Revision (ICD-9), codes E960-E978.Population estimates are based on data from the Bureau of the Census (2 ).Trends for both firearmand nonfirearm-related homicides for all ages and for persons aged 15-24 years were reviewed.To assess the accuracy with which the CMS data reflect final statistics, 1993 CMS and FMS homicide rates were compared.During sequential quarters of 1993, compared with FMS quarterly homicide rates, CMS rates differed by -0.4%, -4.6%, +1.2% and -4.6%, indicating the accuracy of weighted CMS rates for estimating final homicide rates. Quarterly homicide rates were analyzed using piecewise regression models to account for the observed changes in linear relations over time.Three time periods (1985-1987, 1988-1991, and 1992-1994) were selected for analysis based on a preliminary review of scatter plots of observed rates and their apparent changes in slopes.Statistical testing was conducted to determine whether the slope of the predicted values of the regression line (i.e., predicted rates) changed over each of these time periods.Statistical testing for a discontinuous piecewise regression model also was conducted to determine whether the rate changed significantly at the beginning of each new time period (i.e., "jump point").No significant jump points were observed, and analyses consistently indicated that the slope of the regression line for 1985-1987 was similar to that for 1988-1991.Therefore, regression lines are presented only for two periods: 1985-1991 and 1992-1994.Overall results and interpretation of the piecewise model using two pieces are no different from those using a model with three pieces. During 1985-1991, the overall rate of homicide in the United States increased significantly (p<0.01) (slope=<0.1, 4% annually); during 1992-1994, the rate decreased significantly (p<0.01) (slope=-0.1, 1% annually) (Figure 1).During 1985-1991, nonfirearm-related homicide rates remained stable, and firearm-related homicide rates increased significantly (p<0.01).During 1992-1994, nonfirearm-related homicide rates declined significantly (p<0.01), and firearm-related homicide rates stabilized. During 1985-1991, the rate of total homicide increased significantly for persons aged 15-24 years (p<0.01) (slope=0.4, 16% annually).Firearm-related homicide rates for this age group also increased during 1985-1991 (p<0.01) (slope=0.4, 23% annually) (Figure 2), with most of the increase occurring during 1988-1991.During 1992-1994, the rates of total and firearm-related homicide were stable.For all other age groups, the trend in firearm-related homicide rates followed a similar pattern, with significant increases during 1985-1991 (p<0.01) and stable rates during 1992-1994 (Figure 2).Nonfirearm-related homicide rates for persons aged 15-24 years and all other ages were lower than firearm-related homicide rates and were stable during 1985-1991 and decreased significantly during 1992-1994 (p<0.01). Analysis of firearm-related homicide rates by sex for persons aged 15-24 years indicates that rates for males and females reflected the overall trend for this age 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 Quarter and Year Symbol=Observed Line=Predicted *Per 100,000 population. † Final Mortality Statistics were used for 1985-1993.Current Mortality Sample was used for 1994.Rate 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 Quarter and Year Editorial Note: The findings in this report confirm that the overall homicide rate increased rapidly during the late 1980s and began to decline in 1992; in addition, nonfirearm-related homicide rates decreased, and the percentage of firearm-related homicides increased.During 1985-1994, the percentage of firearm-related homicides among all homicides in the total population increased from 60% to 72% and among persons aged 15-24 years, from 67% to 87% (3 ).These increases illustrate that changes in overall homicide rates primarily reflect changes in firearm-related homicides.The stabilization of firearm-related homicide rates during 1992-1994-particularly among those aged 15-24 years-reflects a change from the increasing rates in previous years, even though rates remain at record-high levels.The findings in this report also indicate the usefulness of CMS data as a source of information for monitoring homicide in the United States.Because of the timely availability of CMS data and their accuracy in reflecting final mortality-based homicide rates, these data enable more timely analyses of temporal trends, objective policy formulation, and measurement of progress toward public health goals.The findings in this report are subject to at least two limitations.First, because of the small numbers based on CMS data, rates were not examined among age-, race-, and sex-specific subgroups.Second, estimates for some causes of death may be incomplete or skewed because reporting of the underlying cause of death data may not have been complete when the monthly sample was obtained (the data for this potential undercount are adjusted in the annual summary ). Strategies for preventing homicide and violence require integration of approaches from multiple disciplines, including criminal justice, education, social services, community advocacy, and public health.For example, public health approaches to prevent violence have focused on 1) changing individual knowledge, skills, and/or attitudes; 2) changing the social and physical environments; and 3) increasing community awareness of the causes and prevention of violence.The public health community also has recognized the influence of social class and poverty on violence.Communities increasingly are adopting programs emphasizing strategies to enhance the skills of youth and parents to reduce violence.These strategies include, for example, 1) school-based curricula that teach coping, communication, and mediation skills (4 ); 2) family-intervention programs that focus on parental training to positively alter parental practices and family cohesion (5 ); and 3) preschool efforts to develop intellectual and social skills (6 ).Because evaluation of prevention strategies is a critical component of public health interventions, CDC is evaluating the effectiveness of selected programs in reducing violent behavior and injury (7 ). Homicide and assaultive violence now are recognized as global public health problems.Although the U.S. homicide rate ranks higher overall and higher for males aged 15-24 years than those of other highly industrialized countries (8,9 ), in many lessindustrialized countries homicide rates exceed those in the United States (8 ).To address this global problem, in May 1996 the 190 nations of the World Health Organiza-tion (WHO) passed a resolution declaring violence a worldwide public health problem, urging member states to assess the public health impact of violence, and requesting the Director-General of WHO to initiate a science-based public health approach to violence prevention.This resolution provides a scientific framework for action throughout the world addressing global violence.The SOII is a collaborative federal/state program administered by BLS and is based on employer reports from approximately 250,000 private industries in the United States (2 ); the sampling frame is representative at the national level and at the state level for most states (data for 1993 were the most recent available). §Employers identify injuries and illnesses that meet recordkeeping requirements ¶ of the Occupational Safety and Health Administration (OSHA); based on these data, BLS estimates the national incidence of work-related injuries and illnesses.For those injuries and illnesses resulting in lost work days, employers provide demographic information and data about the nature and circumstances of injuries and illnesses.Because employment data provided by employers were not stratified by age, injury and illness rates could not be calculated for specific age groups. # Homicide -Continued # Work-Related Injuries and Illnesses Associated With # National Estimates In 1993, persons aged <18 years incurred an estimated 21,620 injuries and illnesses involving lost work days.Of these, 24% involved 1 lost work day; 43%, 2-5 days; 13%, 6-10 days; 13%, 11-30 days; and 8%, ≥31 days (median: 3 days).Most (96%) injuries and illnesses occurred among persons aged 16-17 years, and males accounted for 59% of cases.Sprains/strains were the most commonly reported problem (31%), followed by cuts/lacerations (17%), contusions/abrasions (13%), heat burns (8%), and fractures/dislocations (5%). Injured and ill persons were employed most frequently by eating and drinking establishments (39%), followed by grocery stores (14%), nursing and personal-care facilities (6%), and department stores (5%).The most common occupations were food preparation and service workers (i.e., waiters and waitresses, cooks, and food counter and kitchen workers) (37%), followed by cashier (10%), stock handler or bagger (9%), health or nursing aide (7%), and janitor and cleaner (5%). Common events resulting in injury included falls on the same level (i.e., falls to floors and falls onto or against objects) (21%), overexertion (i.e., from lifting, pulling, pushing, turning, wielding, holding, carrying, or throwing objects) (17%), striking against objects (i.e., bumping into, stepping on, kicking, and being pushed or thrown into or against objects) (10%), contact with hot objects or substances (9%), being struck by falling objects (7%), and being struck by a slipping hand-held object (e.g., knife, razor, or tool) (6%). # State-Specific Variations In general, national patterns were reflected at the state level, although there were state-specific variations.Median number of lost work days ranged from 1 day (Nebraska and Vermont) to 6 days (Alabama, Arkansas, New York, and Wyoming) (Table 1).The most common worksites were eating and drinking establishments and grocery stores.However, in Alaska, laundry, cleaning, and garment services and the manufacture of specific food products each accounted for 16%-17% of cases.In Cali- § The base sample for SOII is designed to produce national estimates.
However, each year, approximately 40 states participate in a federal/state cooperative program through which, in these states, the base sample is augmented to generate state-specific estimates that meet the individual needs of participating states.In 1993, 42 states participated in this program. ¶OSHA requires employers to record information on every occupational illness and injury that involves one or more of the following: loss of consciousness, restriction of work or motion, transfer to another job, or medical treatment (other than first aid).Employers who are selected for the SOII sample but who are not usually required to keep these records are provided with a copy of instructions and recordkeeping forms for the survey.fornia, worksites providing social and rehabilitation services accounted for 24% of cases.In Florida, Nevada, and South Carolina, 12%-15% of incidents occurred in worksites providing amusement and recreation services.In Hawaii, nearly one fourth (24%) of incidents occurred in construction/special trade worksites (e.g., carpentry and painting).Hotels and motels were the most common site of work-related injuries and illnesses in Vermont (27%) and second most common in Utah (11%). The types of events and exposures resulting in injuries and illnesses varied from national patterns in some states.Exposures to caustic, noxious, or allergenic substances accounted for 11%-23% of cases in Alaska, Montana, Nebraska, Nevada, New Mexico, and Wyoming.Exposure to sun accounted for 22% of cases in Vermont, and falls through roofs accounted for 28% of injuries in Wyoming.Editorial Note: The findings in this report are the first to provide comparable statespecific data for work-related injuries and illnesses among persons aged <18 years; however, the inability to calculate state-specific rates limits comparisons between states.Although many state-specific patterns of injuries and illnesses reflected national patterns, the variations identified are important for targeting prevention efforts at the state level.Workers' compensation data can provide supplemental information to assist state-specific intervention efforts (3-7 ).The approximately 22,000 injuries and illnesses involving lost work days among children aged <18 years in 1993 is probably an underestimate because SOII excludes some categories (e.g., self-employed workers, farms with <11 employees, private households, and government employees) (2 ); employment data suggest that at least 11% of working children aged <18 years are not represented by the SOII (1 ).These estimates exclude injuries and illnesses that did not result in lost work days or in death.During 1992, an estimated 64,000 children aged <18 years were treated in emergency departments for work-related injuries; approximately 70 die from work-related injuries each year (8 ). Safety and health regulations, such as those promulgated and enforced by OSHA, apply to workers of all ages.In addition, children aged <18 years are protected by provisions of child labor laws.For example, federal child labor laws specifically prohibit cooking and baking by persons aged 14-15 years (9 ); however, in this analysis, one third of cases among children aged 14-15 years occurred among persons identified as cooks.During 1983-1990, 1475 serious injuries among persons aged <18 years were associated with violations of federal child labor laws (10 ), and studies during the 1980s suggest that 38%-86% of work-related deaths among children were associated with activities prohibited by federal child labor laws (8 ). The risks for work-related injuries and illnesses among workers of all ages can be reduced through adherence to routine precautions such as prescribed housekeeping practices; training and safe work procedures; use of proper shoes, gloves, and protective clothing; and maintenance and use of equipment with safety features.In addition, workers aged 15 pounds more often than once per minute or ever to lift objects >30 pounds; tasks involving continuous lifting should never last more than 2 hours (8 ).Children aged <18 years should not participate in work requiring routine use of respirators (a means of protecting workers from inhaling hazardous substances) (8 ).Employers should be knowledgeable about and comply with child labor laws, and school guidance counselors and physicians who sign work permits for children also should be familiar with child labor laws and ensure that the work they approve does not involve prohibited activities. Most persons aged <18 years enter the workplace with minimal prior experience for a job.During the summer of 1992, more than half (54%) of persons aged 14-16 years treated in emergency departments for work injuries reported that they had received no training in prevention of the injury they sustained and that a supervisor was present at the time of injury in only approximately 20% of the cases (8 ).Differences in maturity and developmental level regarding learning styles, judgement, and behavior should be considered when providing training for youth in occupational safety and health. Additional state-specific data and information about prevention of work-related injuries can be obtained from NIOSH, telephone (800) 356-4674 or (513) 533-8328.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 (1 ).Information suggesting that zidovudine (ZDV) postexposure prophylaxis (PEP) may reduce the risk for HIV transmission after occupational exposure to HIV-infected blood (2 ) prompted a Public Health Service (PHS) interagency working group, with expert consultation † , to update a previous PHS statement on management of occupational exposure to HIV with the following findings and recommendations on PEP (1 ). § # Background Although failures of ZDV PEP have occurred (3 ), ZDV PEP was associated with a decrease of approximately 79% in the risk for HIV seroconversion after percutaneous exposure to HIV-infected blood in a case-control study among health-care workers (2 ).In a prospective trial in which ZDV was administered to HIV-infected pregnant women and their infants, a direct effect of ZDV prophylaxis on the fetus and/or infant may have contributed to the observed 67% reduction in perinatal HIV transmission (4 ); the protective effect of ZDV was only partly explained by reduction of the HIV titer The interagency working group comprised representatives of CDC, the Food and Drug Administration (FDA), the Health Resources and Services Administration, and the National Institutes of Health.Information included in these recommendations may not represent FDA approval or approved labeling for the particular products or indications in question.Specifically, the terms "safe" and "effective" may not be synonymous with the FDA-defined legal standards for product approval. †CDC and the National Foundation for Infectious Diseases cosponsored a workshop, HIV Post-Exposure Management for Health Care Workers, on March 4-5, 1996; proceedings of the workshop will be published in the American Journal of Medicine. §Single copies of this report will be available free until June 7, 1997, from the CDC National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20849-6003; telephone (800) 458-5231 or (301) 217-0023.in maternal blood (5 ).PEP also prevented or ameliorated retroviral infection in some studies in animals (6,7 ). The average risk for HIV infection from all types of reported percutaneous exposures to HIV-infected blood is 0.3% (3 ).In the case-control study (2 ), risk was increased for exposures involving 1) a deep injury to the health-care worker, 2) visible blood on the device causing the injury, 3) a device previously placed in the sourcepatient's vein or artery (e.g., a needle used for phlebotomy), or 4) a source-patient who died as a result of acquired immunodeficiency syndrome (AIDS) within 60 days postexposure (and therefore was presumed to have a high titer of HIV) (2 ).Identification of these risk factors in the case-control study suggests that the risk for HIV infection exceeds 0.3% for percutaneous exposures involving a larger blood volume and/or higher HIV titer in blood.The risks after mucous membrane and skin exposures to HIV-infected blood (on average, approximately 0.1% and <0.1%, respectively ) probably also depend on volume of blood and titer of HIV.The risk is probably higher for skin contact that is prolonged, involves an area that is extensive or in which skin integrity is visibly compromised, and/or involves a higher HIV titer. Although information about the potency and toxicity of antiretroviral drugs is available from studies of HIV-infected patients, it is uncertain to what extent this information can be applied to uninfected persons receiving PEP.In HIV-infected patients, combination therapy with the nucleosides ZDV and lamivudine (3TC) has greater antiretroviral activity than ZDV alone and is active against many ZDV-resistant HIV strains without significantly increased toxicity (8 ).Adding a protease inhibitor provides even greater increases in antiretroviral activity; among protease inhibitors, indinavir (IDV) is more potent than saquinavir at currently recommended doses and appears to have fewer drug interactions and short-term adverse effects than ritonavir (8 ).Few data exist to assess possible long-term (i.e., delayed) toxicity resulting from use of these drugs in persons not infected with HIV. In currently recommended doses, ZDV PEP usually is tolerated well by health-care workers; short-term toxicity associated with higher doses primarily includes gastrointestinal symptoms, fatigue, and headache (3,7 ).The toxicity of other antiretroviral drugs in persons not infected with HIV has not been well characterized.In HIV-infected adults, 3TC can cause gastrointestinal symptoms and, in rare instances, pancreatitis.IDV toxicity includes gastrointestinal symptoms and, usually after prolonged use, mild hyperbilirubinemia (10%) and kidney stones (4%); the latter may be limited by drinking at least 48 oz (1.5 L) of fluid per 24-hour period (8 ).During the first 4 weeks of IDV therapy, the reported incidence of kidney stones was 0.8% (Merck Research Laboratories, unpublished data, 1996).As stated in the package insert, the concurrent use of IDV and certain other drugs, including some nonsedating antihistamines, is contraindicated.Based on limited data, ZDV use in the second and third trimesters of pregnancy and early infancy was not associated with serious adverse effects in mothers or infants (4,9 ); data are limited regarding the safety of ZDV during the first trimester of pregnancy or of other antiretroviral agents during pregnancy.Although 3TC has been associated with pancreatitis in HIV-infected children (8 ), whether 3TC causes fetal toxicity is unknown. # Recommendations The following recommendations are provisional because they are based on limited data regarding efficacy and toxicity of PEP and risk for HIV infection after different types of exposure.Because most occupational exposures to HIV do not result in infection transmission, 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.Changes in drug regimens may be appropriate, based on factors such as the probable antiretroviral drug resistance profile of HIV from the source patient; local availability of drugs; and medical conditions, concurrent drug therapy, and drug toxicity in the exposed worker.These recommendations were not developed to address nonoccupational (e.g., sexual) exposures.1.Chemoprophylaxis should be recommended to exposed workers after occupational exposures associated with the highest risk for HIV transmission.For exposures with a lower, but nonnegligible risk, PEP should be offered, balancing the lower risk against the use of drugs having uncertain efficacy and toxicity.For exposures with negligible risk, PEP is not justified (Table 1).Exposed workers should be informed that a) knowledge about the efficacy and toxicity of PEP is limited; b) for agents other than ZDV, data are limited regarding toxicity in persons without HIV infection or who are pregnant; and c) any or all drugs for PEP may be declined by the exposed worker.2.At present, ZDV should be considered for all PEP regimens because ZDV is the only agent for which data support the efficacy of PEP in the clinical setting.3TC should usually be added to ZDV for increased antiretroviral activity and activity against many ZDV-resistant strains.A protease inhibitor (preferably IDV because of the characteristics summarized in this report) should be added for exposures with the highest risk for HIV transmission (Table 1).Adding a protease inhibitor also may be considered for lower risk exposures if ZDV-resistant strains are likely, although it is uncertain whether the potential additional toxicity of a third drug is justified for lower risk exposures.For HIV strains resistant to both ZDV and 3TC or resistant to a protease inhibitor, or if these drugs are contraindicated or poorly tolerated, the optimal PEP regimen is uncertain; expert consultation is advised ¶ .3.PEP should be initiated promptly, preferably within 1-2 hours postexposure.Although animal studies suggest that PEP probably is not effective when started later than 24-36 hours postexposure (6,7 ), the interval after which there is no benefit from PEP for humans is undefined.Initiating therapy after a longer interval (e.g., 1-2 weeks) may be considered for the highest risk exposures; even if infection is not prevented, early treatment of acute HIV infection may be beneficial (10 ).The optimal duration of PEP is unknown; because 4 weeks of ZDV appeared protective (2 ), PEP should probably be administered for 4 weeks, if tolerated.4.If the source patient or the patient's HIV status is unknown, initiating PEP should be decided on a case-by-case basis, based on the exposure risk and likelihood of HIV infection in known or possible source patients.If additional information becomes available, decisions about PEP can be modified. ¶An HIV strain is more likely to be resistant to a specific antiretroviral agent if it is derived from a patient who has been exposed to the agent for a prolonged period of time (e.g., 6-12 months or longer).In general, resistance develops more readily in persons with more advanced HIV infection (e.g., CD4+ T-lymphocyte count of <200 cells/mm 3 ), reflecting the increasing rate of viral replication during later stages of the illness. # Workers with occupational exposures to HIV should receive follow-up counseling and medical evaluation, including HIV-antibody tests at baseline and periodically for at least 6 months postexposure (e.g., 6 weeks, 12 weeks, and 6 months), and should observe precautions to prevent possible secondary transmission (1 ).If PEP is used, drug-toxicity monitoring should include a complete blood count and renal and hepatic chemical function tests at baseline and 2 weeks after starting PEP.If subjective or objective toxicity is noted, dose reduction or drug substitution should be considered with expert consultation, and further diagnostic studies may be indi- *Any exposure to concentrated HIV (e.g., in a research laboratory or production facility) is treated as percutaneous exposure to blood with highest risk. †Recommend-Postexposure prophylaxis (PEP) should be recommended to the exposed worker with counseling (see text).Offer-PEP should be offered to the exposed worker with counseling (see text).Not offer-PEP should not be offered because these are not occupational exposures to HIV (1 ). §Regimens: zidovudine (ZDV), 200 mg three times a day; lamivudine (3TC), 150 mg two times a day; indinavir (IDV), 800 mg three times a day (if IDV is not available, saquinavir may be used, 600 mg three times a day).Prophylaxis is given for 4 weeks.For full prescribing information, see package inserts. ¶Highest risk-BOTH larger volume of blood (e.g., deep injury with large diameter hollow needle previously in source patient's vein or artery, especially involving an injection of source-patient's blood) AND blood containing a high titer of HIV (e.g., source with acute retroviral illness or end-stage AIDS; viral load measurement may be considered, but its use in relation to PEP has not been evaluated).Increased risk-EITHER exposure to larger volume of blood OR blood with a high titer of HIV.No increased risk-NEITHER exposure to larger volume of blood NOR blood with a high titer of HIV (e.g., solid suture needle injury from source patient with asymptomatic HIV infection).Possible toxicity of additional drug may not be warranted (see text). † † Includes semen; vaginal secretions; cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids. § §For skin, risk is increased for exposures involving a high titer of HIV, prolonged contact, an extensive area, or an area in which skin integrity is visibly compromised.For skin exposures without increased risk, the risk for drug toxicity outweighs the benefit of PEP. # Contributors to the Production of the MMWR (Weekly) Weekly
Routine vaccination of children is an effective way to reduce hepatitis A incidence in the United States.Since licensure of hepatitis A vaccine during 1995-1996, the hepatitis A childhood immunization strategy has been implemented incrementally, starting with the recommendation of the Advisory Committee on Immunization Practices (ACIP) in 1996 to vaccinate children living in communities with the highest disease rates and continuing in 1999 with ACIP's recommendations for vaccination of children living in states, counties, and communities with consistently elevated hepatitis A rates.These updated recommendations represent the final step in the childhood hepatitis A immunization strategy, routine hepatitis A vaccination of children nationwide.Implementation of these recommendations will reinforce existing vaccination programs, extend the benefits associated with hepatitis A vaccination to the rest of the country, and create the foundation for eventual consideration of elimination of indigenous hepatitis A virus transmission.This report updates ACIP's 1999 recommendations concerning the prevention of hepatitis A through immunization (CDC.Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices .MMWR 1999:48:1-37) and includes 1) new data on the epidemiology of hepatitis A in the era of hepatitis A vaccination of children in selected U.S. areas, 2) results of analyses of the economics of nationwide routine vaccination of children, and 3) recommendations for the routine vaccination of children in the United States.Previous recommendations for vaccination of persons in groups at increased risk for hepatitis A or its adverse consequences and recommendations regarding the use of immune globulin for protection against hepatitis A are unchanged from the 1999 recommendations.persons in groups shown to be at high risk for infection and children living in communities with high rates of disease (2).In 1999, as the next step in a strategy of incremental implementation of recommendations for routine vaccination of children, ACIP expanded the recommendations to include vaccination of children living in states, counties, and communities in which hepatitis A rates were consistently above the national average (3).Coincident with implementation of these recommendations, hepatitis A rates have declined to the lowest level ever recorded (4).Because declines were largest in the areas in which routine vaccination of children was occurring, rates are now more equivalent across regions, with the highest rates occurring among children in parts of the country where vaccination has not been recommended (5).This statement includes recommendations for the final step in this incremental strategy, routine hepatitis A vaccination of children nationwide.Implementation of these recommendations will reinforce existing vaccination programs, extend the benefits associated with hepatitis A vaccination to the rest of the country, and create the foundation for eventual consideration of elimination of indigenous HAV transmission.#Introduction During 1980-1995, approximately 22,000-36,000 cases of hepatitis A were reported annually in the United States, representing an estimated average of 271,000 infections per year when anicteric disease and asymptomatic infections are taken in account (1).During 1995-1996, highly effective hepatitis A vaccines became available in the United States for use among persons aged >2 years, providing an opportunity to reduce hepatitis A incidence substantially and potentially eliminate indigenous transmission of hepatitis A virus (HAV). In 1996, the Advisory Committee on Immunization Practices (ACIP) first made recommendations to prevent hepatitis A through immunization, focusing primarily on vaccinating # Primary Changes in the Statement Changes in recommendations include the following: - updated data regarding the epidemiology of hepatitis A since the advent of hepatitis A vaccination of children in selected areas of the United States, - results of recent economic analyses of nationwide routine vaccination of children, and - recommendations for the routine vaccination of children aged >1 year in the United States.Previous recommendations for 1) vaccination of persons in groups at increased risk for hepatitis A or its adverse consequences and 2) use of immune globulin (IG) for protection against hepatitis A are unchanged (3). # Clinical and Diagnostic Features of Hepatitis A Clinical Illness HAV, a 27-nm RNA agent classified as a picornavirus, can produce either asymptomatic or symptomatic infection in humans after an average incubation period of 28 days (range: 15-50 days) (6).Illness caused by HAV infection typically has an abrupt onset that can include fever, malaise, anorexia, nausea, abdominal discomfort, dark urine, and jaundice.The likelihood of having symptoms with HAV infection is related to age.In children aged 70% of patients (8).Signs and symptoms typically last 50 years; persons with chronic liver disease are at increased risk for acute liver failure (5,(10)(11)(12)(13)(14)(15). In infected persons, HAV replicates in the liver, is excreted in bile, and is shed in stool.Peak infectivity of infected persons occurs during the 2-week period before onset of jaundice or elevation of liver enzymes, when concentration of virus in stool is highest (16).Concentration of virus in stool declines after jaundice appears.Children can shed HAV for longer periods than do adults, lasting up to 10 weeks (17) after onset of clinical illness; infants infected as neonates in one nosocomial outbreak shed HAV for up to 6 months (18).Chronic shedding of HAV in feces does not occur; however, recurrent shedding occurs during relapses among persons who have relapsing illness (19).Viremia occurs soon after infection and persists through the period of liver enzyme elevation, but at concentrations several orders of magnitude lower than in stool (20,21). # Diagnosis Hepatitis A cannot be differentiated from other types of viral hepatitis on the basis of clinical or epidemiologic features alone.Serologic testing to detect immunoglobulin M (IgM) antibody to the capsid proteins of HAV (IgM anti-HAV) is required to confirm a diagnosis of acute HAV infection.Sensitive tests for IgM and immunoglobulin G (IgG) anti-HAV in saliva have been developed but are not licensed in the United States (22).In the majority of persons, serum IgM anti-HAV becomes detectable 5-10 days before onset of symptoms (21,23).IgG anti-HAV, which appears early in the course of infection, remains detectable for the person's lifetime and provides lifelong protection against the disease.Two serologic tests are licensed for the detection of antibodies to HAV: 1) IgM anti-HAV and 2) total anti-HAV (i.e., IgM and IgG anti-HAV, referred to in this report as anti-HAV) (24).In the majority of patients, IgM anti-HAV declines to undetectable levels 1 year after infection have been reported, as have likely false-positive tests in persons without evidence of recent HAV infection (25)(26)(27).Total anti-HAV testing is used in epidemiologic studies to measure the prevalence of previous infection or by clinicians to determine whether a person with an indication for preexposure prophylaxis is already immune. HAV RNA can be detected in the blood and stool of the majority of persons during the acute phase of infection by using nucleic acid amplification methods, and nucleic acid sequencing has been used to determine the relatedness of HAV isolates for epidemiologic investigations (28)(29)(30).However, only a limited number of research laboratories have the capacity to use these methods. # Epidemiology of Hepatitis A Modes of Transmission Person-to-person transmission through the fecal-oral route is the primary means of HAV transmission in the United States.Transmission occurs most frequently among close contacts, especially in households and extended family settings (31).Because the majority of children have asymptomatic or unrecognized infections, they play a key role in HAV transmission and serve as a source of infection for others (32,33).In one study of adults without an identified source, 52% of their households included a child aged <6 years, and the presence of a young child was associated with HAV transmission in the household (32).In studies in which serologic testing of the household contacts of adults without an identified source of infection was performed, 25%-40% of contacts aged <6 years had serologic evidence of acute HAV infection (IgM anti-HAV) (17,32). Common-source outbreaks and sporadic cases also can occur from exposure to fecally contaminated food or water.Uncooked foods have been recognized frequently as a source of outbreaks (34).Cooked foods also can transmit HAV if cooking is inadequate to kill the virus or if food is contaminated after cooking, as occurs commonly in outbreaks associated with infected food handlers (34)(35)(36)(37).Waterborne outbreaks of hepatitis A are infrequent in developed countries with well-maintained sanitation and water supplies.The majority of waterborne outbreaks are associated with sewage-contaminated or inadequately treated water (38)(39)(40).Outbreaks in the context of floods or other natural disasters (e.g., hurricanes) have not been reported in the United States. Depending on conditions, HAV can be stable in the environment for months (41).Heating foods at temperatures >185°F (>85°C) for 1 minute or disinfecting surfaces with a 1:100 dilution of sodium hypochlorite (i.e., household bleach) in tap water is necessary to inactivate HAV (42). On rare occasions, HAV infection has been transmitted by transfusion of blood or blood products collected from donors during the viremic phase of their infection (20,43).Since 2002, nucleic acid amplification tests such as polymerase chain reaction (PCR) have been applied to the screening of source plasma used for the manufacture of plasma-derived products (44). In experimentally infected nonhuman primates, HAV has been detected in saliva during the incubation period (45).However, transmission by saliva has not been demonstrated. # Disease Patterns Prevaccine Era Hepatitis A epidemiology in the United States has fundamentally changed with licensure of hepatitis A vaccine and implementation of national ACIP recommendations for its use.Before vaccine licensure during 1995-1996, hepatitis A incidence was primarily cyclic, with peaks occurring every 10-15 years.In the United States, during 1980-1995, approximately 22,000-36,000 hepatitis A cases were reported annually to CDC (rate: 9.0-14.5 cases per 100,000 population), but incidence models indicate that the number of infections was substantially higher (1,5).One such analysis estimated an average of 271,000 infections per year during 1980-1999, representing 10.4 times the reported number of cases (1).Each year in the United States, an estimated 100 persons died as a result of acute liver failure attributed to hepatitis A. The costs associated with hepatitis A are substantial.Surveillance data indicate that 11%-22% of persons with hepatitis A are hospitalized (3).The average duration of work loss for adults who become ill has been estimated at 15.5 days for nonhospitalized patients and 33.2 days for hospitalized patients (46).Estimates of the annual direct and indirect costs of hepatitis A in the United States have ranged from $300 million to $488.8 million in 1997 dollars (3,46).A recent Markov model analysis estimated economic costs of $133.5 million during the lifetime of a single age cohort of children born in 2005, in the absence of vaccination (CDC, unpublished data, 2005). Variation by Age, Race/Ethnicity, and Region.During the prevaccine era, the reported incidence of hepatitis A was highest among children aged 5-14 years, with approximately one third of reported cases involving children aged <15 years (Figure 1) (5).Because young children frequently have unrecognized or asymptomatic infection, a relatively smaller proportion of infections among children than adults are detected by routine disease surveillance.Incidence models indicate that during 1980-1999, the majority of HAV infections occurred among children aged <10 years, and the highest incidence was among those aged 0-4 years (1).Before the use of hepatitis A vaccine, rates among American Indians and Alaska Natives were more than five times higher than rates in other racial/ethnic populations, and rates among Hispanics were ap- # ACIP recommendations proximately three times higher than rates among non-Hispanics (Figure 2) (5,(47)(48)(49). Since the 1960s, the highest hepatitis A rates and the majority of cases occurred in a limited number of states and counties concentrated in the western and southwestern United States (Figure 3) (4).Despite year-to-year fluctuations, rates in these areas consistently remained above the national average.In 11 states (Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, and Washington) with consistently elevated rates, representing 22% of the U.S. population, average annual hepatitis A incidence was >20 cases per 100,000 during 1987-1997 (twice the national average of approximately 10 cases per 100,000 population); cases among residents of these states accounted for an average of 50% of reported cases (3).An additional 18% of cases occurred among residents of six states (Arkansas, Colorado, Missouri, Montana, Texas, and Wyoming) with average annual rates above (but less than twice) the national average during this time. Approximately 31% of the U.S. population had serologic evidence of previous HAV infection, when measured in the Third National Health and Nutrition Examination Survey (NHANES-III) conducted during 1988-1994 (50).Anti-HAV prevalence varied directly with age: among persons aged 6-11 years, prevalence was 9%; 20-29 years, 19%; 40-49 years, 33%; and >70 years, 75%.Age-adjusted anti-HAV prevalence was considerably higher among Mexican-American (70%) compared with black (39%) and white (23%) participants, and among foreign-born (69%) compared with U.S.-born (25%) participants. Sources of Infection.In the prevaccine era, the majority of U.S. cases of hepatitis A resulted from person-to-person transmission of HAV during communitywide outbreaks (31,51).The most frequently reported source of infection (in 12%-26% of cases) was household or sexual contact with a person with hepatitis A (52).Cyclic outbreaks occurred among users of injection and noninjection drugs and among men who have sex with men (MSM) (53)(54)(55)(56)(57), and up to 15% of nationally reported cases occurred among persons reporting one or more of these behaviors.Other potential sources of infection (e.g., international travel and recognized foodborne outbreaks) were reported among 3%-6% of cases (52).For approximately 50% of persons with hepatitis A, no source was identified for their infection.Communitywide Epidemics.During communitywide epidemics, infection was transmitted from person to person in households and extended family settings.These epidemics typically spread throughout the community, and no single risk factor or risk group could be identified that accounted for the majority of cases (31).Once initiated, epidemics often persisted for 1-2 years and proved difficult to control (58,59).Because children often have unrecognized or asymptomatic infection, they played a key role in sustaining HAV transmission during these epidemics. # Vaccine Era With the licensure of inactivated hepatitis A vaccines by the Food and Drug Administration (FDA) during 1995-1996, hepatitis A became a disease that was not only common but also vaccine-preventable.Since 1996, and particularly since ACIP's 1999 recommendations for routine vaccination of children living in areas with consistently elevated hepatitis A rates, national hepatitis A rates have declined sharply (4).The 1999 recommendations called for routine vaccination of children living in states and communities in which the average hepatitis A rate during a baseline period of 1987-1997 was >20 cases per 100,000 population, approximately twice the national average, and for consideration of hepatitis A vaccination of children in those states and communities in which the average rate during the baseline period was at least the national average (3). In 2004, a total of 5,683 cases (rate: 1.9 cases per 100,000 population) were reported, representing an estimated 24,000 acute clinical cases when underreporting is taken into account.This rate was the lowest ever recorded and was 79% lower than the previously recorded low in 1992 (5).This decline is reflected in other fundamental shifts in hepatitis A epidemiology. Variation by Age, Race/Ethnicity, and Region.Beginning in the late 1990s, national age-specific rates declined more rapidly among children than adults; as a result, in recent years, rates have been similar among all age groups (Figure 1) (4).Historic differences in rates among racial/ethnic populations also have narrowed in the vaccine era.For example, recent rates among American Indians and Alaska Natives represent a 99% decline compared with the prevaccine era and are now approximately the same or lower than those of other racial/ ethnic populations (49).Rates among Hispanics also declined 87% during this period, from 20.6 cases per 100,000 population during 1990-1997 to 2.7 per 100,000 in 2004, but remain higher than those for non-Hispanics (Figure 2) (4,5).Elimination of historic geographic differences in incidence rates has also occurred, and since 2001, rates in states where vaccination was recommended have been approximately equal to the rest of the United States (5).In recent years, counties with higher rates have varied from year to year and have been distributed throughout the country (Figure 3) (4). Incidence declined sharply in states with historically consistently elevated rates included in the 1999 ACIP recommendations for routine vaccination of children.As a result, the majority of hepatitis A cases during recent years have been reported from states with historically low rates in which hepatitis A vaccination of children has not been widely implemented (4).In addition, the narrowing or elimination of national differences in age, race/ethnicity, and state-specific rates can be attributed largely to changes that occurred in the states in which routine hepatitis A vaccination of children was recommended and implemented.In 2004, for example, approximately two thirds of the nearly 6,000 cases were reported from states without childhood vaccination recommendations (60).The 2004 rate among all Hispanics in these states remained four times higher than among non-Hispanics and was seven times higher among Hispanic compared with non-Hispanic children.The highest rate in any demographic subgroup occurred among Hispanic children in states for which routine hepatitis A vaccination of children is not recommended (60). Sources of Infection.In recent years, sexual or household contact with a person with hepatitis A has been reported in a smaller proportion of cases but continued to account for 13% of cases during 2002-2004 (5).The proportion of persons with hepatitis A reporting exposure to child care centers also has declined to approximately 9% (5).The number of international travel-associated cases has remained approximately the same, but as overall incidence has declined, the proportion of cases attributable to this exposure has increased, accounting for an average of 13% of cases during 2002-2004 (5).During this time, >25% of cases among children aged <15 years could be attributed to international travel.Approximately 75% of all travel-related cases were associated with travel to Mexico or to Central or South America (5).Outbreaks among MSM and users of illicit drugs also continue to occur (5,57).
# MMWR May 19, 2006 # Groups at Increased Risk for Hepatitis A Travelers Persons from developed countries who travel to developing countries are at substantial risk for acquiring hepatitis A (61).Such persons include tourists, immigrants and their children returning to their country of origin to visit friends or relatives, military personnel, missionaries, and others who work or study abroad in countries that have high or intermediate endemicity of hepatitis A (Figure 4).Hepatitis A remains one of the most common vaccine-preventable diseases acquired during travel.One study estimated the risk among persons who did not receive IG or vaccine before departure to be four to 30 cases per 100,000 months of stay in developing countries (62).The risk might be higher among travelers staying in areas with poor hygienic conditions, varies according to the region and the length of stay, and appears to be increased even among travelers who reported observing protective measures and staying in urban areas or luxury hotels (CDC, unpublished data, 2005).In the United States, children account for approximately 50% of reported travel-related cases (5).In one study of Hispanic children in San Diego with hepatitis A, two thirds reported international travel (to Mexico) during the incubation period; travel was the only exposure associated with infection in a case-control study (63).Travelers who acquire hepatitis A during their trips also might transmit to others on their return. # MSM Hepatitis A outbreaks among MSM have been reported frequently.Cyclic outbreaks have occurred in urban areas in the United States, Canada, Europe, and Australia and can occur in the context of an outbreak in the larger community (28,31,53,(64)(65)(66)(67).Seroprevalence surveys have not consistently demonstrated an elevated prevalence of anti-HAV compared with a similarly aged general population (68,69).Certain studies have identified specific sex practices associated with illness, whereas others have not demonstrated such associations (53,67,68).Since 1996, ACIP has recommended hepatitis A vaccination of MSM (2).Although precise data are lacking, vaccine coverage appears to be low (53). # Users of Injection and Noninjection Drugs During the preceeding 2 decades, outbreaks have been reported with increasing frequency among users of injection and noninjection drugs in Australia, Europe, and North America (31,54,56,57,70).In the United States, outbreaks have frequently involved users of injected and noninjected methamphetamine, who have accounted for up to 48% of reported cases during outbreaks (57,71).Cross-sectional serologic surveys have demonstrated that injection-drug users have a higher prevalence of anti-HAV than the general U.S. population (68,72).Transmission among injection-drug users probably occurs through both percutaneous and fecaloral routes (71).Since 1996, ACIP has recommended hepatitis A vaccination of users of illicit drugs, but vaccine coverage data are not available (2). # Persons with Clotting-Factor Disorders During 1992-1993, outbreaks of hepatitis A were reported in Europe among persons with clotting-factor disorders who had been administered solvent-detergent-treated, "highpurity" factor VIII concentrates that presumably had been contaminated from plasma donors incubating hepatitis A (73).In the United States, data from one serologic study suggested that persons with hemophilia might be at increased risk for HAV infection (74).HAV is resistant to solvent-detergent treatment, and during 1995-1996, one study identified six patients with clotting-factor disorders who had hepatitis A after having been administered solvent-detergent-treated factor VIII # FIGURE 4.Geographic distribution of hepatitis A endemicity, 2005* - For multiple countries, estimates of prevalence of antibody to hepatitis A virus (anti-HAV), a marker of previous HAV infection, are based on limited data and might not reflect current prevalence.In addition, anti-HAV prevalence might vary within countries by subpopulation and locality.As used on this map, the terms "high," "medium," and "low" endemicity reflect available evidence of how widespread infection is within each country rather than precise quantitative assessments. and factor IX concentrates (43).However, changes in viral inactivation procedures, high hepatitis A vaccine coverage, and improved donor screening have decreased the risk for HAV transmission from clotting factors.During May 1998-July 2002, no new cases of HAV infection attributed to blood products were identified in an analysis of serosurveillance data from 140 participating hemophilia treatment centers (75). # Persons Working with Nonhuman Primates Outbreaks of hepatitis A have been reported among persons working with nonhuman primates that are susceptible to HAV infection, including Old and New World species (76,77).Primates that were infected were those that had been born in the wild, not those born and raised in captivity. # Risk for Severe Adverse Consequences of Hepatitis A Among Persons with Chronic Liver Disease Although not at increased risk for HAV infection, persons with chronic liver disease are at increased risk for fulminant hepatitis A (12,14,15).Death certificate data indicate a higher prevalence of chronic liver disease among persons who died of fulminant hepatitis A compared with persons who died of other causes (10). # Risk for Hepatitis A in Other Groups and Settings # Food-Service Establishments and Food Handlers Foodborne hepatitis A outbreaks are recognized relatively infrequently in the United States.Outbreaks typically are associated with contamination of food during preparation by an HAV-infected food handler; a single infected food handler can transmit HAV to dozens or even hundreds of persons (34,36,37,(78)(79)(80)(81).However, the majority of food handlers with hepatitis A do not transmit HAV.Food handlers are not at increased risk for hepatitis A because of their occupation.However, among the approximately 40,000 adults with hepatitis A reported during 1992-2000 for whom an occupation was known, 8% were identified as food handlers, reflecting the large number of persons employed in the food service industry (34).Evaluating HAV-infected food handlers is a common and labor-intensive task for public health departments.In a 1992 common-source outbreak involving 43 persons, the estimated total medical and disease control cost was approximately $800,000 (82). Outbreaks associated with food, especially green onions and other raw produce, that has been contaminated before reaching a food-service establishment have been recognized increasingly in recent years (29,30,(83)(84)(85)(86)(87)(88).Low attack rates are common, and outbreaks often have been recognized in association with a single restaurant in which no infected food handler was identified on subsequent investigation (29,83,88). # Child Care Centers Outbreaks among children attending child care centers and persons employed at these centers have been recognized since the 1970s, but their frequency has decreased as overall hepatitis A incidence among children has declined in recent years (5,7,89).Because infection among children is typically mild or asymptomatic, outbreaks often are identified only when adult contacts (typically parents) become ill (7,90).Poor hygiene among children who wear diapers and the handling and changing of diapers by staff contribute to the spread of HAV infection; outbreaks rarely occur in child care centers in which care is provided only to children who are toilet trained. Although child care centers might have been the source of outbreaks of hepatitis A in certain communities, disease in child care centers more commonly reflects extended transmission from the community.Despite the occurrence of outbreaks when HAV is introduced into child care centers, results of serologic surveys do not indicate a substantially increased prevalence of HAV infection among staff at child care centers compared with prevalence among control populations (91). # Health-Care Institutions Nosocomial HAV transmission is rare.Outbreaks have occasionally been observed in neonatal intensive-care units because of infants acquiring infection from transfused blood and subsequently transmitting hepatitis A to other infants and staff (18,92,93).Outbreaks of hepatitis A caused by transmission from adult patients to health-care workers are typically associated with fecal incontinence, although the majority of hospitalized patients who have hepatitis A are admitted after onset of jaundice, when they are beyond the point of peak infectivity (94,95).Data from serologic surveys of health-care workers have not indicated an increased prevalence of HAV infection in these groups compared with that in control populations (96). # Institutions for Persons with Developmental Disabilities Historically, HAV infection was highly endemic in institutions for persons with developmental disabilities (97).As fewer children have been institutionalized and as conditions in institutions have improved, the incidence and prevalence of HAV infection have decreased, although outbreaks can occur in these settings. # MMWR May 19, 2006 # Schools In the United States, the occurrence of cases of hepatitis A in elementary or secondary schools typically reflects disease acquisition in the community.Child-to-child disease transmission in the school setting is uncommon; if multiple cases occur among children at a school, the possibility of a common source of infection should be investigated (30,84). # Workers Exposed to Sewage Data from serologic studies conducted outside the United States indicate that workers who had been exposed to sewage had a possible elevated risk for HAV infection; however, these analyses did not control for other risk factors (e.g., socioeconomic status) (98-100).In published reports of three serologic surveys conducted among U.S. wastewater workers and appropriate comparison populations, no substantial or consistent increase in the prevalence of anti-HAV was identified among wastewater workers (101)(102)(103).No work-related instances of HAV transmission have been reported among wastewater workers in the United States. # Strategy to Prevent and Control Hepatitis A Through Vaccination With the availability of hepatitis A vaccines beginning in 1995, hepatitis A became a disease that was not only common but also vaccine-preventable (104).Use of these highly effective vaccines provided the opportunity to protect persons from infection, reduce disease incidence by preventing transmission, and ultimately eliminate indigenous HAV transmission. Soon after hepatitis A vaccines became available in the United States, a strategy of routine vaccination of children was recognized to have the potential to achieve a sustained reduction in the overall incidence of hepatitis A by preventing infection among persons in age groups that accounted for at least one third of cases and eliminating a major source of infection for others.However, hepatitis A vaccines could not be readily incorporated into the routine infant and early childhood schedule because they were not licensed for children aged <2 years.To overcome these logistical barriers to use of hepatitis A vaccines among children, a novel vaccination strategy was developed on the basis of distinct features of hepatitis A epidemiology and experience gathered from demonstration projects and other research and involving incremental implementation of routine childhood hepatitis A vaccination. Initial recommendations primarily involved vaccination of persons in populations at increased risk for hepatitis A and, as the first step in the incremental strategy, of children living in communities with the highest disease rates (2).Vaccination of persons in groups at increased risk for hepatitis A (e.g., travelers) or its adverse outcomes (e.g., persons with chronic liver disease) provided protection to these persons but had little effect on national disease rates because the majority of cases did not occur among persons in these groups.Although routine vaccination of children living in communities with the highest rates of disease was effective in reducing disease rates in these communities, the impact on national disease incidence was limited because the majority of nationally reported cases occurred outside these communities. A further step in the incremental implementation of routine vaccination of children was possible because areas with consistently elevated hepatitis A rates could be identified that contributed the majority of cases to the national disease burden (3).To date, the 1999 ACIP recommendations for routine vaccination of children living in these areas with consistently elevated rates have been implemented primarily by voluntary measures.The 2004 National Immunization Survey among children aged 24-35 months indicated first-dose coverage of approximately 54% in states for which vaccination is recommended, 27% in states for which it is to be considered, and 2% in the rest of the country (CDC, unpublished data, 2005).Although limited information on trends is available, these coverage estimates represent increases of 2%-3% compared with the previous year (105).Coincident with implementation of these recommendations, national disease incidence has declined to historic lows, with the largest declines occurring in the age groups and parts of the country for which vaccination is recommended (4).The majority of disease (and the highest incidence) occurs in areas for which hepatitis A vaccination of children has not been recommended previously.Examination of historical incidence trends in these areas and theoretic models of incidence dynamics after introduction of a new vaccine suggest that incidence might increase again, although to what level is unknown (106). A decade has passed since hepatitis A vaccines first became available in the United States.Multiple considerations make this an appropriate time to implement the final step in the incremental strategy, thereby bringing hepatitis A vaccination policy into line with that of other routinely recommended childhood vaccines.First, hepatitis A vaccine became available for children aged 12-23 months in 2005, allowing for its incorporation into the routine early childhood vaccination schedule.Second, as disease rates equalize across regions of the United States, questions remain regarding the validity and ultimate sustainability of the interim limited strategy.Continuation of this policy in light of current hepatitis A epidemiology means that vaccination of children is not presently recommended for the areas with the highest overall and age-specific disease incidence.Nationwide hepatitis A vaccination of children is likely to result in further narrowing of current demographic disparities and in lower overall rates.Ultimately, elimination of indigenous HAV transmission in the United States is an attainable goal. # Prophylaxis Against Hepatitis A Virus Infection Immune Globulin IG is a sterile preparation of concentrated antibodies (immunoglobulins) made from pooled human plasma processed by cold ethanol fractionation (107).In the United States, only plasma that has tested negative for hepatitis B surface antigen (HBsAg), antibody to human immunodeficiency virus (HIV), and antibody to hepatitis C virus (HCV) is used to produce IG.In addition, FDA requires that the process used to produce IG include a viral inactivation step or that final products test negative for HCV RNA by PCR.Anti-HAV concentrations differ among IG lots, and slightly lower concentrations have been observed over the preceding 30 years, probably because of the decreasing prevalence of previous HAV infection among plasma donors (108).However, no clinical or epidemiologic evidence of decreased protection has been observed. IG provides protection against hepatitis A through passive transfer of antibody.Both IG administered intramuscularly (IM) and IG for intravenous administration (IGIV) contain anti-HAV, but IG administered intramuscularly is the product used for the prevention of HAV infection.No transmission of hepatitis B virus (HBV), HIV, HCV, or other viruses has been reported from intramuscular IG (109,110).The concentrations of IgG anti-HAV achieved after administration of IG intramuscularly are below the level of detection of the majority of commercially available diagnostic tests (111).When administered for preexposure prophylaxis, 1 dose of 0.02 mL/kg IM confers protection for <3 months, and 1 dose of 0.06 mL/kg IM confers protection for 3-5 months (Table 1).When administered within 2 weeks after an exposure to HAV (0.02 mL/kg IM), IG is 80%-90% effective in preventing hepatitis A. Efficacy is greatest when IG is administered early in the incubation period; when administered later in the incubation period, IG might only attenuate the clinical expression of HAV infection (112). IG is available in single-use (2 mL) and multidose (10 mL) vials.Preparations are formulated without a preservative.For administration of IG, an appropriate muscle mass (i.e., the deltoid or gluteal muscle) should be chosen into which a substantial volume can be injected, using a needle length appro-priate for the person's age and size.If a gluteal muscle is used, the central region of the buttock should be avoided; only the upper outer quadrant should be used, and the needle should be directed anteriorly to minimize the possibility of injury to the sciatic nerve (113). Serious adverse events from IG are rare.Anaphylaxis has been reported after repeated administration to persons with known immunoglobulin A (IgA) deficiency; thus, IG should not be administered to these persons (114).Pregnancy or lactation is not a contraindication to IG administration. IG does not interfere with the immune response to oral poliovirus vaccine or yellow fever vaccine, or, in general, to inactivated vaccines.However, IG can interfere with the response to other live, attenuated vaccines (e.g., measles, mumps, and rubella vaccine and varicella vaccine) when administered either as individual or combination vaccines.Administration of MMR should be delayed for >3 months and varicella vaccine for >5 months after administration of IG for hepatitis A prophylaxis.IG should not be administered <2 weeks after administration of MMR or <3 weeks after varicella vaccine unless the benefits of IG administration exceed the benefits of vaccination (113,115).If IG is administered <2 weeks after administration of MMR or <3 weeks after administration of varicella vaccine, the person should be revaccinated, but not sooner than 3 months after IG administration for MMR or 5 months for varicella vaccine (113). # Hepatitis A Vaccine Inactivated and attenuated hepatitis A vaccines have been developed and evaluated in human clinical trials and in nonhuman primate models of HAV infection (116); however, only vaccines made from inactivated HAV have been evaluated for efficacy in controlled clinical trials (117)(118)(119).The vaccines containing HAV antigen that are currently licensed in the United States are the single-antigen vaccines HAVRIX ® (manufactured by GlaxoSmithKline, Rixensart, Belgium) and VAQTA ® (manufactured by Merck & Co., Inc., Whitehouse Station, New Jersey) and the combination vaccine TWINRIX ® (containing both HAV and HBV antigens; manufactured by GlaxoSmithKline).All are inactivated vaccines. # Preparation Inactivated hepatitis A vaccines are prepared by methods similar to those used for inactivated poliovirus vaccine (120,121).Cell-culture-adapted virus is propagated in human fibroblasts, purified from cell lysates by ultrafiltration and exclusion gel chromatography or other methods, formalin inactivated, and adsorbed to an aluminum hydroxide adjuvant; 2-phenoxyethanol is used as a preservative for HAVRIX and TWINRIX, and VAQTA is formulated without a preservative.For HAVRIX and TWINRIX, the antigen content of the final aqueous preparation is determined by reactivity in a quantitative immunoassay for HAV antigen, and final vaccine potency (per dose) is expressed as enzyme-linked immunosorbent assay (ELISA) units (EL.U.).For VAQTA, the antigen content is expressed as units (U) of HAV antigen.
# Vaccine Storage and Shipment Hepatitis A vaccine should be stored and shipped at temperatures ranging from 35.6°F-46.4°F (2°C-8°C) and should not be frozen.However, the reactogenicity and immunogenicity of HAVRIX after storage at 98.6°F (37°C) for 1 week and the stability profile of VAQTA when stored at this temperature for >12 months do not differ from those of vaccines stored at the recommended temperature (122; Merck & Co., Inc., unpublished data, 1996). # Route of Administration, Vaccination Schedule, and Dosage The vaccine should be administered intramuscularly into the deltoid muscle.A needle length appropriate for the person's age and size should be used (113). VAQTA is licensed in two formulations, which differ according to the person's age.Persons aged 12 months-18 years should receive 25 U per dose in a 2-dose schedule; persons aged >18 years should receive 50 U per dose in a 2-dose schedule (Table 2). HAVRIX is available in two formulations, which differ according to the person's age: for persons aged 12 months-18 years, 720 EL.U. per dose in a 2-dose schedule; and for persons aged >18 years, 1,440 EL.U. per dose in a 2-dose schedule (Table 3).A pediatric formulation of 360 EL.U. per dose administered in a 3-dose schedule is no longer available. TWINRIX is licensed for use in persons aged >18 years.TWINRIX is a combined hepatitis A and hepatitis B vaccine containing 720 EL.U. of hepatitis A antigen (half of the HAVRIX adult dose) and 20 mcg of recombinant hepatitis B surface antigen protein (the same as the ENGERIX-B adult dose) (Table 4).Primary immunization consists of 3 doses, administered on a 0-, 1-, and 6-month schedule, the same schedule as that commonly used for single-antigen hepatitis B vaccine.TWINRIX contains aluminum phosphate and aluminum hydroxide as adjuvant and 2-phenoxyethanol as a preservative.After 3 doses of TWINRIX, antibody responses to both antigens are equivalent to responses seen after the singleantigen vaccines are administered separately on standard schedules (123,124). # Vaccine Performance Detection of Anti-HAV After Vaccination.Concentrations of antibody achieved after passive transfer by IG or active induction by vaccination are 10-to 100-fold lower than those produced after natural infection and can be below the level of detection of certain commercially available diagnostic assays (111).To measure lower levels of antibody, more sensitive immunoassays were developed for immunogenicity studies that correlate more closely with neutralizing antibody assays (111).Anti-HAV concentrations are measured in comparison with a World Health Organization reference immunoglobulin reagent and are expressed as milli-International Units per milliliter (mIU/mL).The lower limits of detection have typically been approximately 100 mIU/mL by unmodified commercially available assays and 10 mIU/mL by more sensitive assays.A positive anti-HAV result by a standard assay indicates protection.However, after vaccination, persons who are anti-HAV negative by standard assays might nevertheless have protective levels of antibody. The absolute lower limit of anti-HAV required to prevent HAV infection has not been defined.In vitro studies using cell-culture-derived virus indicate that low levels of antibody (e.g., 20 mIU/mL, or >33 mIU/mL in more recent studies, as measured with modified enzyme immunoassays, and studies conducted with VAQTA have used levels >10 mIU/mL as measured with a modified radioimmunoassay (127,128). Immunogenicity in Adults.All licensed vaccines are highly immunogenic in persons aged >18 years when administered according to the recommended schedules (128)(129)(130).Protective antibody levels were identified in 94%-100% of adults 1 month after the first dose.After the second dose, all persons had protective levels of antibody, with high geometric mean antibody concentrations (GMCs). Limited data are available regarding the timing of the appearance of neutralizing antibody.Among a sample of vaccinated persons, 54%-62% were positive for neutralizing antibody 14 days after the first dose, and 94%-100% were positive at 1 month (128; GlaxoSmithKline, unpublished data, 1994). Immunogenicity in Children and Adolescents.Both vaccines are highly immunogenic when administered to children and adolescents according to multiple schedules; 97%-100% of persons aged 2-18 years had protective levels of antibody 1 month after receiving the first dose, and 100% had protective levels 1 month after the second dose, with high GMCs (128)(129)(130)(131)(132)(133).Children with Down syndrome responded to vaccination as well as other children and had similar levels of protective antibody (134). Immunogenicity in Infants.Available data indicate that inactivated hepatitis A vaccines are immunogenic in children aged <2 years who do not have passively acquired maternal antibody.All such infants administered hepatitis A vaccine subsequently had protective antibody levels, with the final GMCs varying depending on the dosage and schedule (135)(136)(137)(138)(139).Infants with passively acquired maternal antibody had reduced GMCs after vaccination (see Factors Associated with Reduced Immunogenicity) (135,136). # IgM Anti-HAV After Vaccination.Hepatitis A vaccination can induce IgM anti-HAV that is detectable by standard assays, particularly if the test is conducted soon after vaccination.IgM anti-HAV has been detected 2-3 weeks after administration of one dose of vaccine in 8%-20% of adults (140; CDC, unpublished data, 1995). Efficacy.The efficacy of HAVRIX was evaluated in a doubleblind, controlled, randomized clinical trial conducted in Thailand among approximately 40,000 children aged 1-16 years living in villages that had high rates of hepatitis A (117).After 2 doses of vaccine (360 EL.U. per dose) administered 1 month apart, the efficacy of vaccine in protecting against clinical hepatitis A was 94% (95% confidence interval = 79%-99%).A doubleblind, placebo-controlled, randomized clinical trial using VAQTA was conducted among approximately 1,000 children aged 2-16 years living in a New York community that had a high rate of hepatitis A (118).The protective efficacy against clinical hepatitis A was 100% (lower bound of the 95% CI = 87%) after administration of 1 dose (25 U) of vaccine. Efficacy After Exposure.Studies of chimpanzees indicate that hepatitis A vaccine can prevent HAV infection if administered shortly after exposure (141).Because the incubation period of hepatitis A can be 50 days, the fact that during a clinical efficacy trial, no cases of hepatitis A occurred in vaccine recipients beginning 17 days after vaccination also suggests a possible postexposure effect (118,142).In a limited randomized trial, investigators determined that hepatitis A vaccine was 79% efficacious in preventing IgM anti-HAV positivity after household exposure to hepatitis A compared with no treatment.However, the CI was extremely wide (7%-95%), and investigators did not assess the efficacy of the vaccine compared with IG (143).Results of an appropriately designed clinical trial comparing the postexposure efficacy of vaccine with that of IG are needed to determine if hepatitis A vaccine without IG can be recommended to prevent hepatitis A after exposure (144). Effectiveness in Populations.The effectiveness of hepatitis A vaccine in populations has been studied in demonstration projects and by analysis of surveillance and vaccine coverage data.The earliest such studies focused on communities with the historically highest hepatitis A rates, such as Alaska Native and American Indian communities.Demonstration projects conducted soon after hepatitis A vaccines became available indicated that routine vaccination of children living in these communities was feasible and that when relatively high vaccination coverage was achieved and sustained, ongoing epidemics were interrupted and a reduction in disease incidence was sustained (145)(146)(147).For example, a 1992-1993 communitywide epidemic among Alaska Natives in one rural area ended within 4-8 weeks of vaccinating May 19, 2006 approximately 80% of children and young adults (146).After publication in 1996 of ACIP recommendations for routine vaccination of children in these areas, surveys indicated that vaccine coverage among preschool-and school-aged American Indian and Alaska Native children was 50%-80%, suggesting that recommendations were being implemented (2,49).By 2000, hepatitis A incidence among American Indians and Alaska Natives had declined 97% compared with the beginning of the decade and was lower than the overall U.S. rate (49).These low rates have been sustained in subsequent years; the 2004 rate of 0.1 case per 100,000 population among American Indian and Alaska Natives was the lowest of any racial/ ethnic population (5). Results of a demonstration project in Butte County, California, provided evidence that considerable reductions in overall incidence also could be achieved in populations with consistently elevated hepatitis A rates with a program of ongoing routine vaccination of children that achieved fairly modest coverage (148).During the 6-year project, 66% of the approximately 45,000 eligible children aged >2 years received >1 dose of hepatitis A vaccine.The number of reported cases declined 94%, and the four cases reported in 2000 during the last year of the project was the lowest number ever reported in the county since hepatitis surveillance began in 1966. The most comprehensive indication of the performance of hepatitis A vaccines in populations is derived from analysis of trends in hepatitis A incidence after publication of ACIP's 1999 recommendations for routine vaccination of children living in 17 states with consistently elevated hepatitis A rates.The 2003 rate (2.5 cases per 100,000 population) in these states represented a decline of approximately 88% compared with the average rate (21.1 cases per 100,000 population) during the baseline prevaccine period on which the recommendations were based of (4).Rates among regions with and without statewide recommendations for routine vaccination of children are now approximately equal (Figure 5).Compared with 1990-1997, rates declined most dramatically among children aged 2-18 years, and the proportion of cases among children declined from 35% to 19%.Because hepatitis A incidence has been cyclic in the United States, the precise contribution of vaccination of children to the observed decline in rates has been difficult to quantify.Modeling studies suggested that during 1995-2001, an estimated 97,800 hepatitis A cases were averted because of the direct effects of immunization and herd immunity, including 39% of potential cases in 2001 (149). Available information concerning vaccine use indicates that the observed declines in rates among children appear to have been achieved with modest levels of vaccine coverage, suggesting a strong herd immunity effect (105,150).Declines in rates among adults also suggest that vaccination of children might have reduced transmission in other age groups through herd immunity.Similar findings have been reported from other countries (e.g., Israel and parts of Spain) in which routine hepatitis A vaccination of infants or children has been implemented (151,152).Results of modeling the relationship between hepatitis A incidence and vaccine coverage have also indicated a strong herd immunity effect, accounting for more than one third of the estimated number of cases prevented by vaccination (149). Interest has been expressed regarding use of hepatitis A vaccine to interrupt ongoing communitywide epidemics by vaccinating children in these populations, but the strategy has proved difficult to implement.Typically, first-dose coverage was low (20%-45%), and the impact of vaccination always was limited to vaccinated age groups that did not represent the majority of cases (59).Efforts are probably better directed towards sustained routine vaccination of children to maintain high levels of immunity and prevent future epidemics. Long-Term Protection.All 31 adults who received 3 doses of HAVRIX (720 EL.U. per dose at 0-, 1-, and 6-month intervals) had anti-HAV levels >15 mIU/mL 12 years after the initial dose (153).Ten years after vaccination, all 307 adults administered 2 doses of 1,440 EL.U. of HAVRIX had anti-HAV levels >20 mIU/mL (154).Protective levels of anti-HAV were still observed in 544 (99%) of 549 children evaluated 5-6 years after receiving VAQTA (155).A recent review concluded that estimates of antibody persistence derived from kinetic models of antibody decline indicate that protective levels of anti-HAV could be present for >25 years in adults and >14-20 years in children (156).Whether other mecha- nisms (e.g., cellular memory) also contribute to long-term protection is unknown.Surveillance data and population-based studies are being used to monitor the long-term protective efficacy of hepatitis A vaccine and to determine the possible need for a booster dose.In the longest such follow-up study reported to date, no cases of hepatitis A have been detected among children studied for 9 years after vaccination (157).Vaccination Schedules.Results of multiple studies indicate that, among adults administered hepatitis A vaccine according to a schedule that mixed the two currently licensed vaccines, the proportion that subsequently had protective antibody levels did not differ from that of adults vaccinated according to the licensed schedules, and final GMCs were high (158,159).Although using the vaccines according to the licensed schedule is preferable, on the basis of the similar immunogenicity of both vaccines in adults and children, these data indicate that the two brands of hepatitis A vaccine can be considered interchangeable. Limited data are available regarding response to a delayed second vaccine dose.In one study, 85 (97%) of 88 persons aged >18 years who had received 1 dose of VAQTA (50 U) had anti-HAV levels >10 mIU/mL 18 months later.None reported a history of hepatitis A, and all responded to a second dose.Final GMCs were not different compared with persons vaccinated according to a 0-, 6-month schedule (160).In another study, 132 (84%) of 156 persons aged 1 month-64 years who had responded to 1 dose of HAVRIX (720 EL.U. for children aged 20 mIU/mL a mean of 27 months later.None of these persons reported a history of hepatitis A. All but one of these persons responded to a second dose, with a substantial rise in antibody levels (161).In a third study, 18 (72%) of 25 adults who had received 1 dose of HAVRIX 4-8 years previously had anti-HAV levels >10 mIU/mL, and all 25 responded to a second dose of vaccine with a substantial increase in anti-HAV levels (162). Factors Associated with Reduced Immunogenicity.The presence of passively acquired anti-HAV at the time of vaccination appears to diminish the immune response.Administration of IG concurrently with the first dose of hepatitis A vaccine did not decrease the proportion of adults who subsequently had protective levels of antibody compared with adults who had been administered hepatitis A vaccine alone, but GMCs of adults who received IG were substantially lower 1 month after completion of the vaccine series than GMCs of adults who had been administered hepatitis A vaccine alone (163,164).However, their antibody levels were >100-fold higher than levels considered to be protective, suggesting that the reduced immunogenicity of hepatitis A vaccine that occurs with concurrent administration of IG is not clinically significant in the short term.The effect of reduced GMCs on long-term protection is unknown. Reduced vaccine immunogenicity also has been observed in infants who had passively acquired antibody because of previous maternal HAV infection and were administered hepatitis A vaccine according to a number of different schedules (135)(136)(137).In the majority of studies, all infants subsequently had protective levels of antibody, but the final GMCs were approximately one third to one tenth those of infants born to anti-HAV-negative mothers and vaccinated according to the same schedule.Infants with passively acquired antibody who receive hepatitis A vaccine had substantially lower concentrations of anti-HAV 6 years later compared with vaccinated infants with no passively acquired antibody (165).Despite lower antibody levels after the primary series, the majority of infants with passively acquired antibody had an anamnestic response to a booster dose 1-6 years later (136,165,166).Passively acquired antibody declines to undetectable levels in the majority of infants by age 1 year (167,168).Hepatitis A vaccine is highly immunogenic for children who begin vaccination at age >1 year, regardless of maternal anti-HAV status (136,168). Hepatitis A vaccine using a standard dose and schedule is immunogenic for children and adults with HIV infection.Those with higher CD4 counts (>300 cells/mm 3 ) respond nearly as well as persons who are not immunocompromised, but adults with lower CD4 counts are less likely to acquire protective levels of antibody.Protective levels of antibody developed after vaccination in 61%-87% of HIV-infected adults (169)(170)(171) and in 100% of 32 HIV-infected children (172).Lower CD4 cell count at the time of vaccination, but not the CD4 cell count nadir, was associated with lack of response, suggesting that immunologic reconstitution with highly active antiretroviral therapy might restore the ability to respond to vaccination (173). Vaccination of children or adults with chronic liver disease of viral or nonviral etiology produced seroprotection rates similar to those observed in healthy adults.However, final antibody levels were substantially lower for each group of chronic liver disease patients than for healthy adults (174)(175)(176)(177)(178)(179).Immunogenicity in liver transplant recipients has varied among studies.In one study, none of the eight patients who had received a liver transplant responded to hepatitis A vaccination; in another study, only six (26%) of 23 liver transplant recipients responded (176,179).However, hepatitis A vaccine was immunogenic for liver transplant patients in another study, with 38 (97%) responding to a standard dose and schedule (180).Only 28 (72%) of 39 kidney transplant recipients in this study subsequently had protective levels of antibody.A follow-up study indicated that antibody levels might decline more rapidly for MMWR May 19, 2006 both liver and kidney transplant recipients compared with typical rates of decline for healthy patients (181). Limited data indicate that age might reduce the immunogenicity of hepatitis A vaccine.In certain studies, the proportion of persons aged >40 years who had protective antibody levels was similar to that of persons aged <40 years, but final antibody levels were lower in the older age group (130,(182)(183)(184).Additional factors associated with decreased immunogenicity to other vaccines (e.g., smoking and obesity) have not been evaluated for the currently licensed formulations of hepatitis A vaccine.No data are available pertaining to response rates to revaccination among persons who do not respond to the primary vaccine series. Simultaneous Administration with Other Vaccines.Limited data from studies conducted among adults indicate that simultaneous administration of hepatitis A vaccine with diphtheria, poliovirus (oral and inactivated), tetanus, typhoid (both oral and IM), cholera, Japanese encephalitis, rabies, or yellow fever vaccines does not decrease the immune response to either vaccine or increase the frequency of reported adverse events (185)(186)(187).
Studies indicating that hepatitis B vaccine can be administered simultaneously with hepatitis A vaccine without affecting either vaccine's immunogenicity or increasing the frequency of adverse events led to the licensure of TWINRIX (188).Studies conducted among infants and young children aged <18 months have demonstrated that simultaneous administration of hepatitis A vaccine with diphtheria-tetanus-acellular pertussis (DTaP), Haemophilus influenzae type b (Hib), hepatitis B, MMR, or inactivated poliovirus vaccines does not affect the immunogenicity and reactogenicity of these vaccines (136,(189)(190)(191)(192). # Side Effects and Adverse Events Data on adverse events are derived from prelicensure clinical studies worldwide, reports following licensure of HAVRIX in Europe and Asia, other postlicensure studies, and reports to the national Vaccine Adverse Events Reporting System (VAERS) following licensure of HAVRIX and VAQTA in the United States. # Local Reactions Approximately 50,000 persons were administered HAVRIX in prelicensure clinical studies (190).No serious adverse events were attributed definitively to hepatitis A vaccine.Among adults, the most frequently reported side effects occurring <3 days after the 1,440-EL.U. dose were soreness at the injection site (56%), headache (14%), and malaise (7%).In clinical studies among children, the most frequently reported side effects were soreness at the injection site (15%), feeding problems (8%), headache (4%), and injection-site induration (4%).The frequency of side effects after administration of TWINRIX was similar to those reported when the two single-antigen vaccines were administered (123,124,191). Approximately 10,000 persons were administered VAQTA in prelicensure clinical studies, and no serious adverse events were reported among participants (192).Among adults, the most frequent side effects that occurred <5 days after vaccination included tenderness (53%), pain (51%), and warmth (17%) at the injection site and headache (16%).Among children, the most common side effects reported were pain (19%), tenderness (17%), and warmth (9%) at the injection site.In one placebo-controlled trial among children, adverse reactions among vaccine recipients did not differ substantially from those that occurred among persons who received placebo (118). # Serious Adverse Events An estimated 1.3 million persons in Europe and Asia were vaccinated with HAVRIX before the vaccine's licensure in the United States in 1995.Reports of serious adverse events, without regard to causality, received by the vaccine manufacturer included anaphylaxis, Guillain-Barré syndrome, brachial plexus neuropathy, transverse myelitis, multiple sclerosis, encephalopathy, and erythema multiforme (SmithKline Beecham Biologicals, unpublished data, 1995).The majority of these events occurred among adults, and approximately one third occurred among persons receiving other vaccines concurrently.For serious adverse events for which background incidence data can be estimated (e.g., Guillain-Barré syndrome and brachial plexus neuropathy), rates for vaccine recipients were not higher than would be expected for an unvaccinated population (CDC, unpublished data, 1995). No serious adverse events were reported for approximately 40,000 children who were administered the 360-EL.U. dose of HAVRIX in the protective efficacy study (117).In a postlicensure study of 11,417 children and 25,023 adults who were administered VAQTA, no serious adverse events occurred that were considered to be associated with administration of vaccine (Merck & Co., Inc., unpublished data, 2005).A published postlicensure evaluation of safety among 2,000 child and adult recipients identified no serious adverse events associated with VAQTA (193). Since (FDA, unpublished data, 2005).The most common events were fever, injection-site reactions, rash, and headache.The 871 reports of serious adverse events included reports of Guillain-Barré syndrome, transaminitis, and idiopathic thrombocytopenic purpura, which had been described previously in a published safety review, and seizures among children (194).The relation, if any, between the vaccine and reported serious events was not clear.In the original safety review, reported adverse events were similar for VAQTA and HAVRIX (194).The safety of the vaccine will continue to be assessed through ongoing monitoring of data from VAERS and other surveillance systems. Any adverse event suspected to be associated with hepatitis A vaccination should be reported to VAERS.Information on how to report adverse events is available at / cber/vaers/vaers.htm; forms for this purpose can be obtained at telephone 800-822-7967. # Contraindications and Precautions Hepatitis A vaccine should not be administered to persons with a history of a severe allergic reaction to a previous dose of hepatitis A vaccine or to a vaccine component.The safety of hepatitis A vaccination during pregnancy has not been determined; however, because hepatitis A vaccine is produced from inactivated HAV, the theoretic risk to the developing fetus is expected to be low.The risk associated with vaccination should be weighed against the risk for hepatitis A in pregnant women who might be at high risk for exposure to HAV.Because hepatitis A vaccine is inactivated, no special precautions need to be taken when vaccinating immunocompromised persons. # Prevaccination Serologic Testing for Susceptibility Antibody production in response to HAV infection results in lifelong immunity to hepatitis A and, presumably, to HAV infection.Vaccination of a person who is immune because of previous infection does not increase the risk for adverse events.In populations that have expected high rates of previous HAV infection, prevaccination testing may be considered to reduce costs by not vaccinating persons who are already immune.Testing of children is not indicated because of their expected low prevalence of infection.For adults, the decision to test should be based on 1) the expected prevalence of immunity, 2) the cost of vaccination compared with the cost of serologic testing (including the cost of an additional visit), and 3) the likelihood that testing will not interfere with initiation of vaccination.For example, if the cost of screening (including laboratory and office visits) is one third the cost of the vaccine series, then screening potential recipients in populations for which the prevalence of infection is likely to be >33% should be cost-effective (195). Persons for whom prevaccination testing will likely be most cost-effective include adults who were either born in or lived for extensive periods in geographic areas that have a high or intermediate endemicity of hepatitis A (Figure 4); older adolescents and adults in certain population groups (i.e., American Indians, Alaska Natives, and Hispanics); and adults in certain groups that have a high prevalence of infection (e.g., injectiondrug users).In addition, prevalence might be high enough among all older adults to warrant prevaccination testing.Overall anti-HAV prevalence among persons aged >40 years, determined by NHANES-III testing, was >33% (50).Therefore, if the cost of screening is one third the cost of the vaccine series, prevaccination testing of any person aged >40 years would likely be cost-effective.Commercially available tests for total anti-HAV should be used for prevaccination testing. # Postvaccination Testing for Serologic Response Postvaccination testing is not indicated because of the high rate of vaccine response among adults and children.In addition, not all testing methods approved for routine diagnostic use in the United States have the sensitivity to detect low anti-HAV concentrations after vaccination. # Cost-Effectiveness of Hepatitis A Vaccination of Children The cost-effectiveness of nationwide routine hepatitis A vaccination was evaluated in an analysis that used a Markov model to follow a single U.S. birth cohort of approximately 4 million persons from birth in 2005 through age 95 years or death.Compared with no childhood vaccination, routine vaccination at age 1 year would result in 183,806 fewer infections and 32 fewer deaths in each cohort (CDC, unpublished data, 2005).The cost-effectiveness ratio was estimated at $173,000 per life year gained and $24,000 per qualityadjusted life year (QALY) gained.Compared with 2003 vaccine coverage levels, the incremental cost-effectiveness ratio of routine nationwide vaccination at age 1 year was $73,000 per QALY gained.When out-of-cohort herd immunity was taken into account, vaccination at age 1 year yielded a societal cost of $1,000 per QALY gained.Another economic analysis that included the estimated reduction in secondary cases among household contacts of infected children yielded similar results (196). # MMWR May 19, 2006 # Recommendations for Use of Hepatitis A Vaccine and Immune Globulin Preexposure Protection Against HAV Infection The following recommendations for hepatitis A vaccination are intended to further reduce hepatitis A morbidity and mortality in the United States and make possible consideration of eventual elimination of HAV transmission.Hepatitis A vaccination is recommended routinely for children, for persons who are at increased risk for infection, and for any person wishing to obtain immunity. # Children - All children should receive hepatitis A vaccine at age 1 year (i.e., 12-23 months).Vaccination should be completed according to the licensed schedules (Tables 2 and 3) and integrated into the routine childhood vaccination schedule.Children who are not vaccinated by age 2 years can be vaccinated at subsequent visits. -States, counties, and communities with existing hepatitis A vaccination programs for children aged 2-18 years are encouraged to maintain these programs.In these areas, new efforts focused on routine vaccination of children aged 1 year should enhance, not replace, ongoing programs directed at a broader population of children. -In areas without existing hepatitis A vaccination programs, catch-up vaccination of unvaccinated children aged 2-18 years can be considered.Such programs might especially be warranted in the context of increasing incidence or ongoing outbreaks among children or adolescents. # Persons At Increased Risk for HAV Infection # Persons Traveling to or Working in Countries That Have High or Intermediate Endemicity of Infection All susceptible persons traveling to or working in countries that have high or intermediate hepatitis A endemicity (Figure 4) should be vaccinated or receive IG before departure (Tables 1-4).Hepatitis A vaccination at the ageappropriate dose is preferred (Tables 2-4).Prevaccination testing should be considered for older travelers or for younger persons in certain population groups (see Prevaccination Serologic Testing for Susceptibility). Travelers to Australia, Canada, western Europe, Japan, or New Zealand (i.e., countries in which endemicity is low) are at no greater risk for infection than persons in the United States.Data are not available regarding the risk for hepatitis A for persons traveling to certain areas of the Caribbean, although vaccine or IG should be considered if travel to areas that have questionable sanitation is anticipated. The first dose of hepatitis A vaccine should be administered as soon as travel is considered.Travelers who are administered vaccine can be assumed to be protected within 4 weeks after receiving the first vaccine dose.Persons administered singleantigen hepatitis A vaccine often will have detectable anti-HAV by 2 weeks after the first vaccine dose; the proportion of persons who will have detectable anti-HAV at 2 weeks might be lower when lower vaccine dosages are used (e.g., in TWINRIX).However, no data are available regarding the risk for hepatitis A among persons vaccinated 2-4 weeks before departure.Because protection might not be complete until 4 weeks after vaccination, for optimal protection, persons traveling to an area in which risk is high <4 weeks after the initial dose also may be administered IG (0.02 mL/kg), but at a different anatomic injection site.Travelers departing in <4 weeks who do not or cannot receive IG should nonetheless receive hepatitis A vaccine and be informed that they might not be optimally protected from acquiring hepatitis A in the immediate future (i.e., subsequent 2-4 weeks).Completion of the vaccine series according to the licensed schedule (Tables 2-4) is necessary for long-term protection. Travelers who are allergic to a vaccine component or who elect not to receive vaccine should receive a single dose of IG (0.02 mL/kg), which provides effective protection against hepatitis A for up to 3 months (Table 1).Travelers whose travel period is >2 months should be administered IG at 0.06 mL/kg; administration must be repeated if the travel period is >5 months (Table 1). # MSM MSM (both adolescents and adults) should be vaccinated.Prevaccination testing is not indicated for the vaccination of adolescents and young adults in this population but might be warranted for older adults (see Prevaccination Serologic Testing for susceptibility).Studies have suggested that the majority of MSM would accept hepatitis A vaccination if recommended by their providers (53).Health-care providers in primary-care and specialty medical settings in which MSM receive care should offer hepatitis A vaccine to patients at risk.Implementation strategies to overcome barriers and increase coverage (e.g., use of standing orders) should be considered. # Users of Injection and Noninjection Drugs Vaccination is recommended for users of injection and noninjection illicit drugs.Prevaccination testing is not indicated for the vaccination of adolescent users of illicit drugs but might be warranted for certain adults.The need might depend on the particular characteristics of the population of drug users, including the type and duration of drug use.Providers should obtain a thorough history to identify patients who use or are at risk for using illicit drugs and might benefit from hepatitis A vaccination.Implementation strategies to overcome barriers and increase coverage (e.g., use of standing orders) should be considered. # Persons Who Have Occupational Risk for Infection Persons who work with HAV-infected primates or with HAV in a research laboratory setting should be vaccinated.Studies conducted among U.S. workers exposed to raw sewage do not indicate increased risk for HAV infection.No other populations have been demonstrated to be at increased risk for HAV infection because of occupational exposure. # Persons with Clotting-Factor Disorders Susceptible persons who are administered clotting-factor concentrates, especially solvent-detergent-treated preparations, should receive hepatitis A vaccine.Changes in clotting factor preparation practices and donor screening have greatly reduced the risk for hepatitis A for recipients of clotting factors. # Vaccination of Persons with Chronic Liver Disease Susceptible persons with chronic liver disease should be vaccinated.Available data do not indicate a need for routine vaccination of persons with chronic HBV or HCV infections without evidence of chronic liver disease.Susceptible persons who are either awaiting or have received liver transplants should be vaccinated. # Hepatitis A Vaccination During Outbreaks The frequency of large communitywide outbreaks has diminished considerably since implementation of the recommended childhood hepatitis A vaccination programs.Implementation of the recommendations in this report should further reduce occurrence of outbreaks.If communitywide outbreaks occur, accelerated vaccination may be considered as an additional control measure.Factors to consider in deciding whether to initiate an outbreak-control vaccination program include the feasibility of rapidly vaccinating the target population of children, adolescents, or young adults, and program cost.Ongoing vaccination of children should be sustained to maintain high levels of immunity and prevent future epidemics. Limited outbreaks, especially those involving adults at increased risk (e.g., illicit drug users or MSM), are likely to continue to occur until higher vaccine coverage is achieved in these populations.Vaccination programs to control these outbreaks have been difficult to implement.Programs to control hepatitis A outbreaks among users of illicit drugs, especially methamphetamine, that focused on vaccination in county jails and similar venues (e.g., court-ordered diversion programs) have met with some limited success, at least in terms of the provision of vaccine (57).In general, efforts to control and prevent hepatitis A outbreaks among adults in these populations should be focused primarily on initiating and sustaining routine vaccination of these persons. The frequency of outbreaks in child care centers has also decreased in recent years and should continue to decrease with more widespread vaccination of young children.Limited data exist regarding the role of hepatitis A vaccine in controlling outbreaks in these settings.If outbreaks are recognized in child care centers, use of IG as recommended is effective in limiting transmission to employees and families of attendees (see Postexposure Prophylaxis with IG).Previously unvaccinated children receiving postexposure prophylaxis with IG should also receive hepatitis A vaccine. Persons who work as food handlers can contract hepatitis A and potentially transmit HAV to others.One national economic analysis concluded that routine vaccination of all food handlers would not be economical from a societal or restaurant owner's perspective (197).Nonetheless, to decrease the frequency of evaluations of food handlers with hepatitis A and the need for postexposure prophylaxis of patrons, consideration may be given to vaccination of employees who work in areas where state and local health authorities or private employers determine that such vaccination is appropriate.Food handlers who receive hepatitis A vaccine should be provided with a record of the immunization.Those who do not should be informed of the signs and symptoms of hepatitis A and taught food preparation practices that reduce the risk for fecal contamination. # Postexposure Prophylaxis with IG Persons who have been recently exposed to HAV and who have not previously received hepatitis A vaccine should be administered a single dose of IG (0.02 mL/kg) as soon as possible.Efficacy when administered >2 weeks after exposure has not been established.Persons who have been administered 1 dose of hepatitis A vaccine at >1 month before exposure to HAV do not need IG. Because hepatitis A cannot be reliably diagnosed on clinical presentation alone, serologic confirmation of HAV infection in index patients by IgM anti-HAV testing is recommended before postexposure treatment of contacts.Screening of con-tacts for immunity before administering IG is not recommended because screening would result in delay. If hepatitis A vaccine is recommended for a person being administered IG (e.g., a person with a recent exposure but also an indication for vaccination), it may be administered simultaneously with IG at a separate anatomic injection site.Unlike IG, hepatitis A vaccine is not licensed for use as postexposure prophylaxis.The completion of studies comparing IG with hepatitis A vaccine for postexposure prophylaxis is needed before vaccine can be recommended in this setting.IG should be administered to previously unvaccinated persons in the following situations. # Close Personal Contact IG should be administered to all previously unvaccinated household and sexual contacts of persons with serologically confirmed hepatitis A. In addition, persons who have shared illicit drugs with a person who has serologically confirmed hepatitis A should receive IG and hepatitis A vaccine.Consideration should also be given to providing IG to persons with other types of ongoing, close personal contact with a person with hepatitis A (e.g., regular babysitting).
# Child Care Centers IG should be administered to all previously unvaccinated staff and attendees of child care centers or homes if 1) one or more cases of hepatitis A are recognized in children or employees or 2) cases are recognized in two or more households of center attendees.In centers that do not provide care to children who wear diapers, IG need be administered only to classroom contacts of an index patient.When an outbreak occurs (i.e., hepatitis A cases in three or more families), IG also should be considered for members of households that have children (center attendees) in diapers.Hepatitis A vaccine may be administered at the same time as IG for children receiving postexposure prophylaxis in child care centers. # Common-Source Exposure If a food handler receives a diagnosis of hepatitis A, IG should be administered to other food handlers at the same establishment.Because common-source transmission to patrons is unlikely, IG administration to patrons typically is not indicated but may be considered if 1) during the time when the food handler was likely to be infectious, the food handler both directly handled uncooked foods or foods after cooking and had diarrhea or poor hygienic practices, and 2) patrons can be identified and treated <2 weeks after the exposure.In settings in which repeated exposures to HAV might have occurred (e.g., institutional cafeterias), stronger consideration of IG use might be warranted.In the event of a common-source out-break, IG should not be administered to exposed persons after cases have begun to occur because the 2-week period during which IG is effective will have been exceeded. # Schools, Hospitals, and Work Settings IG is not routinely indicated when a single case occurs in an elementary or secondary school, an office, or other work settings, and the source of infection is outside the school or work setting.Similarly, when a person who has hepatitis A is admitted to a hospital, staff should not routinely be administered IG; instead, careful hygienic practices should be emphasized.IG should be administered to persons who have close contact with index patients if an epidemiologic investigation indicates HAV transmission has occurred among students in a school or among patients or between patients and staff in a hospital. 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 2.5 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 0.2 continuing education units to participants who successfully complete this activity. # Continuing Nursing Education (CNE). This activity for 2.8 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.You must complete and return the response form electronically or by mail by MAY 19, 2009, to receive continuing education credit.If you answer all of the questions, you will receive an award letter for 2.5 # Goal and Objectives This report provides updated recommendations made by the Advisory Committee on Immunization Practices (ACIP) concerning vaccination to prevent hepatitis A virus (HAV) infection in the United States.The goal of this report is to guide clinical practice and policy development related to the prevention of HAV infection.Upon completion of this educational activity, the reader should be able to 1) identify recommendations for the routine hepatitis A vaccination of children in the United States, 2) describe the epidemiology of hepatitis A in selected areas of the United States after implementation of ACIP's 1996 and 1999 recommendations for use of hepatitis A vaccine, 3) list the primary target groups for routine hepatitis A vaccination, and 4) describe the characteristics of currently licensed hepatitis A vaccines. To receive continuing education credit, please answer all of the following questions. # Which best describes your professional # In recent years, the majority of hepatitis A cases have been reported from states with historically low rates of hepatitis A in which hepatitis A vaccination of children has not been implemented widely. A. True.B. False.
As the nation's prevention agency, CDC strives to accomplish its vision of "Healthy People in a Healthy World...Through Prevention."For women, this involves working to better understand the health issues that have an adverse impact on women, disproportionately affect women, occur only in women, or have an impact on infant outcomes as a direct result of a pregnancy-related event.Women's health once focused primarily on puberty, pregnancy, and menopause.Now, women's health is recognized as being broad in focus and warranting additional attention and study and involves not only chronic conditions but individual lifestyle choices and environmental and organizational factors.This publication focuses on some of the specific issues affecting women's health: falls and resulting hip fractures, sports injuries, breast and cervical cancer, and congenital toxoplasmosis.For each report, prevention recommendations and specific research recommendations are provided.Much still needs to be done.The publication addresses diverse and seemingly unconnected women's health issues; however, these issues are very much connected, and several themes run throughout each of the reports.For example: - Prevention -whether primary or secondary -continues to reduce or prevent injury, disease, death, and disability.Prevention is an essential component to maintaining health.ii MMWR March 31, 2000 Contents Reducing Falls and Resulting Hip Fractures Among Older Women .# - Science continues to strengthen and support public health action on the individual, local, and national level. - Although much progress has been made in the area of women's health to reduce morbidity and mortality, more prevention research needs to be done. - Public health affects every phase of our lives: how we live, work, and play. Whether the topic is falls in the home, injuries associated with leisure or workrelated activities, screening for toxoplasmosis, or implementation of an early detection program, prevention plays a vital role.Our partners in prevention (e.g., other health agencies, business, education, communities, and individuals) also play a vital role by developing and implementing prevention strategies and policies and by promoting healthy behaviors and environments. After reviewing each of these reports, examine current practices that have an impact on women's health where you live, work, and play.Are there opportunities for improvement?As costs related to disease, disability, and injury continue to increase, the role of prevention to maintain health becomes more critical.Prevention is about staying healthy and living well-and prevention works for women. # Yvonne Green Associate Director Office on Women's Health # SCOPE OF THE PROBLEM Falls are the leading cause of injury deaths and disabilities among persons aged ³65 years.In the United States, one of every three older adults falls each year (2,3 ).In 1997, nearly 9,000 persons aged ³65 years died from falls (4 ).Of those who fall, 20%-30% sustain moderate to severe injuries that reduce mobility and independence and increase the risk for premature death (5 ).Older adults are hospitalized for fall-related injuries five times more often than they are for injuries from other causes (5 ), and women are nearly three times more likely than men to be hospitalized for a fall-related injury (5 ). The most prevalent fall-related injuries among older adults are fractures of the hip; spine; upper arm; forearm; and bones of the pelvis, hand, and ankle (6 ).Of these, the most serious injury is hip fracture, a leading cause of morbidity and excess mortality among older adults (7 ).During 1988During -1996, the estimated number of hospital admissions for hip fracture increased from 230,000 to 340,000 (Figure 1).In 1996, 80% of the admissions for hip fracture occurred among women (8 ). The rate of hospitalization for hip fracture differs by sex.The hip fracture hospitalization rate for persons aged ³65 years is significantly higher for women than men (9 ).During 1988-1996, the rates for women increased significantly, from 972 per 100,000 to 1,356; for men, rates remained stable (9 ).A Healthy People 2010 objective is to reduce the hip fracture hospitalization rate among women aged ³65 years to no more than 879 per 100,000 (objective 15-28a). Hip fracture hospitalization rates are substantially higher for white women than black women.In 1996, the hospitalization rate for white women aged ³65 years was 1,174 per 100,000, five times the rate for black women (9 ).A Healthy People 2010 objective is to reduce hip fracture hospitalization rates among white women aged ³65 years to no more than 932 per 100,000 (objective 15-28a). The overall increase in hip fracture hospitalization rates can be explained in part by the increasing U.S. population of very old adults (i.e., persons aged ³85 years).Today, a larger proportion of the population is living to age ³85 years than in the past because of reduced mortality from cardiovascular and other chronic diseases.Since 1987, death rates from coronary heart disease, stroke, and cancer have declined, and the proportion of adults aged ³70 years living with some functional limitation- has increased (10 ).Frail older adults are twice as likely to fall as healthier persons (11 ). Hip fractures are expensive.A recent study documented that the cost of a hip fracture (including direct medical care, formal nonmedical care, and informal care provided by family and friends) was $16,300-$18,700 during the first year following the injury (12 ).In 1991, hip fracture accounted for an estimated $2.9 billion in Medicare costs (13 ).On the basis of the annual cost of hip fracture in 1984, an assumption that the average cost will remain constant, an inflation rate of 3%-5%, and the increasing number of hip fractures, the estimated total annual cost of hip fracture in the United States could reach $82-$240 billion by the year 2040 (14 ). An even more important factor than the monetary cost of hip fracture is the injury's impact on a person's life in the form of loss of independence and decreased quality of life.Nationwide, only 50% of older adults hospitalized for hip fracture are able to return home or live independently after the injury (15,16 ). # ETIOLOGIC OR RISK FACTORS Approximately 95% of hip fractures are caused by falls (17 ).Other causes include being knocked over and being injured in a motor-vehicle crash; <2% of hip fractures occur spontaneously (e.g., as the result of a metabolic bone disease) (17 ).Not all falls are *Defined as having difficulty with two or more activities of daily living. # FIGURE 1.Estimated number of hospital admissions for hip fracture among persons aged ³65 years -United States, 1988-1996 Source: CDC's National Hospital Discharge Survey.1988 1989 1990 1991 1992 1993 1994 1995 1996 equally likely to cause hip fracture.Biomechanical studies have demonstrated that, although both bone strength and the force of the impact are important factors, the point of impact must be on or near the hip for a fall to cause a hip fracture (18 ).Many factors contribute to falls and subsequent fall injury.Fall risk increases rapidly with advancing age for persons aged ³65 years (19 ).Other fall risk factors include lack of current or previous physical activity (20,21 ), muscle weakness or balance problems that can contribute both to the risk for falling and the inability to break the impact of a fall (2,22,23 ), functional limitations (e.g., difficulty with activities of daily living such as dressing or bathing) (22,24 ), cognitive impairment or dementia (2 ), use of psychoactive medications (e.g., tranquilizers or antidepressants), some combinations of medications (2,25 ), environmental factors (e.g., tripping hazards) (26 ), having fallen previously (27 ), having more than one chronic disease (28 ), having had a stroke (28 ), Parkinson disease (29 ) or a neuromuscular disease (30 ), urinary incontinence (31 ), and visual difficulties (32,33 ).Less clear is the fall risk associated with wearing shoes with thick, soft soles (e.g., jogging shoes) that can affect balance and proprioception or become a tripping hazard by catching in carpeting (34 ). Similar to fall risk, hip fracture risk increases sharply with advancing age (19 ).Women aged ³85 years are nearly eight times more likely than women aged 65-74 years to be hospitalized for hip fracture (9 ).White women aged ³65 years are at higher risk for hip fracture (19 ) than black women, in part because the prevalence and severity of osteoporosis-a condition that predisposes to bone fragility-is greatest among white women.Other risk factors include low body mass index (weight in kilograms divided by height in meters squared /height squared ) (7,35,36 ), previous history of osteoporosis (27 ), and having sustained a previous hip fracture (27 ). Falls are caused by personal (intrinsic) and environmental (extrinsic) factors.Personal risk factors include problems with gait and balance, functional impairments or limitations in activities of daily living, visual problems, and behavioral risk factors (e.g., lack of physical activity and taking certain psychoactive medications such as tranquillizers or antidepressants).Environmental factors include home hazards (e.g., clutter; no stair railings; loose rugs or other tripping hazards; no grab bars in the bathroom; and poor lighting, especially on stairs).Frequently, a fall is the result of an interaction between personal and environmental factors. # RECOMMENDATIONS FOR PREVENTION Because approximately 95% of hip fractures result from falls (17 ), minimizing fall risk is a practical approach to reducing these serious injuries.Primary prevention of fallrelated injuries involves reducing the occurrence of falls; secondary prevention of fall-related injuries involves preventing injuries when falls occur. # Primary Prevention Primary prevention of fall-related injuries among older adults can be targeted to persons living independently in the community or residents of nursing homes.Research has established that effective fall intervention programs employ a multifaceted approach and incorporate both behavioral and environmental elements: exercises to improve strength and balance, environmental modifications, education about fall prevention, medication review and assessment to minimize side effects, and risk factor reduction (36)(37)(38)(39). # Community Intervention Approximately 90% of adults aged ³65 years live in the community and many fall prevention programs target these persons; however, few of these programs have been evaluated for effectiveness.During 1990-1992, a prospective, multifaceted, fallprevention study was conducted among 301 community-dwelling men and women who were aged ³70 years and had at least one fall risk factor (e.g., sedative use or some limitation in arm or leg strength) (36 ).A total of 153 persons participated in an intervention that consisted of behavioral instructions and training to reduce specific risk factors (e.g., persons with gait or balance impairments received specialized training in these areas), exercise programs to increase strength, and medication adjustments.After 1 year, the group that received the intervention had 30% fewer falls than the control group.Further research is needed to evaluate the effectiveness of such a program among all persons aged ³65 years living independently in the community. Physical Activity.Increasing physical activity can be an effective component of fall prevention programs.Activities that improve strength, balance, and coordination can reduce the risk for falls and fall-related injuries among healthy (40,41 ) and frail persons (42 ).Studies have demonstrated a 40%-60% reduction in hip fracture risk with increasing levels of physical activity (36,43 ).Although fall prevention programs have focused on several techniques to improve strength, balance, coordination, mobility, and flexibility, Tai Chi is probably the most frequently studied type of exercise (40 ).Effective programs have been employed with persons of different ages and with varied physical abilities; however, persons with functional limitations might require more individualized physical activity programs (44 ). Environmental Modifications.Because approximately 50%-60% of all falls among older adults occur at home, fall prevention programs should address home hazards that can contribute to falls (45 ).Home-visiting programs (e.g., those using visiting nurses) provide opportunities to identify potential fall hazards and take corrective action.These programs can increase awareness of fall risks among informal caregivers, (e.g., family and friends who frequently visit the homes of older adults) and the older adults themselves. Health Education.Fall prevention programs frequently include health education and health promotion materials about reducing fall hazards that are distributed at central locations (e.g., senior centers or health fairs).However, educational materials alone might not promote behavioral changes.Many programs employ home-hazard checklists that can be used by the caregiver or health agency personnel (e.g., a visiting nurse or home health aide) to help persons identify fall hazards and to suggest corrective action (e.g., eliminating potential tripping hazards such as clutter and throw rugs, adding stair railings, improving lighting, adding nonslip floor surfaces, and installing grab bars in bathrooms).Checklists are also given to residents to help them assess personal and environmental risks and take preventive action, including behavioral changes (45 ).Research is needed to evaluate and assess the effectiveness of educational materials and home-hazard checklists to promote fall-risk reduction activities and behaviors. Risk Factor Reduction.Approaches that address specific risk factors can supplement fall prevention program efforts.Medical approaches might include reducing fall risk factors (e.g., maximizing control of concomitant chronic diseases) and reducing hip fracture risk factors (e.g., counseling women aged ³65 years against inappropriate weight loss). # MMWR March 31, 2000 # Nursing-Home Intervention Nursing-home residents, who constitute approximately 5% of the population aged ³65 years, are at particularly high risk for fall-related injuries.Approximately one half of the estimated 1.7 million nursing-home residents in the United States fall at least once each year, and 11% sustain a serious fall-related injury (46 ).A randomized trial of seven pairs of nursing homes that included 500 residents evaluated an intensive, multifaceted intervention of extensive environmental modifications (e.g., obtaining wheel locks for beds, changing lighting, modifying floor plans, and purchasing raised toilet seats), medication review, and increased attention to individual resident needs (39 ).Repeat falls declined 19% among nursing-home residents who had fallen at least once during the previous year.However, approximately one third of the safety recommendations implemented in the study group were discontinued within 3 months of the completion of the study.Strategies are needed to institutionalize fall prevention interventions in the nursing-home setting, and additional programs designed for high-risk nursing-home residents need to be implemented and evaluated. # Secondary Prevention Secondary prevention strategies are being developed to reduce the incidence of hip fracture among older women (47 ).Most hip fractures are caused by falling directly on the hip, and biomechanical studies have demonstrated that a pad that shunts the energy away from the point of impact is highly effective in reducing the force of a fall on the proximal femur (48 ).A 1993 clinical study in a Copenhagen nursing home demonstrated that hip protectors reduced the risk for hip fracture by approximately 50% (47 ).During 1994-1996, researchers in Finland conducted a study to determine whether nursinghome residents would wear an undergarment with energy-shunting hip pads.The findings indicated that 63% of the residents wore the pads (49 ).U.S. manufacturers have considered producing and marketing an undergarment with energy-absorbing hip pads, but how acceptable and effective this garment might be among community-dwelling older adults is unknown. A promising technologic innovation for preventing fall-related injuries is a recently developed safety floor (50 ).Under laboratory conditions, this flooring material provides a firm walking surface and, if a fall occurs, reduces the force of impact through the use of special energy-absorbing flooring material.Field trials are under way in nursing homes to evaluate the effectiveness of this material in preventing fall-related hip fractures among nursing-home residents.professionals, caretakers, and other persons concerned about reducing injuries among older adults. Researchers do not know all the factors that contribute to falls and fall-related injuries or how personal and environmental factors interact to cause a fall.These factors have been difficult to identify because persons frequently cannot explain the causes or circumstances surrounding fall events.In one prospective study, one fourth to one third of the participants did not remember a fall that occurred 3-6 months earlier (51 ).Older adults might either blame themselves for falling or consider falls to be an inevitable consequence of the aging process.Longitudinal prospective studies are needed to accurately assess the associations between fall risk factors (e.g., interactions between intrinsic and extrinsic factors), the occurrence of falls, and fall outcomes (e.g., frequency of falls, whether an injury results, and level of injury severity). To decrease the incidence and severity of fall-related injuries, injury-prevention programs for older adults need to integrate research findings into multifaceted, communitylevel programs that include both implementation and evaluation components.A model program would employ a prospective design to accurately record fall occurrences and establish whether a fall resulted in an injury.Such a program should incorporate four critical elements: a) education and skill-building activities to increase knowledge about fall risk factors, b) exercise to increase strength and improve balance, c) home safety modifications and repairs to reduce fall hazards, and d) medication review to maximize control of comorbid conditions while reducing adverse side effects.Because persons must take an active role to reduce their risk for falling, a model fall prevention program should also include effective strategies to promote behavioral changes. Because of the increasing number of persons aged ³65 years in the United States, the need is increasing to develop an effective national plan to address the problem of falls and fall-related injuries within the constraints of limited health-care resources.To accomplish this goal, efforts are needed to increase collaboration among national experts from various disciplines (e.g., gerontologists, health educators, behavioral epidemiologists, home designers, and ergonomic experts), to reach consensus regarding the priority research areas and program issues, and to work toward long-term strategies for reducing falls and fall-related injuries among older adults.Some subgroups of older adults (e.g., women aged ³85 years and older adults with functional limitations) might have different fall-injury risks than most communitydwelling older adults (44 ).Efforts are needed to adapt existing fall prevention programs or develop new interventions to reduce falls in these groups.
Finally, in addition to existing behavioral and environmental interventions, new fall prevention approaches (e.g., characterizing footwear that promotes stability and developing more effective home lighting) need to be developed. # CONCLUSION Persons aged ³65 years constitute the fastest-growing segment of the U.S. population.The average life expectancy for both men and women is increasing, in part because of healthier life styles and better control and treatment of chronic conditions (e.g., cardiovascular disease).Without effective intervention strategies, the number of hip fractures will increase as the U.S. population ages. Fall prevention programs have effectively reduced falls in select populations by 30%-50%, using multifaceted approaches that include various combinations of education, exercise, medication assessment, risk factor reduction, and environmental modifications.Such programs need to be expanded to include multiple intervention components tailored for diverse populations of older adults and evaluated for effectiveness.In addition, secondary prevention strategies (e.g., reducing the amount of energy transferred to the hip) are needed to prevent hip fracture when falls occur. The problem of fall-related hip fractures will continue to increase unless effective intervention strategies are developed and implemented to improve fall prevention interventions and expand existing programs.Older adults must take an active role in reducing their risk for falling.Because most older adults live independently, fall prevention programs must include effective strategies to promote behavioral changes.Innovative and effective fall prevention strategies are needed to reduce future morbidity and mortality associated with hip fractures, increase independence, and improve quality of life for the growing number of older adults. # Exercise-Related Injuries Among Women: Strategies for Prevention from Civilian and Military Studies Etiologic Factors: Injury risks increase as the amount of training increases (increased exposure).The same exercise parameters that can be modified to enhance physical fitness (i.e., frequency, duration, and intensity) also influence the risk for injury in a dose-response manner.Higher levels of current physical fitness (aerobic fitness) protect the participant against future injury.A history of previous injury is a risk factor for future injury.Smoking cigarettes has been associated with increased risk for exercise-related injury.Studies conducted in military populations suggest that the most important risk factor for injuries among persons engaged in vigorous weightbearing aerobic physical activity might be low aerobic fitness rather than female sex.Recommendations for Prevention: Because of the limited scientific research regarding women engaging in exercise, general recommendations are provided.Women starting exercise programs should be realistic about their goals and start slowly at frequency, duration, and intensity levels commensurate with their current physical fitness condition.Women should be informed about the early indicators of potential injury.Women who have sustained an injury should take precautions to prevent reinjury (e.g., ensuring appropriate recovery and rehabilitation).Research Agenda: In general, a combination of factors affects the risk for exerciserelated injury in women.How these factors act singly and in combination to influence injury risk is not well understood.Additional research regarding exercise-related injury in women is needed to answer many of the remaining epidemiologic questions and to help develop exercise programs that improve health while reducing the risk for injury. # MMWR March 31, 2000 Conclusion: Exercise is an important component in improving and maintaining health; however, injury is also an accompanying risk.A review of key military and civilian research studies regarding exercise-related injuries provides some clues to reducing these injuries in women.Greater adherence to exercise guidelines can help decrease these risks. # BACKGROUND In 1996, the U.S. Surgeon General's report on physical activity brought together for the first time current knowledge regarding the health benefits of regular physical activity (1 ).The report concluded that persons who are inactive can improve their current and future health by becoming moderately active on a regular basis.In addition, the report indicated that activity does not need to be strenuous to achieve some health benefits, but that greater health benefits can be achieved by increasing the amount (frequency, duration, or intensity) of physical activity.Although many studies have documented the hazards of inactivity, few have assessed the adverse effects of increased physical activity (e.g., injury).Increased physical activity increases the risk for injury.Although opportunities for women to participate in sports and organized fitness activities have increased substantially during the preceding century, little is known about the risks for injuries associated with increased physical activity and exercise for women.This report reviews key military and civilian research studies regarding musculoskeletal injury associated with common weight-bearing exercise (e.g., running, walking, and aerobics) and provides general recommendations for preventing exercise-related injuries among women. Recent public health reports have reviewed the scientific evidence supporting the association between physical activity and several health benefits (1,2 ).Documented health benefits of regular physical activity include reducing the risk for coronary heart disease, noninsulin-dependent diabetes, hypertension, colon cancer, osteoporosis, and other disorders (1 ).Physical activity decreases the symptoms and might reduce episodes of anxiety and depression (1 ).In addition, regular physical activity improves physical fitness (e.g., cardiorespiratory endurance and muscle strength); reduces body fat; and builds and maintains healthy bones, joints, and muscles (1 ).Physical activity enhances strength, balance, and coordination (1 ).These benefits might be particularly important in preventing falls and maintaining independence in older adults.As a consequence of these health benefits, regular physical activity is highly recommended for women and men of all ages (1 ). The U.S. Surgeon General's report indicated that approximately 60% of adult women in the United States did not engage in the recommended amount of physical activity, and 25% did not participate in physical activity during their leisure time (1 ).Physical inactivity is more common in women than men (1,3 ).To help increase the proportion of persons engaged in regular physical activity, two of the Healthy People 2010 objectives are to a) reduce to £20% the proportion of persons aged ³18 years who engage in no leisure-time physical activity (objective 22-1) and b) increase to ³30% the proportion of persons aged ³18 years who engage in regular, preferably daily, moderate physical activity for at least 30 minutes per day (objective 22-2).Because regular physical activity is considered essential to health, it has been included as one of the leading health indicators for health promotion and disease prevention in the United States (4 ). Although physical activity has many health benefits, exercise has corresponding injury risks.Participants are at risk for exercise-related traumatic or overuse injuries.Some of the consequences of these injuries can be long-term (e.g., osteoarthritis and adverse health effects resulting from inactivity because of an injury).Injury causes many persons to stop participating in exercise (2,5 ).Efforts to increase physical activity and exercise in women must also be balanced with efforts to prevent injury. Because lifestyles have become more sedentary and work has become less physically demanding, planned physical activity intended to improve physical fitness has become more important.Consequently, many adults choose to participate in exercise programs or sports.Health-related exercise programs and sports are excellent ways for women to increase their physical activity. Opportunities for young women to participate in sports have substantially increased in recent decades.Since passage of the 1972 Title IX legislation that prevented sex discrimination in educational settings, the number of young women who participate in high school athletics has increased from approximately 300,000 during the early 1970s to nearly 2.7 million (one in three high school women) in the 1998-99 school year (6,7 ).This increased participation in high school athletics has fostered increased participation in college and elite athletics as well.Women now comprise approximately one third of all college athletes and 37% of U.S. Olympic athletes (7 ). Many adult women participate in recreational aerobic activities.The National Sporting Goods Association reported that an estimated 37.4 million women participate more than twice a week in common aerobic activities (i.e., aerobic dance, cycling, exercise walking, exercising with equipment, calisthenics, swimming, and running) (8 ).Walking is the most prevalent physical activity among adults in the United States (1,9 ).If trends of increased participation in women's sports expand to include increased participation in recreational and other physical activities, the number of exercise-related injuries can also be expected to increase. Injuries occur in association with physical activity, exercise, and sports (10-13 ), but the incidence and underlying causes of such injuries are not well understood.At the peak of the fitness boom in the 1980s, researchers knew little about exercise-related injuries and injury rates, even for common activities (e.g., walking and running) (12 ).During that period, researchers were only beginning to study the epidemiology of and risk factors for exercise-related injuries (12,14 ).Today, injury risk factors for physically active men remain poorly defined, and the specific risks for women who exercise are even less understood.Studies of runners have provided the most thorough examination of injury incidence and some related risk factors in civilian populations (5,12,(14)(15)(16)(17). Studies of military populations provide sex-specific information on injury risks associated with physical training and exercise; activities are controlled, and complete and detailed health records, physical examinations, and physical fitness assessments are available (18,19 ).Studies of basic combat training, which occurs in all branches of the military and involves running, marching, and other weight-bearing aerobic activities, can often provide information relevant to civilian populations.Uniformity of training within military units provides unique control for the variability observed in exercise routines in the civilian population.Examination of military studies provides some data on exposure risks (18,20 ) and intrinsic risk factors (e.g., sex, previous injuries, health behaviors, sports participation, physical fitness, and anatomic factors) (19)(20)(21)(22)(23)(24). # MMWR March 31, 2000 This report describes civilian and military research related to weight-bearing aerobic exercise and injuries.Aerobic exercises (e.g., running, walking, and aerobic dance) are highlighted in this report because they are popular and commonly prescribed activities.Military studies of training-related injuries are presented to identify shared and sexspecific intrinsic risk factors.Risks for men will be discussed briefly for comparative purposes.This report focuses on modifiable risk factors, which underlie the recommendations for prevention and future research. # Definitions In this report, distinctions between the terms "physical activity," "exercise," and "physical training" are important.Physical activity has been defined as movement created by skeletal muscle contractions, resulting in energy expenditure.Exercise is a type of physical activity that is planned, repetitive, and designed to improve or maintain at least one of the health-related components of physical fitness (25 ).Physical training (as used in the military) is organized exercise intended to enhance fitness.The terms exercise and physical training are used interchangeably.Physical fitness can be categorized into five health-related components: a) cardiorespiratory endurance (aerobic fitness), b) muscle endurance, c) strength, d) flexibility, and e) body composition (1,25 ).The focus of this report is on exercise for women aimed at enhancing cardiorespiratory endurance (aerobic fitness).When discussing research results from cited literature, the terms "significant" and "not significant" refer to a documented p-value of 0.05, respectively, unless otherwise stated. Musculoskeletal injuries related to exercise can be classified as either traumatic (acute) injuries (e.g., sprains and fractures) or overuse injuries (e.g., tendinitis, bursitis, and stress fractures).A distinction is also made between extrinsic and intrinsic risk factors for musculoskeletal injury.Extrinsic risk factors refer to the parameters of training (e.g., frequency, duration, and intensity) and the conditions associated with the environment in which the exercise takes place.Intrinsic risk factors refer to the personal and internal characteristics of the participant (Table 1). # SCOPE OF THE PROBLEM # Findings from Civilian Studies The incidence of exercise-related injury among women in the civilian population is not well documented.Civilian studies of male and female exercise participants provide some indication of the frequency of such injuries.Surveys demonstrate that the incidence of self-reported running-related injury is high.Annually, approximately 25%-65% of male and female runners report being injured to the extent that they reduced or stopped training (5,13,(15)(16)(17)(18)26 ).In addition, 14%-50% of these injured runners seek medical care for their injuries (5,13,(15)(16)(17)(18), representing substantial health-care costs for treatment and rehabilitation.Prospective studies that incorporated follow-up of injury among runners and other persons involved in vigorous physical activities suggest that the incidence of injuries might be even higher (11,(27)(28)(29). In an 18-month study of runners training for a marathon, 85% experienced ³1 injury, and 174 injuries were reported among the 73 participants (159 injuries per 100 runners per year) (27 ).In a 12-week study of aerobic dancers, 200 (49%) of 411 participants reported complaints associated with aerobics, and approximately 25% had to modify or stop participation because of an injury (28 ).In a study of participants engaged in several recreational sporting activities, 475 injuries occurred among 986 participants during a 12-week period (192 injuries per 100 participants per year) (11 ).In a 6-month study of walkers who averaged 14 miles per week, 21% stopped walking for ³1 week because of injury (29 ).Although injuries during fitness activities are common, few studies of women or men who participate in recreational fitness activities are available to quantify risk or identify modifiable risk factors. # Findings from Military Studies Many civilian fitness activities (e.g., walking and jogging) have corollaries in military physical training (e.g., marching and running).The incidence of injury and related intrinsic risk factors for these activities have been more thoroughly studied in military populations than in civilians.Because physical fitness is required for military readiness, recruits undergo a vigorous basic training (BT) course, and substantial research has been devoted to methods of enhancing fitness and understanding the causes of training-related injuries.Studies from the U.S. Army 8-week BT have documented cumulative injury rates from 42% to 67% among women during the course of training (19,20,30 ).Of women in the U.S. Air Force, 33% incurred an injury during the 6-week BT (20 ).Similarly, 22% of women in the U.S. Navy sustained an injury during the 9-week BT, and 49% of women in the U.S. Marine Corps were injured during the 11-week BT (20 ).The range of injury incidence (22%-67%) among women in the different services and over time might be explained by differences in the duration and intensity of BT. Most of the injuries to both women and men engaged in military BT are overuse injuries (e.g., achilles tendinitis, patellar-femoral syndrome, plantar fasciitis, and stress fractures).Most injuries occur to the lower extremities.Studies during Army BT indicate that 60%-80% of BT injuries are related to overuse, and 80%-90% occur to the lower extremities (21,22,30 ). Injuries in the military have substantial effects on training and combat readiness because they require greater rehabilitation and recovery time than illnesses.Approximately 50% of health-care visits in these young, vigorously active military populations are injury-related (20 ).The rate ratios of injury-to-illness sick call visits for women in the Army, Marine Corps, and Air Force are 1.0, 1.0, and 0.8, respectively.Furthermore, the rates of limited duty days (i.e., days when a trainee cannot fully function on duty) are often substantially higher from an injury than from illness (20,24 ).In one Army study, women were assigned 129 injury-related limited duty days per 100 female trainees per month compared with 6 illness-related limited duty days per 100 trainees per month.The rate ratio between injury and illness limited-duty days was 22, even though 50% of sick-call visits were for illnesses (20 ).Among men, the rates of limited duty for injury were five times higher than the rates of limited duty for illness.In the physically active and generally healthy military populations, injury can be expected to account for a substantial proportion of morbidity, health-care costs, and rehabilitation time in comparison with illnesses.The burden of injuries among physically active civilian populations might reflect a similar pattern. # Risk Factors for Exercise-Related Injuries Risk factors for exercise-related injuries can be either extrinsic or intrinsic to the participant (Table 1).This report focuses on extrinsic training factors, perhaps the most important factors in determining injury risks, and addresses selected intrinsic factors.The association between training parameters and injury risks in civilian and military populations will be examined first because they are potentially the most important. # Extrinsic Training Factors The same training parameters that are modified to achieve a training effect (i.e., frequency, duration, and intensity of exercise) are also the most important factors re-lated to injury.Several surveys of distance runners indicate a relation between a higher number of miles run per week and a higher incidence of injury in both women and men (5,10,13,15,26 ).Several studies have demonstrated that the relative risk (RR) of injury among civilian women and men is a function of the miles run per week (Table 2) (5,15,26 ).One classic study indicated that as the average weekly training mileage increased in 10mile increments from 50 miles per week, the incidence of injury for women increased from 29% to 57%.The incidence of injury for men increased in a similar manner (5 ).Two additional studies reported similar sex-specific trends (15,26 ).The annual incidence of injury among female and male runners was approximately the same, and the RRs of injury for both sexes increased with increasing miles run.These and other studies suggest that, for weight-bearing exercise (e.g., running), injury rates increase as the amount of training increases in a dose-response manner. In a study that examined the benefits of aerobic fitness and injury risks associated with increased duration or frequency of training among men, injury rates increased with duration of exercise (when frequency and intensity remained constant).Participants received limited additional aerobic fitness benefits when they exercised 45 minutes compared with 30 minutes.As duration of running increased from 15 minutes to 30 minutes to 45 minutes per workout, injury rates increased from 22% to 24% to 54%, respectively, whereas aerobic fitness (measured by maximal oxygen uptake) improved only 9%, 16%, and 17%, respectively.Although a plateau in fitness occurred, more exercise increased the incidence of injury.
This study also demonstrated that frequency of exercise (number of training sessions per week), although positively related to aerobic fitness, was also positively related to injury (31 ). A similar study of male walkers and joggers demonstrated that injury rates were more related to total mileage walked and jogged than to the intensity of exercise.This study controlled the total amount of activity in two groups of participants during a 6month period.Both groups exercised the same duration per day (30 minutes); however, the walkers exercised more frequently (more days per week) than the joggers to accumulate approximately the same mileage.The walkers averaged 120 minutes of exercise per week, and the joggers averaged 90 minutes per week; however, the total distance accumulated by both groups was approximately the same (13.7 km per week and 14.7 km per week, respectively).At the end of the 6-month study period, the two groups had similar injury rates: 21% of the walkers and 25% of the joggers had sustained injuries sufficiently severe to require terminating their activity for ³1 week (29 ).Studies such as these indicate that the total amount of training is an important determinant of injury risk.These studies were conducted with men, and similar studies of women are needed. Studies of military populations have also examined the relation between training frequency and duration, gains in cardiorespiratory fitness, and injury risk.As mileage during physical training increases, both aerobic fitness and the risk of injury increases.Similar to the findings in civilian populations (31 ), military studies have documented thresholds in physical training, above which increased training does not improve fitness levels but continues to increase the likelihood of injury (18)(19)(20).These studies of military populations examined the association between training parameters and injury risk among men only.Additional studies among women are needed. # MMWR 23 # Intrinsic Training Factors Military BT provides a unique opportunity to study some intrinsic risk factors for exercise-related injuries.Unlike civilian fitness participants, regimentation in military training requires that trainees do the same type and amount of training.Researchers studying military populations have systematically examined several intrinsic factors and their relation to musculoskeletal injury risk.The most consistently identified intrinsic risk factors have been a) sex, b) age, c) history of previous injury, d) adverse health behaviors (e.g., smoking tobacco), e) previous physical activity (e.g., sedentary lifestyle), and f) current level of physical fitness. Sex.Sex has consistently been identified as a risk factor for injury in military BT.In studies from the 1980s to 1997 that examined women and men at the same training site who performed essentially the same physical training, incidences of injuries for women were 1.7-2.2 times higher than those for men (19,20,21,30,32,33 ) (Table 3). In addition, rates of some specific injuries during military training (e.g., stress fractures) are higher for women than men (20,24,30,33,34 ).In Army training, RR for stress fractures is 2-10 times higher for women than men engaged in the same training regimen (20,21,30,(34)(35)(36).In the Marine Corps recruit training, the risk for stress fractures is 3.7 times higher for women than men (20 ).Some specific injuries (e.g., anterior cruciate ligament tears in the knee) occur more frequently in female athletes (37 ).However, in studies comparing civilian runners (the most extensively studied civilian recreational fitness activity), the overall rates of exercise-related injury are similar among women and men.Researchers suggest that female civilian runners have the same injury rates as men because they can modulate their training frequency, duration, and intensity (unlike military trainees) to accommodate their fitness levels and the minor overuse injuries that might occur (10 ).Injury studies among military populations suggest that without controlling for physical fitness, at any fixed level of activity, women will be at greater risk for injury than men (Table 3).Age.Results of military studies regarding the effects of age on training and injuries have been inconsistent.Some studies have revealed that during BT, female (38 ) and male trainees aged >23 years are at greater risk for injury (22,38,39 ).Other military studies have indicated no statistically significant difference in injury risk by age (20,36,40 ).Studies of civilian runners have also had inconsistent results.Some studies have demonstrated that age is not an important risk factor, whereas others have demonstrated that rates of injury decrease with age (10,13,15,16,26 ).Among civilian women, older age was not associated with elevated risk (10 ).Unlike military trainees, older participants in civilian studies might have been able to decrease their risk by modulating the frequency, duration, or intensity of their personal training regimens (10 ).Alternatively, a "survivor effect" might exist, whereby persons who have sustained injury change activities or cease participation and thus are unavailable for inclusion in studies (10 ).Data from military and civilian studies suggest that among adults aged <45 years, age alone is not a strong predictor of injury in exercise. History of Previous Injury.A history of previous musculoskeletal injury has also been reported as a risk factor for injury in both civilian and military studies.In a systematic review of the literature regarding the prevention of ankle sprains in sports, the most commonly identified risk factor for an ankle sprain was a previous ankle sprain (41 ).Overuse injuries occurred twice as frequently in trainees with a previous history of ankle sprain (19 ).A previous ankle sprain is also a risk factor for injuries among male trainees in Army BT (22 ).In addition, data from the Marine Corps suggest that previous injuries pose a risk for future injury (20,40 ).These findings are consistent with civilian studies of female and male distance runners, in which RR for an injury in a person who has had an injury during the preceding year was 1.8-2.4 for women and 1.7-2.7 for men (15,26 ). Health-Related Behaviors.Health behaviors engaged in before entry into military service (e.g., smoking tobacco and participating in regular physical activity) can influence a woman's injury risk during BT. Smoking.Both female and male smokers who participate in Army or Marine Corps BT are at a significantly higher risk for injury than nonsmokers (20 ).Women who were smokers on entry into the Army were 25% more likely to be injured in BT; injury rates were 77% for smokers and 62% for nonsmokers (20 ).Similarly, the risk for injury among women in the Marine Corps who smoked before beginning BT was 1.7 times higher than for those who were nonsmokers (20 ).Male smokers in Army and Marine Corps BT were 1.9 times and 2.3 times more likely to have an injury, respectively, than their nonsmoking male counterparts (20,22 ).Studies have not indicated whether civilian athletes or exercise participants who smoke tobacco are at greater risk for injury.However, in a literature review of the potential association between smoking and injuries, researchers estimated that smokers were two times more likely than nonsmokers to sustain unintentional injuries in the workplace, although some of these injuries might not be related to physical activity (42 ).Data from these studies suggest that women who smoke are at a higher risk for training-related injuries than women who do not smoke. Previous Physical Activity.Although some health behaviors (e.g., smoking) might increase injury risk, previous regular physical activity might be protective against injury.This protective effect has been documented in men in the Army and Marine Corps (20)(21)(22)32,39 ).Among male trainees in the Army, running before entry into the service might be protective.For military women, the association between previous regular physi-cal activity and injury risk has not been documented (20,32,36 ).Researchers documented that, for men, more years of participating in running was protective against injury; however, for women, more years of participating in running might be associated with higher risk for injury (15 ).These results are difficult to interpret because of possible survivor effects (e.g., injured runners cease to run).Because no comparable data in civilian populations of women exist, no conclusions can be drawn regarding the influence of previous regular physical activity as a protective factor against injury among women.Further research is needed regarding the influence of previous physical activities and exercise-related injury risk among women and men in both military and civilian populations. Current Level of Physical Fitness.A person's current level of physical fitness has been one of the most important predictors of injury in military studies (19)(20)(21)24,32,33,40 ).Of the five health-related components, low levels of aerobic fitness and, to a lesser extent, low muscular endurance have consistently been associated with injury risk during BT.Other factors (e.g., body composition and strength) demonstrated weaker and less consistent associations with injury risk. Aerobic fitness, as measured by timed performance of 1-to 2-mile runs during Army or Marine Corps physical fitness entry tests, has been the single most consistently and strongly associated intrinsic risk factor for subsequent training-related injury.During Army BT, women who scored in the slowest quartile on the initial entry physical fitness test experienced 1.5-1.7 times greater injury risk than women in the fastest quartile (21,36 ) (Table 4).Findings were similar for women in Marine Corps BT: women in the slowest quartile experienced 2.4 times greater risk for injury than women in the fastest quartile.Women and men with the slowest run times (i.e., least aerobically fit) were consistently at greater risk for injury than those with the fastest run times (i.e., most aerobically fit).Comparable trends were documented among female Army cadets at West Point Academy, New York (24 ).Among men, the inverse relation of aerobic fitness and injury risk is similar to that of women.Male trainees with slower run times were at greater risk for injury than those who ran the fastest (20,36 ). In addition to being at greater risk for injury, women who had the slowest run times experienced 2.5 times the risk of stress fractures and stress reactions compared with women who had faster run times (20,32 ).Similar findings were documented among women in Marine Corps BT (20,40 ).Researchers demonstrated that the least aerobically fit and least physically active trainees were 3.5 times more likely than persons who were the most fit and most active to sustain a stress fracture (23 ). A prospective study of Army trainees in BT demonstrated an association between maximal oxygen consumption (ml O 2 per kg body weight per minute), which is a measure of aerobic fitness, and subsequent risk for injury.Maximal oxygen consumption (VO 2 max) was measured in trainees running on a treadmill before the start of BT.For women in successive tertiles of VO 2 max, risk for injury increased from 39% in the highest tertile to 50% in the middle tertile, to 55% in the lowest.Similarly, men with the lowest VO 2 max were at greatest risk for injury (36).Prospective studies among civilians examining the association between aerobic fitness and injury are not available.Military research suggests that higher levels of baseline physical fitness is protective, at least at the start of a training program.Further research is needed to determine the degree and duration of this protection. # MMWR March 31, 2000 Higher levels of muscular endurance and strength can also be protective against injury in military BT.For both women and men, greater muscular endurance (measured by the number of push-ups completed in 2 minutes) was associated with fewer training-related injuries (20 ).When categorized into quartiles, risk for injury decreased for women who could do more push-ups.The cumulative incidence of injury was 57% for women who completed the least number of push-ups in 2 minutes and 38% for women who did the most push-ups.Similarly, Army women who could not lift >34 kg had RR for injury of 1.4 compared with women who could lift >46 kg (20 ). The relation of body composition to exercise-related injury risk is complex.Some studies indicate no association between body composition and exercise-related injury risk (20,36 ).When an association between measures of body fat and injury incidence for women in Army BT has been identified, the relation has been bimodal (U-shaped).Women with the least and the most body fat were at greater risk for injury (21,32,40 ).Among women in Army BT, the risk for injury varies by body mass index (BMI).To obtain BMI, weight in kilograms is divided by height in meters squared (weight / ).The cumulative incidence of injuries in successive quartiles of increasing BMI were 56% (lowest quartile), 46%, 38%, and 63% (highest quartile).The corresponding RRs were 1.5, 1.2, 1.0, and 1.6, respectively.BMI for women ranged from 18 kg/m 2 to 27 kg/m 2 (32 ).A study of civilian male distance runners demonstrated a statistically significant bimodal relation between BMI and injury (16 ).A study of civilian female runners indicated a statistically not significant but also bimodal relation between BMI and injury (15 ).Additional research is needed to better determine the relation # MMWR 27 between body fat, BMI, and incidence of injury; these studies should control for physical fitness and previous physical activity. # The Relation Between Sex and Level of Physical Fitness The observation that low levels of physical fitness on entry into BT is related to injuries during BT is particularly relevant to the issue of injuries among women.The incidence of injuries among women in Army BT is consistently 1.6-2.1 times higher than the incidence for men in Army BT.However, several studies also document that on entry into the Army, women are less physically fit than men (20,21,32,35,43 ).On average, women have slower run times, perform fewer push-ups, and have a higher percentage of body fat than men. What would be the effect of controlling for level of fitness when making comparisons between men and women?In several studies, injury risks were stratified by quartiles or quintiles of run times to enable comparison of groups of women and men who performed similarly on the initial-entry physical training test (20,32,35,43 ).In these studies, initial RRs of injury for women were higher than for men, with RRs ranging from 1.6 to 2.1.However, when stratified by aerobic fitness (run times), the stratumspecific risk ratios all approached 1.0, and the summary risk ratios declined (range = 0.9-1.2).In a logistic regression model that controlled for physical fitness (i.e., run times, numbers of push-ups and sit-ups, and strength), age, and race, the odds ratio for women versus men was 1.1 (20,43 ).Slower run times were the only component of fitness associated with increased odds of injury.Odds of injury progressively increased for successive quintiles of run time from fastest to slowest: 1.0, 1.4, 1.5, 2.5, and 3.2, respectively.In another logistic regression model, female sex was initially a risk factor, with an odds ratio of 2.5 for women compared with men, until run time was entered into the model.When corrected for run times, the odds ratio for females declined to 1.0; however, run time remained a significant predictor (32 ).These findings suggest that the most important underlying risk factor for injuries among military trainees engaged in vigorous aerobic weight-bearing activities (e.g., running and marching) is aerobic fitness level and not female sex (33,43 ).Studies that compare injury risks between men and women with similar fitness levels have not been conducted in civilian populations. Because the findings in this report are derived from studies of special populations (e.g., runners and military trainees), they might not be generalizable to other U.S. populations.A review of the studies in these special populations provides guidance toward establishing general principles that will be valuable in preventing injuries and guiding research in the general population. # RECOMMENDATIONS FOR PREVENTION Scientific research regarding injuries related to physical training and exercise has focused on men rather than women, on military trainees rather than physically active civilians, and on competitive rather than recreational athletes.In addition, the studies of military populations generally involve a young, healthy population.Studies of recreational athletes in the civilian population are difficult to conduct and might not be able to completely control for the frequency, duration, and intensity of activity, as is possible in studies of military populations.In addition, measures of current physical fitness might be difficult to obtain. # MMWR March 31, 2000 Based on the limited scientific research regarding physical activity, exercise, and injuries among women and generally agreed on "best practices," the following recommendations are made to reduce the risk of exercise-related injury among women: - Although most healthy women do not need to visit their physician before starting a moderate-intensity exercise program, women aged >50 years or women who have either a chronic disease or risk factors for a chronic disease should consult their physician to ensure that their exercise program is safe and appropriate. - The choice of an exercise program should be tailored to a woman's current physical fitness level.Resources that include examples of activities categorized by exercise intensity levels are available and can aid women in choosing activities based on their respective physical fitness levels. - Decisions regarding the frequency, duration, and intensity of exercise should be individualized, based on the woman's current level of physical fitness, history of physical activity, and history of injury. - Women, particularly those with lower fitness levels, should begin participating in exercise at a lower level of training (frequency, duration, and intensity) and progress slowly.Women who are sedentary and start a new exercise program or activity might need to begin with intervals of activity as short as 5-10 minutes of light-intensity activity and gradually increase to the desired intensity and/or duration of participation. - Participants should be aware of early signs of potential injury (i.e., increasing muscle soreness, bone and joint pain, excessive fatigue, and performance decrements).Coaches, personal trainers, and instructors should be alert to these signs among the women they are supervising.
- When a participant senses any of the warning signs (i.e., increasing muscle soreness, bone and joint pain, excessive fatigue, performance decrements, or current injury), she should incrementally decrease training (i.e., reduce frequency, duration, or intensity) until symptoms diminish or cease participation temporarily, depending on the severity of injury. - Women who sustain a musculoskeletal injury should allow sufficient recovery and rehabilitation time and take precautions to prevent reinjury. - Women who smoke should be informed that smoking might increase their risk for exercise-related injury.They should make every effort to stop smoking, not only to reduce their risk for injury, but also to enhance their long-term overall health. - Women should be realistic in setting their exercise goals by balancing the desire for measurable weight reduction, increases in endurance or strength, or other health-related fitness benefits with the risk for injury. # MMWR 29 RESEARCH AGENDA # Research Needs This report provides an overview of the relation between extrinsic training factors, selected intrinsic factors, and musculoskeletal injury risks during exercise.Some research exists regarding exercise-related injury risk factors among military or elite athletic populations; however, little research has been conducted among other physically active populations.Even less research specifically addresses the particular risks to women who exercise.These gaps in current knowledge limit the specificity with which recommendations can be made.Future research is needed to identify methods of promoting physical activity while preventing or reducing the risk for injury.As researchers continue to define the benefits of regular exercise, the following suggestions might help develop complementary research regarding injury risks: Surveillance systems need to be developed to monitor physical fitness, health, injury, and other medical outcomes of physical activity and exercise.Questions regarding exercise-related injuries need to be incorporated into existing surveillance instruments that monitor physical activity participation levels.Measures of exposure in physical activity (i.e., frequency, duration, and intensity) by sex, age, and activity should be incorporated into data-gathering systems to better characterize population-based injury risks. Research regarding the etiology of exercise-related injuries is needed to determine the incidence of and risk factors for injuries in common exercise activities (e.g., walking, hiking, bicycling, and aerobic dance) and active sports (e.g., tennis, racquetball, basketball, and soccer) for women.Identification of the amount (i.e., frequency, duration, and intensity), type (e.g., jogging, walking, biking, and dancing), and progression of exercise that is appropriate for women of differing physical fitness levels and body composition is needed to maximize fitness while minimizing injury risk.To prevent overuse injuries among women, the appropriate amounts and balance of training and recovery for different types of exercise and activity need to be determined.In addition, sex-specific exercise-related injury risks need to be determined to guide the choices women make regarding exercise.These risks include but are not limited to a) anterior cruciate ligament rupture, b) stress fractures, c) pregnancy and postpartum injury risks, and d) risks (and benefits) of exercise in older women and women with osteoporosis. Conducting longitudinal intervention trials to monitor injury occurrences while measuring changes in fitness is essential for developing and evaluating injury reduction measures.Determination of the long-term effects of exercise-related injuries on health outcomes (e.g., osteoarthritis, late or chronic sequelae, and disability) and future exercise participation is needed because a decrease in physical activity might increase the risk for chronic diseases.Finally, to document the impact of exercise-related injury and the importance of further research, the economic and social costs of exercise-related injury and any resultant nonadherence to exercise regimens need to be determined. # MMWR March 31, 2000 CONCLUSION Persons who participate in vigorous exercise might incur a higher number of musculoskeletal injuries than more sedentary persons.However, several intrinsic and extrinsic factors interact to modify the risk for incurring an exercise-related injury.For activities other than running and military training, little data are available regarding the incidence or risk factors for such injuries.The data suggest that a combination of factors (e.g., sex, current level of fitness, previous exercise experience, smoking, previous injury, and body composition) might affect the risk for exercise-related injury in women.However, how these factors act singly and in combination to influence injury risk is not well understood.The following conclusions might help in the development of further research regarding the relation between exercise and the risk for injury: - The most important risk factors for exercise-or training-related injuries are the frequency, duration, and intensity of the physical training activity.The total amount of exercise (e.g., the frequency, duration, and intensity) is the most consistently identified predictor for injury risk. - Physical fitness is inversely related to injury risk; as physical fitness level increases, risk for injury decreases.Men and women who participate in the same activities and have the same physical fitness levels generally have similar incidences of injury.Thus, physical fitness rather than female sex is the underlying risk factor. - A dose-response relation exists between the amount of weight-bearing exercise performed and the risk of injury for both women and men. - A training threshold exists, above which increased training does not appreciably increase fitness but will substantially increase risk for injury.This threshold might be different for each person. - Although higher current amounts of exercise or physical activity are risk factors for injury because of increased exposure, at any fixed amount of activity, men with a history of higher amounts of physical activity are at lower risk for injury.For women, the relation is unclear. - At any given amount of aerobic weight-bearing activity, women and men who have the highest aerobic fitness levels can be expected to have lower subsequent injury rates. - The combined findings of research regarding the association of training, previous physical activity, and current physical fitness levels suggest that tailoring exercise to accommodate a person's current level of fitness and previous physical activity reduces injury rates.Changes in frequency, duration, or intensity of exercise can have cumulative effects on injury risk.These findings are particularly important for persons who are the least fit or most sedentary because they are at the greatest risk for injury when initiating physical activity. - The protective effect against injury of higher levels of aerobic fitness provides an incentive to become more physically active.It suggests that incremental increases in fitness are beneficial in terms of increasing health benefits and decreasing injury risks. - The relation between previous injuries and higher risk for subsequent exerciserelated injuries provides some indication of the importance of a) recovery and rehabilitation and b) consideration of the history of previous injuries when planning exercise programs. - The association between smoking tobacco and higher exercise-related injury risks suggests another possible reason to discourage smoking, both for injury reduction in the short-term and increased overall health benefits in the longterm. - Although the association of body composition with exercise-related injury risks is not completely clear, the bimodal relation that exists suggests that proper maintenance of body weight in the normal range (i.e., BMI 18.5 kg/m 2 -24.9 kg/m 2 ) is important not only for health and appearance but also to reduce risks for injury. Further research is needed to answer many of the remaining epidemiologic questions and to help develop exercise programs for women that improve health while reducing the risk for injury. # Implementing Recommendations for the Early Detection of Breast and Cervical Cancer Among Low-Income Women Abstract Scope of the Problem: Among U.S. women, breast cancer is the most commonly diagnosed cancer and remains second only to lung cancer as a cause of cancer-related mortality.The American Cancer Society (ACS) estimates that 182,800 new cases of female breast cancer and 41,200 deaths from breast cancer will occur in 2000.Since the 1950s, the incidence of invasive cervical cancer and mortality from this disease have decreased substantially; much of the decline is attributed to widespread use of the Papanicolaou (Pap) test.ACS estimates that 12,800 new cases of invasive cervical cancer will be diagnosed, and 4,600 deaths from this disease will occur in the United States in 2000.Etiologic Factors: The risk for breast cancer increases with advancing age; other risk factors include personal or family history of breast cancer, certain benign breast diseases, early age at menarche, late age at menopause, white race, nulliparity, and higher socioeconomic status.Risk factors for cervical cancer include certain human papilloma virus infections, early age at first intercourse, multiple male sex partners, a history of sexually transmitted diseases, and low socioeconomic status.Black, Hispanic, or American Indian racial/ethnic background is considered a risk factor because cervical cancer detection and death rates are higher among these women.Recommendations for Prevention: Because studies of the etiology of breast cancer have failed to identify feasible primary prevention strategies suitable for use in the general population, reducing mortality from breast cancer through early detection has become a high priority.The potential for reducing death rates from breast cancer is contingent on increasing mammography screening rates and subsequently detecting the disease at an early stage -when more treatment options are available and survival rates are higher.Effective control of cervical cancer depends primarily on early detection of precancerous lesions through use of the Papanicolaou test, followed by timely evaluation and treatment.Thus, the intended outcome of cervical cancer screening differs from that of breast cancer screening.In 1991, the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) was implemented to increase breast and cervical cancer screening among uninsured, low-income women.Research Agenda: To support recommended priority activities for NBCCEDP, CDC has developed a research agenda comprising six priorities.These six priorities are a) determining effective strategies to communicate changes in NBCCEDP policy to cancer screening providers and women enrolled in the program; b) identifying effective # INTRODUCTION Although the causes and natural histories of breast and cervical cancer are different, the public health responses to these diseases have been similar.Early detection of breast cancer and primary prevention of cervical cancer are possible through community-based screening programs; however, early detection of both breast and cervical cancer is less common among low-income- women (1 ).This report presents morbidity and mortality data regarding breast and cervical cancer, screening recommendations, an update on the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), and recommended priority activities for NBCCEDP.NBCCEDP is a major public health effort to increase breast and cervical cancer screening among uninsured, low-income women. # SCOPE OF THE PROBLEM Breast Cancer Among women in the United States, breast cancer is the most commonly diagnosed cancer and remains second only to lung cancer as a cause of cancer-related death.The American Cancer Society (ACS) estimates that 182,800 new cases of female breast cancer and 41,200 deaths from breast cancer will occur in 2000 (2 ).In 1996, data from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) Program † indicated that the incidence of breast cancer increased 25.3% during 1973-1996 (Figure 1).Most of the increase occurred during 1973-1991; incidence rates remained stable during 1992-1996.In 1996, the incidence rate for breast cancer was 110.7 cases per 100,000 women, a 29.6% increase since 1980.In addition, in 1996, the case-fatality rate for breast cancer was 24.3 per 100,000 women, a 4.5% decrease since 1992, representing the first sustained decline in breast cancer-related mortality since 1973 (when SEER surveillance for breast cancer began).Although the percentage increases in incidence during 1973-1996 were similar among black and white women, the percentage decrease in mortality during 1992-1996 was substantially greater among white women than black women (3,4 ). Overall during 1992-1996, breast cancer incidence rates were higher among white women (113.1 per 100,000) than black women (100.3), but breast cancer death rates were lower among white women (25.1) than black women (32.0).Furthermore, these race-specific differences in rates varied by age.Among women aged <50 years, the incidence rate for black women (32.7) was higher than that for white women (31.1).Among women aged ³50 years, the rate was higher for white women (365.8) than for black women (308.7).The death rate among women aged <65 years was higher for black women (20.4) than for white women (14.3).Although the death rate among women aged ³65 years was higher for white women than for black women before 1987, recent data indicate that the death rate among this age group is higher for black women (130.9) than for white women (124.0) (4,5 ).On the basis of SEER data for 1988-1992 (most recent data available), incidence rates were highest for white (145.7), Hawaiian (105.6), and black women (95.4) and lowest for Korean (28.5), American Indian (31.6), and Vietnamese (37.5) women.Incidence rates among white, non-Hispanic women were four times higher than among Korean women (3 ). # MMWR March 31, 2000 Stage-specific survival rates among women with breast cancer have increased slightly since the 1970s (6 ).The overall 5-year survival rates for women during 1989-95 were 86% for white women and 71% for black women (4 ).Survival was greatest at the earliest stage of disease.Age-specific survival rates were similar for white and black women.One explanation for the disparity in race-specific survival rates is that white women, on average, seek medical care for tumors at an earlier stage of disease than black women.However, the interim between symptom recognition and medical consultation does not appear to account for these race-specific differences in survival rates or stage at diagnosis of breast cancer (6 ).Limited data are available regarding survival for other ethnic groups in the United States.In a study of stage at diagnosis and tumor histology among white and Asian women, the 5-year survival rate at all stages was higher among Asian women than among white women (7 ).In addition, based on data from another study, the survival rate among Hispanic women is similar to the rate among white women in the United States (8 ). # Cervical Cancer Since the 1950s, the incidence of invasive cervical cancer and mortality from this disease have decreased substantially.In large part, the decline has been attributed to widespread use of the Papanicolaou (Pap) test -a highly effective preventive measure.However, the rate of decline in invasive cervical cancer has slowed since the early 1980s and appears to have stabilized in recent years (Figure 2).ACS projects that approximately 12,800 cases of invasive cervical cancer will be diagnosed and that approxi- (2 ).During 1992-1996, the incidence rate at SEER sites was 7.9 cases per 100,000 women, and the death rate for cervical cancer was 2.8 per 100,000 women (4 ). On the basis of SEER data, both incidence and death rates for cervical cancer vary among racial/ethnic groups.The incidence rate for cervical cancer is highest among Vietnamese women (43.0), and the death rate for cervical cancer is highest among black women (6.7) (3 ).The incidence rate among black women (11.2 per 100,000) is approximately 50% higher than among white women (7.3) (3,4 ).Death rates among black women (5.9) are approximately twice as high as those among white women (2.4).Although the disparities in rates between blacks and whites have declined since 1990, differences in rates persist.This persistent disparity has been attributed to several factors, including differences in the prevalence of risk factors for cervical cancer; differences in screening, diagnostic evaluation, and treatment; and differences in the stage of disease at diagnosis (9 ).Race-specific differences in incidence and death rates for cervical cancer also varied by age (4 ).During 1992-1996, among women aged 40 years than for white women the same age.Regardless of race, most cervical cancer deaths occur among women aged ³50 years (4 ). For women in whom invasive but localized (i.e., Stage I) cervical cancer has been diagnosed, the 5-year relative survival rate is approximately 90% (4 ).In contrast, for women with advanced invasive cervical cancer (beyond the cervix and pelvis ), the 5-year relative survival rate is approximately 12%.As with breast cancer, diagnosis of invasive cervical cancer in black women usually occurs at a later stage of disease compared with white women.Moreover, 5-year relative survival rates for local and regional stages are lower for blacks than for whites. # ETIOLOGIC FACTORS # Breast Cancer The risk for breast cancer increases with advancing age.Other risk factors include personal or family history of breast cancer, history of certain benign breast diseases, early age at menarche, late age at menopause, exposure to ionizing radiation, obesity, white race, nulliparity, late age at first birth, nodular densities on mammogram, higher socioeconomic status, and residence in urban areas of the northern United States (6,10 ).Less clearly established risk factors include the duration between menstrual periods, use of oral contraceptives, use of replacement hormones (estrogen), height, alcohol consumption, and not breast-feeding. Studies of immigrants to the United States suggest that environmental factors rather than genetic factors are responsible for variations in breast cancer rates among countries.For example, the rate of breast cancer among first-generation Japanese-American women is only slightly higher than the rate among their mothers, but the rate among their daughters is considerably higher (6 ).No primary prevention measures suitable for use in the general population have been established for breast cancer.Preliminary results from clinical trials among highrisk women regarding the use of the drug tamoxifen indicate a 45% decline in incidence from its use (11 ).Although side effects and potential development of other neoplasms are associated with tamoxifen use, other medications in its class might offer even greater benefits in breast cancer treatment.The Study of Tamoxifen and Raloxifene (STAR) trial is under way to evaluate tamoxifen versus raloxifene and the potential for reducing the incidence of breast cancer in high-risk postmenopausal women.
# Cervical Cancer The risk for cancer of the cervix has been associated with several factors, including infection with certain types of human papilloma virus (HPV), early age at first intercourse, multiple male sex partners, a history of sexually transmitted diseases, smoking, certain nutritional deficiencies, and low socioeconomic status (12 ).HPV is widely accepted as the cause of most squamous cell cervical cancers, and the sexual practices listed are well-established risk factors for the disease; however, the role of other demographic and behavioral factors is less clear.Black, Hispanic, or American Indian race/ ethnicity is considered a risk factor for cervical cancer because rates of detection and death from cervical cancer are higher among these women (13 ).However, some of the racial/ethnic differences in cervical cancer rates can be explained by the strong inverse association between socioeconomic indicators and the risk for invasive cervical cancer (13 ).This increased risk could be associated with differences in access to care and cultural behavior. # RECOMMENDATIONS FOR PREVENTION # Breast Cancer Studies of the etiology of breast cancer have failed to identify feasible primary prevention strategies suitable for use in the general population.Many established risk factors for the disease are neither environmental nor behavioral and, therefore, are not amenable to prevention.Most of the hypothesized behavioral factors are not fully accepted as risk factors and are typically difficult to alter at the individual level.For these reasons, reducing mortality from breast cancer through early detection has become a high priority.The potential for reducing death rates from breast cancer is contingent on increasing initial and repeat mammography screening rates and subsequently detecting the disease at an early stage -when more treatment options are available, and survival rates are higher. Mammography is the most effective method of detecting breast cancer in its earliest and most treatable stage (14 ).Mammography is a low-dose X-ray procedure that visualizes the internal structure of the breast to detect cancers too small to be palpated during a clinical breast examination (CBE) performed by a health-care provider.Mammography detects cancer before the woman can palpate the lump herself.Cancers detected at a small size are more likely to be localized (i.e., not spread to regional lymph nodes or distant body sites). The sensitivity of mammography (75%-94%) is higher than comparable values for CBE alone or breast self-examination (14,15 ).The specificity of mammography (i.e., the likelihood that a mammogram will correctly indicate that breast cancer is not present) is also high (83%-98%) (14,15 ).Widespread use of this procedure, alone or with a CBE performed by a trained health-care provider, can reduce overall mortality from breast cancer (14,16 ).Since the 1970s, scientific studies have demonstrated that regular screening mammograms among women aged 50-69 years can reduce mortality from breast cancer by 30% (14,(17)(18)(19).However, evidence is not as conclusive for women aged 40-49 years and ³70 years (14 ). The ability of mammography to identify breast cancer at an early stage improves the opportunity for effective treatment and survival.Women in whom localized/Stage I disease has been diagnosed have a 5-year relative survival rate of 94% (4 ).In comparison, women with disease spread beyond regional lymph nodes have a 5-year relative survival rate of only 18.2%.Treatment at this late stage is substantially less effective, as well as more debilitating. # Breast Cancer Screening Guidelines Recommended by Various Groups Annual breast cancer screening for women aged ³50 years is widely recommended.In addition, screening is recommended for women aged 40-49 years; however, consensus has not been reached regarding the effectiveness of screening or the optimal interval for screening in this age group (20 ).Several review groups have reached different conclusions about the efficacy of mammography among younger women because of the limitations of studies conducted among women in this age group.These limitations include small sample sizes and limited duration of follow-up after entry into the screening programs (21 ). In 1996, the U.S. Preventive Services Task Force (USPSTF) recommended that women aged 50-69 years receive routine breast cancer screening every 1-2 years using mammography alone or mammography combined with annual CBE (14 ).USPSTF noted that insufficient evidence exists to recommend or not recommend routine mammography or CBE for women aged 40-49 years and ³70 years.Moreover, insufficient evidence exists to recommend CBE alone or teaching breast self-examination.In addition, USPSTF noted that recommendations for mammography among high-risk women aged 40-49 years and among healthy women aged ³70 years might be made on other grounds. In 1997, a National Institutes of Health Consensus Development Conference panel reviewed new data not previously available to USPSTF, which documented mortality benefit from mammography among women aged 40-49 years (22 ).However, the panel concluded that these data did not warrant a universal recommendation for mammography for women aged 40-49 years.As a result, the panel encourages these women to determine for themselves whether to receive mammography on the basis of objective analysis of scientific evidence, individual health history, and perceived risks and benefits (20 ). Because mortality can be reduced among women aged 40-49 years, in 1997 the National Cancer Institute (NCI) accepted new guidelines for mammography screening recommended by the presidentially appointed National Cancer Advisory Board.These guidelines recommend that all women aged ³40 years receive mammography every 1-2 years to achieve the best possible outcome if breast cancer is detected (22 ). # Prevalence of Breast Cancer Screening Data collected through CDC's 1997 Behavioral Risk Factor Surveillance System (BRFSS) indicate that 85% of all interviewed women aged ³40 years had ever received a mammogram (23 ).The percentage of low-income women and women without health insurance who had ever received a mammogram was comparable (77% and 69%, respectively).The percentage of all interviewed women aged ³40 years who had received a mammogram within the preceding 2 years was 71%.Rates for low-income women and women without health insurance were substantially lower (58% and 50%, respectively). A Healthy People 2000 objective is to increase to at least 80% the proportion of women aged ³40 years who have ever received a CBE and a mammogram, and to at least 60% those aged ³50 years who have received them within the preceding 1-2 years (objective 16.11) (24 ).Although 1997 BRFSS data indicate the goal has been attained for all women interviewed aged ³40 years who had ever received a mammogram, progress is still needed to attain the goal for low-income women and women without health insurance. # Cervical Cancer Effective control of cervical cancer depends primarily on early detection of precancerous lesions through use of the Pap test, followed by timely evaluation and treatment.The Pap test is probably the most successful screening test ever developed to detect a cancer.Although the efficacy of cervical cancer screening using the Pap test has not been evaluated in clinical trials, at least two factors support the positive impact of this screening test: a) evidence from many observational studies and b) the marked decline in cervical cancer incidence and death rates in the United States and other countries since the introduction of the Pap test >40 years ago (14,25 ). In the United States, approximately 50 million Pap tests are performed annually (26 ).Approximately 10% of these tests indicate an abnormality requiring further testing.Detection and treatment of precancerous cervical intraepithelial neoplasia (CIN) lesions identified by the Pap test can prevent cervical cancer.Thus, the intended outcome of cervical cancer screening differs from breast cancer screening.The primary goal of cervical cancer screening is to detect and treat CIN to prevent the occurrence of invasive cancer.For women in whom CIN lesions have been detected, the likelihood of survival is nearly 100% with appropriate evaluation, treatment, and follow-up. # Cervical Cancer Screening Guidelines Recommended by Various Groups The American College of Obstetricians and Gynecologists (ACOG) and ACS recommend that women have a Pap test and pelvic examination when they become sexually active or at age 18 years, whichever occurs first (13 ).Annual Pap tests are recommended until three consecutive Pap tests are interpreted as being normal.Following this, the two groups recommend that Pap tests can be performed less frequently at the discretion of the provider (13 ). In 1996, USPSTF recommended routine screening for women who are or who have been sexually active and who have a uterine cervix (14 ).The task force recommends Pap tests with the onset of sexual activity and repeated screening every 3 years.A reduced interval between screenings can be recommended by the physician on the basis of a woman's risk factors for cervical cancer.In addition, USPSTF recommends that, on the basis of existing evidence, Pap screening might not be necessary for women after age 65 years.Moreover, USPSTF recommended not performing Pap tests on women who have undergone total hysterectomies for diseases unrelated to cervical cancer or its precursors (14 ). In recent years, several studies have been conducted to determine the value of expanding HPV testing from testing only women with abnormal Pap test results to routinely testing all women to detect those women at greatest risk for developing CIN or invasive cervical cancer.Evidence from these studies does not support routine HPV testing to screen for cervical cancer (26 ).Although new cervical cancer screening technologies have been approved for primary screening, professional organizations have not endorsed their widespread use because of concerns about cost effectiveness. An increasing concern is that rescreening the same women annually will not result in further reductions in cervical cancer mortality (27 ).Increased effort is needed to target groups with large proportions of unscreened or rarely screened women, including women residing in rural areas; minorities; and recent immigrants who have different attitudes, knowledge, and behaviors regarding disease prevention and health promotion.Screening for cervical cancer among these women could further reduce the burden of disease from cervical cancer. # Prevalence of Cervical Cancer Screening The 1997 BRFSS documented that 93% of women aged ³18 years with a uterine cervix reported ever having received a Pap test (23 ).Corresponding values for lowincome and uninsured women were 89% and 85%, respectively.Among all women with a uterine cervix, 80% had obtained a Pap test within the preceding 2 years.For low-income women and uninsured women, the proportion who had obtained a Pap test was substantially lower (69% and 65%, respectively). A Healthy People 2000 objective is to increase to at least 95% the proportion of women aged ³18 years with a uterine cervix who have ever received a Pap test, and to at least 85% those who have received a Pap test within the preceding 1-3 years (objective 16.12) (24 ).Although 1997 BRFSS data indicate the goal for women aged ³18 years with a uterine cervix who reported ever having received a Pap test is near attainment, progress is still needed, as with breast cancer screening, to attain the goal for lowincome women and women without health insurance. Low income and lack of health insurance are barriers to both cervical and breast cancer screening.These factors increase the likelihood that these diseases will be diagnosed at a later stage, when survival rates are lower (1 ). # Implementation of the National Breast and Cervical Cancer Early Detection Program In August 1990, Congress enacted the Breast and Cervical Cancer Mortality Prevention Act, thereby authorizing CDC to establish a national public health infrastructure to increase breast and cervical cancer screening among low-income women who are uninsured (28 ).Consequently, CDC established the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a comprehensive women's health initiative imple-mented through cooperative agreements with qualifying health agencies (including state and territorial health departments and American Indian/Alaska Native tribes and tribal organizations).In addition to providing breast and cervical cancer screening, participating programs provide diagnostic testing, surveillance and follow-up, case management, public education and outreach, professional education and training, quality assurance of screening tests, coalition and partnership development, and program evaluation.NBCCEDP-sponsored programs have initiated outreach efforts to serve women in high priority groups (e.g., women with increased risk for breast or cervical cancer and women who do not or rarely access breast and cervical cancer screening), including older women, racial/ethnic minorities, foreign-born women, women with disabilities, lesbians, and women residing in rural or other hard-to-reach areas. Fiscal year (FY) 2000 marked the 10th year of the NBCCEDP, with Congressional appropriations of $167 million.CDC provides funds to all 50 states, six U.S. territories, the District of Columbia, and 15 American Indian/Alaska Native tribes and tribal organizations to implement comprehensive screening programs for breast and cervical cancer (29 ). During the reporting period July 1991-March 1999, approximately 2.2 million screenings for breast and cervical cancer were provided to uninsured women.The program supported 1,049,752 mammograms: 64% of the mammograms were provided to women aged ³50 years; 48% were provided to racial/ethnic minorities (Figure 3).Breast cancer was diagnosed in 6,265 women aged ³40 years.Although the rate of abnormalities detected by a mammogram was highest for younger women, the rate of breast cancers detected per 100,000 mammograms increased directly with advancing age (Figure 4).A total of 1,192,346 Pap tests were performed: 72% of the tests were provided to women aged ³40 years; 47% were provided to racial/ethnic minorities (Figure 5).Cervical intraepithelial neoplasia was detected in 34,046 women.Invasive cervical cancer was diagnosed in 561 women.The rate of abnormal Pap tests varied inversely with age. # Policy of NBCCEDP As NBCCEDP has evolved, the program has addressed many challenges, especially regarding screening recommendations and treatment resources for women in whom precancerous cervical lesions or cancer of the breast or cervix has been diagnosed through NBCCEDP.FY 2000 Congressional appropriations will enable NBCCEDP to screen approximately 12%-15% of the eligible uninsured women aged 50-64 years in the United States (30 ).The remaining unmet need and the absence of funding to cover treatment expenses for women who have received a diagnosis of precancerous cervical lesions or breast or cervical cancer have been persistent challenges to the program.A key public health priority of NBCCEDP is to direct program resources to eligible women who have rarely or have never received breast or cervical cancer screening.To address this priority and maximize efficient use of limited resources, the program has developed cancercontrol policies on the basis of programmatic data, current scientific research, and availability of screening services through other government-supported programs (e.g., Medicare and Title X Family Planning programs). # Breast Cancer Screening Policies Following implementation of NBCCEDP in 1991, CDC encouraged NBCCEDPsponsored programs to place a high priority on screening women aged ³50 years.NBCCEDP data indicated that only 57% of their mammograms were provided to women aged ³50 years.In October 1994, CDC established the first age-specific targets for the breast cancer screening component of NBCCEDP.For 1995, 75% of the mammograms were to be provided to women aged ³50 years.The percentage was gradually increased to 90% by October 1998.A review of NBCCEDP mammography screening data in 12month intervals indicated that, since 1994, programs had screened increasing numbers of women aged ³50 years for breast cancer; however, the age-specific percentage goals had not been attained.For example, the percentage of initial mammograms provided to women aged ³50 years for the reporting period October 1996-September 1997 was 74%. In 1998, NBCCEDP mammogram screening policy was revised in response to new scientific research, recent changes in recommendations by NCI and ACS, changes in Medicare preventive services coverage, and the need to establish a more realistic national target based on historical programmatic screening data.The new NBCCEDP policy is to provide at least 75% of mammograms to women aged ³50 years who are not eligible to receive Medicare Part B benefits or are unable to pay the premium to enroll in Medicare Part B. Correspondingly, no more than 25% of mammograms should be provided to women aged <50 years.As a result of this new policy, some participating health agencies have developed strategies to cover breast cancer screening for women aged 40-49 years.Several programs have obtained breast cancer screening resources for these women from state appropriations or tobacco tax revenues and through collaborative efforts with foundations (e.g., the Susan G. Komen Breast Cancer Foundation).During October 1997-September 1998, 75% of NBCCEDP-sponsored mammograms were provided to women aged ³50 years. # Cervical Cancer Screening Policies The primary purpose of the cervical cancer component of NBCCEDP is to identify and treat precancerous cervical lesions and to detect and treat invasive cervical cancer at an early stage.When the program was established in 1991, CDC implemented program guidelines for cervical cancer screening that were consistent with ACS guidelines.Women enrolled in NBCCEDP who were aged ³18 years, with an intact uterine cervix, were eligible for an annual Pap test and pelvic examination.After a woman has had three consecutive annual examinations with normal findings, Pap tests could be performed less frequently at the discretion of the woman and her health-care provider. In 1999, CDC, in consultation with an external work group comprising clinical experts, epidemiologists, and public health practitioners, reexamined NBCCEDP's cervical cancer screening policy and other emerging issues related to Pap testing.One of the key issues addressed by this work group was recommendations for Pap screening intervals. ACOG's and ACS's recommendations regarding the frequency of screening are similar and advise that after a woman has had three consecutive annual examinations with normal findings, the Pap test can be performed less frequently at the discretion of the woman's provider.Scientific data suggest that once a woman has demonstrated no signs of CIN, as evidenced by three consecutive annual Pap tests with normal findings, her chance of developing CIN II or worse within a 3-year period is extremely low, regardless of other risk factors (31 ).Preliminary analysis of NBCCEDP data supports these findings (CDC, unpublished data, 2000).
Beginning in March 2000, NBCCEDP-sponsored programs will be required to direct more cervical cancer screening resources to women who have never had a Pap test or who have not had a Pap test for at least 5 years.Among all women screened, at least 20% should be women who have either never been screened or have rarely been screened (i.e., not screened for ³5 years).Programs are also being required to reduce over-screening among program-enrolled women.Beginning in October 2001, programs will be required to document that at least 75% of women with three consecutive annual Pap tests with normal findings did not receive a fourth annual Pap test.Their screening interval will be changed to every 3 years.To successfully implement this policy change, CDC will assist NBCCEDP-sponsored programs in assessing current program provider practices, modifying patient recall systems, and developing professional and public education strategies. # Breast and Cervical Cancer Follow-Up and Treatment Policy The policy issue that has caused the greatest controversy in NBCCEDP concerns the availability of funds to pay for treatment of cancerous or precancerous lesions diagnosed in enrolled women (28 ).A crucial component of NBCCEDP is to ensure that all women with abnormal screening results, precancerous breast or cervical lesions, or a diagnosis of cancer receive timely and appropriate follow-up care.Program providers receive reimbursement for most diagnostic procedures, including diagnostic mammography, breast ultrasound, fine-needle aspiration of the breast, breast and cervical biopsies, and colposcopy of the cervix.However, the Breast and Cervical Cancer Mortality Prevention Act of 1990 prohibits use of federal program funds for any component of breast or cervical cancer treatment primarily because of a concern that such payment would rapidly deplete resources available for screening services.NBCCEDP-sponsored programs are required to identify and secure resources for treatment from other sources. # MMWR March 31, 2000 In 1996, CDC conducted in-depth case studies of seven state programs to determine how early detection programs identified and obtained resources for treatment.The results indicated that state health agencies and their partners had developed a wide range of strategies for procuring treatment services in the absence of program resources.However, the study respondents considered the strategies used to obtain these services as short-term solutions that were labor intensive and that diverted resources away from screening activities (32 ). NBCCEDP surveillance data for October 1991-September 1998 indicate that 92% of the clients in whom breast cancer had been diagnosed and 93% of the clients in whom invasive cervical cancer had been diagnosed initiated treatment.The remainder either refused treatment, were lost to follow-up, or had an outcome pending.In FY 1999, CDC received increased Congressional appropriations to expand case-management activities to assist women in overcoming financial, logistical, and other barriers to obtaining these services. # Recommended Priority Activities for CDC The Breast and Cervical Cancer Mortality Prevention Act of 1990 has played an important role in focusing public health efforts on cancer control in the United States.Since 1991, CDC has collaborated with a diverse group of public and private partners to build the public health infrastructure, implement screening services, and conduct research activities.CDC will continue to foster these relationships to achieve goals set in the following four priority areas of screening initiatives, case-management services, professional education and training, and partnerships: # Screening Initiatives - Collaborate with NBCCEDP-sponsored programs to increase public education and outreach strategies to reach women who have rarely or have never received breast or cervical cancer screening. - Collaborate with NBCCEDP-sponsored programs to implement strategies among health-care providers to address missed opportunities for enrolling women into screening. - Collaborate with NBCCEDP-sponsored programs to implement strategies through professional groups and public education to modify screening intervals for all program-enrolled women who have had three consecutive annual Pap tests with normal findings. - Continue to promote the need for routine rescreening for breast and cervical cancer at regular intervals to improve rescreening rates for women enrolled in NBCCEDP. # Case-Management Services - Expand case-management activities to ensure that women enrolled in NBCCEDP receive timely and appropriate rescreening and diagnostic services and treatment services, if indicated. - Increase case-management activities to sustain networks and partnerships to maximize access to and availability of diagnostic, treatment, and essential support services for women enrolled in NBCCEDP.efforts should be, and what proportion of screening resources should be allocated to case-management activities. - Priority: Conduct economic analyses to determine costs of providing screening services in NBCCEDP.Because the funds appropriated by Congress to NBCCEDP are not adequate to screen all eligible women who need breast and cervical cancer screening, economic analyses are necessary to enhance efficient use of the available resources.Important issues include the potential cost advantages of high-volume versus low-volume laboratories and mammography facilities, the sustainability of facilities that are providing program-funded screenings below their current cost levels, and the costs and benefits of mammography vans compared with standard facilities. # CONCLUSION Breast and cervical cancer continue to be major health problems in the United States.Preventive measures are available to reduce morbidity and mortality associated with these diseases.The NBCCEDP, through federal, state, territorial, and tribal governments, in collaboration with national and community-based organizations, has increased access to breast and cervical cancer screening among low-income and uninsured women.In addition, NBCCEDP-sponsored programs have increased the staff working in cancer control and the expertise of these persons, implemented professional education programs for health-care providers, and developed innovative public education and outreach strategies to encourage medically underserved women to seek screening services.This national effort enabled the United States to make substantial progress toward achieving the Healthy People 2000 objectives for breast and cervical cancer control, particularly among racial/ethnic minorities and the medically underserved.However, NBCCEDP still reaches only 12%-15% of uninsured women aged 50-64 years who are eligible for screening services.A continuing challenge for the future is to increase national commitment to providing screening services for all eligible uninsured women to ultimately reduce morbidity and mortality from breast and cervical cancer. # INTRODUCTION Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii.In the United States, an estimated 23% of adolescents and adults have laboratory evidence of infection with T. gondii (1;CDC, unpublished data, 1994).Although these infections are usually either asymptomatic or associated with self-limited symptoms (e.g., fever, malaise, and lymphadenopathy), infection in immunosuppressed persons (e.g., persons with acquired immunodeficiency syndrome ) can be severe.In addition, infections in pregnant women can cause serious health problems in the fetus if the parasites are transmitted (i.e., congenital toxoplasmosis) and cause severe sequelae in the infant (e.g., mental retardation, blindness, and epilepsy).Although congenital toxoplasmosis is not a nationally reportable disease and no national data are available regarding its occurrence, extrapolation from regional studies indicates that an estimated 400-4,000 cases occur in the United States each year.In addition, of the 750 deaths attributed to toxoplasmosis each year, 375 (50%) are believed to be foodborne, making toxoplasmosis the third leading cause of foodborne deaths in this country (2 ). In 1997, the U.S. Department of Health and Human Services, the U.S. Department of Agriculture (USDA), and the U.S. Environmental Protection Agency (EPA) collaborated to develop the National Food Safety Initiative (3 ).The project aims to reduce the incidence of foodborne illness by enhancing surveillance, improving risk assessment, developing new research methods, and furthering food-safety education.Because congenital toxoplasmosis poses a substantial public health problem, CDC has developed prevention recommendations to reduce the risk for congenital infections. In September 1998, CDC convened the National Workshop on Toxoplasmosis: Preventing Congenital Toxoplasmosis (NWTPCT) in Atlanta, Georgia, to discuss research priorities for preventing the disease.Approximately 30 international and national experts in toxoplasmosis participated, representing universities, practitioner associations, research institutions, health-care centers, and other federal agencies.Specific objectives of NWTPCT included defining approaches for reducing the prevalence of congenital toxoplasmosis, determining the data needed to evaluate and implement these strategies, and identifying critical research and prevention efforts for the future.This report summarizes the recommendations from this workshop and the activities that have been undertaken by CDC in response to these recommendations.* # SCOPE OF THE PROBLEM # Burden of Toxoplasmosis in the United States Toxoplasmosis is not a nationally reportable disease in the United States, and no reliable data are available at the national level about the number of cases diagnosed each year.The most reliable information about the burden of toxoplasmosis in the general population is derived from serosurveys, which determine the percentage of persons with elevated levels of Toxoplasma-specific IgG antibodies. Since the 1960s, rates of infection with Toxoplasma in the United States appear to be declining.In the 1960s, a study of U.S. military recruits indicated that the overall seroprevalence of Toxoplasma was 14% (5 ).In 1989, a second study of military recruits indicated a seroprevalence of 9.6% (6 ).Similar downward trends have been observed in France and Sweden (7,8 ). The most reliable estimate of Toxoplasma seroprevalence in the United States is derived from the third National Health and Nutrition Examination Survey (NHANES III) (1 ), which was conducted during 1988-1994.The survey design was a cluster sample of U.S. residents.Serum samples from 17,658 persons were tested at CDC for Toxoplasmaspecific IgG antibodies; 23% were positive.Of 5,988 women of childbearing age (i.e., age 12-49 years), 14% were seropositive (CDC, unpublished data, 1994).No recent U.S. studies of a large population of pregnant women have been conducted to determine the incidence of new infections during pregnancy. Although serosurveys of the general population help define temporal trends in Toxoplasma seropositivity rates and can be used to estimate the number of women of childbearing age who are at risk for acquiring Toxoplasma infections and potentially transmitting it to their fetuses, serosurveys are less helpful in estimating the number of cases of congenital toxoplasmosis.Three prospective studies provide useful information regarding the number of congenital toxoplasmosis cases in the United States. Two prospective studies in the 1970s both reported rates of congenital toxoplasmosis of approximately 10 per 10,000 live births.In one study in the early 1970s, 7,500 consecutive live births at a hospital in Birmingham, Alabama, were screened for Toxoplasma infection; of these, 10 (13 per 10,000 live births) were seropositive (9 ).In a study of acute Toxoplasma infection in 4,048 pregnant women in New York during 1967-1969, six (0.2%) women seroconverted during their pregnancies, and 17 others (0.4%) had at least an eightfold rise in antibody titers during pregnancy (10 ).Of the 23 infants born to these 23 women, three had congenital toxoplasmosis, representing an infection rate of 7 per 10,000 live births in the study population. More recent data regarding the rate of congenital toxoplasmosis are available from the New England Regional Newborn Screening Program (11 ).All infants born in the catchment area of this program are tested for evidence of congenital toxoplasmosis; infected infants undergo clinical evaluation and treatment for 1 year.During 1986-1992, of 635,000 infants who underwent serologic testing, 52 were infected, representing an infection rate of approximately 1 per 10,000 live births.Only two (4%) of these infants were recognized to have congenital toxoplasmosis before the screening results were known; however, follow-up examinations of 19 (40%) of the 48 infants evaluated revealed signs of disease (e.g., abnormal cerebrospinal fluid examinations, hydrocephalus, and retinal lesions). Whether the rates of congenital infection in these three studies are representative of the entire U.S. population is unknown.However, if these rates (i.e., 1 per 10,000 and 10 per 10,000 ) were extrapolated to the approximately 4 million live births in the United States each year, an estimated 400-4,000 infants would be born each year with congenital toxoplasmosis. Limited data are available to assist in estimating the portion of the disease burden of toxoplasmosis attributable to meat consumption.A recent study compared results from a cross-sectional seroprevalence study of Seventh Day Adventists, a religious group that follows a diet containing no meat, with serologic results from a control group of March 31, 2000 volunteers who were not Seventh Day Adventists (12 ).Results from this study documented a significantly lower rate of Toxoplasma infection in Seventh Day Adventists than the control group (24% versus 50%, respectively; p < 0.01).Thus, approximately one half of Toxoplasma exposure might be caused by eating contaminated meat.Furthermore, a statistically significant decrease in risk for infection was observed among nonmeat eaters even after the data were adjusted for age and sex (odds ratio = 0.2; 95% confidence interval = 0.1-0.5).Because this study was originally designed to evaluate the possible association between eating shellfish and Vibrio and Norwalk virus infections, important questions regarding toxoplasmosis (i.e., amount of meat consumed, contact with or ownership of cats, or history of outdoor activity) were not asked in the interview. A report conducted by USDA's Economic Research Service concluded that one half of the toxoplasmosis cases in the United States are caused by eating contaminated meat.The estimated economic burden of these infections is $7.7 billion each year, primarily from congenital toxoplasmosis (13 ). Pork has been implicated by some authorities as the meat most commonly associated with foodborne toxoplasmosis (14 ).In some areas, market pigs from small producers have had higher rates of Toxoplasma infections than pigs from larger producers (15 ); however, overall rates appear to be declining over time (16 ).In 1992, a large survey in Illinois documented that 3.1% of market pigs had serologic evidence of Toxoplasma infection (16 ).Toxoplasma infection has also been identified in other meats, but their contribution to the burden of disease is believed to be small (14 ). Although Toxoplasma infections are associated either with eating contaminated meat or with ingesting oocysts passed in the feces of cats, no laboratory test exists that can determine the origin of a Toxoplasma infection in a specific person and whether it was associated with foodborne, catborne, or soilborne transmission.Epidemiologic studies of the transmission of toxoplasmosis have been hindered by an inability to determine the origin of isolated infections. # Diagnosis and Treatment Acute toxoplasmosis is rarely diagnosed by detecting the parasite in body fluids, tissue, or secretions; the most common method of diagnosis is based on antibody detection.The presence of elevated levels of Toxoplasma-specific IgG antibodies indicates infection has occurred at some point but does not distinguish between an infection acquired recently and one acquired in the distant past.The presence of a high Toxoplasma-specific IgM antibody titer combined with a high IgG titer probably indicates an acute infection within the previous 3 months.A low-to-medium IgM titer and a high IgG titer might indicate an acute infection 3-6 months previously, but IgM antibodies have been detected as long as 18 months after initial infection (17 ).Determining when Toxoplasma infection occurred in a pregnant woman is particularly important because infection before conception poses no substantial risk for transmission of infection to the fetus; however, infection after conception does pose such risk. In the United States, commercial test kits for Toxoplasma-specific IgG and IgM antibodies are readily available.Some commercial IgM tests have had problems with specificity, resulting in unacceptably high rates of false-positive test results.In 1996, FDA and CDC conducted extensive evaluations of the six most commonly used commercial IgM kits in the United States to determine the extent of the problem with the specificity of these kits.Sensitivity and specificity rates for these six kits ranged from 93.3% to 100.0% and from 77.5% to 99.1%, respectively (18 ). As a result of these findings, in 1997 FDA distributed an advisory to physicians in the United States highlighting these test limitations.The agency provided a guide for interpreting test results and issued a recommendation to laboratory personnel and physicians advising them to be aware of the problems associated with the test kits before making decisions about the clinical management of their patients.In addition, IgM-positive results should be confirmed by a Toxoplasma reference laboratory (18 ). Treatment of toxoplasmosis in immunocompetent persons other than pregnant women is generally not indicated unless symptoms are severe or persistent (19)(20)(21).In immunocompromised persons, treatment usually consists of pyrimethamine and sulfadiazine.Depending on gestational age and whether the fetus is known to be infected, pregnant women have been treated with the antibiotic spiramycin or with sulfadiazine alone or the combination of pyrimethamine and sulfadiazine.Treatment of acute infection during pregnancy has been associated with an approximately 50% reduction in fetal infection (22 ). # ETIOLOGIC FACTORS T. gondii has a complex life cycle consisting of three stages: a) tachyzoite -during the acute stage of infection, this form of the parasite invades and replicates within cells; b) bradyzoite -during latent infections, this form of the parasite is present in tissue cysts; and c) sporozoite -this form of the parasite is found in oocysts, which are environmentally resistant.Members of the family Felidae (including domestic and feral cats) are the definitive hosts of Toxoplasma.During acute infections, cats excrete unsporulated (i.e., uninfectious) oocysts in their feces; after several days to several weeks, depending on environmental conditions, the oocysts sporulate and become infectious.Under favorable conditions (i.e., in warm, moist soil), oocysts can remain infectious for approximately 1 year.They do not survive in arid, cool climates and can be destroyed by heating (17,19,20,23,24 ). Toxoplasmosis can be transmitted to humans by three principal routes.First, humans can eat raw or inadequately cooked infected meat or eat uncooked foods that have come in contact with contaminated meat.Second, humans can inadvertently ingest oocysts that cats have passed in their feces, either in a cat litter box or outdoors in soil (e.g., soil from gardening or unwashed fruits or vegetables).Third, a woman can transmit the infection to her unborn fetus. Women infected with Toxoplasma before conception, with rare exceptions, do not transmit the infection to their fetuses.Women infected with Toxoplasma after conception (i.e., during pregnancy) can transmit the infection across the placenta to their fetuses.
Maternal infections early in pregnancy are less likely to be transmitted to the fetus than infections later in pregnancy, but early fetal infections, when they do occur, are more likely than later infections to be severe (25 ).An estimated one half of untreated maternal infections are transmitted to the fetus. The classic triad of signs suggestive of congenital toxoplasmosis include chorioretinitis, intracranial calcifications, and hydrocephalus.However, most infants infected in utero are born with no obvious signs of toxoplasmosis on routine examination, but many develop learning and visual disabilities later in life (26,27 ).If untreated, congenital toxoplasmosis can be associated with severe and even fatal disease (28 ).The severity of Toxoplasma infections is correlated with the immune status of the infected person.Toxoplasmosis in immunocompetent adolescents or adults is generally mild or unapparent.Mild infections can result in lymphadenopathy, fever, fatigue, and malaise, all of which usually resolve within weeks to months without specific treatment.However, infection in immunocompromised persons can be severe.Immunosuppression caused by AIDS or therapies for malignancies, transplants, or lymphoproliferative disorders can result in reactivation of preexisting latent Toxoplasma infections.Reactivation most often involves the central nervous system, and symptoms can include meningoencephalitis or symptoms of a mass lesion. # RECOMMENDATIONS FOR PREVENTION - To prevent toxoplasmosis and other foodborne illnesses, food should be cooked to safe temperatures.A food thermometer should be used to measure the internal temperature of cooked meat to ensure that meat is cooked all the way through.Beef, lamb, and veal roasts and steaks should be cooked to at least 145 F, and pork, ground meat, and wild game should be cooked to 160 F before eating.Whole poultry should be cooked to 180 F in the thigh to ensure doneness. - Fruits and vegetables should be peeled or thoroughly washed before eating. - Cutting boards, dishes, counters, utensils, and hands should always be washed with hot soapy water after they have contacted raw meat, poultry, seafood, or unwashed fruits or vegetables. - Pregnant women should wear gloves when gardening and during any contact with soil or sand because cat waste might be in soil or sand.After gardening or contact with soil or sand, wash hands thoroughly. -Health education for women of childbearing age should include information about meat-related and soilborne toxoplasmosis prevention.Health-care providers should educate pregnant women at their first prenatal visit about food hygiene and prevention of exposure to cat feces. - Health-care providers who care for pregnant women should be educated about two potential problems associated with Toxoplasma serology tests.First, no assay exists that can determine precisely when initial Toxoplasma infection occurred.Second, in populations with a low incidence of Toxoplasma infection, such as in the United States, a substantial proportion of the positive IgM test results will probably be false positive. - The government and the meat industry should continue efforts to reduce Toxoplasma in meat. # RESEARCH AGENDA NWTPCT Recommendations for Research Experts who participated in NWTPCT considered several issues regarding prevention of this disease.These issues included the need to improve estimates of the burden of toxoplasmosis and immunodiagnostics for the disease and to determine the applicability of national toxoplasmosis screening for newborns.Participants discussed current knowledge about these issues, gaps in current knowledge, and needs for future research. # Improving Estimates of the Burden of Toxoplasmosis In their recommendations, NWTPCT participants emphasized the importance of obtaining more complete and accurate data regarding the incidence of new infections and the number of cases by mode of transmission.Participants recommended that CDC obtain population-based data regarding the incidence of and risk factors for toxoplasmosis.In addition, participants recommended the use of existing private data systems (e.g., those of health-maintenance organizations and managed-care systems) for surveillance and research, and development of techniques that would enable tracing the source of individual infections to foodborne, catborne, or soilborne transmission. # Improving Immunodiagnostics for Toxoplasma NWTPCT participants recommended that additional efforts were needed to develop more accurate screening diagnostic tests and improved confirmatory tests.NWTPCT participants also emphasized that resources should be identified to increase current capacity to provide reference diagnostic services in the United States. # Determining the Applicability of National Toxoplasmosis Screening for Newborns Research is under way to determine the need for national toxoplasmosis screening of newborn infants in the United States (See Exhibit).NWTPCT participants identified the need for cost-effectiveness studies to enable comparison of the benefits of expanded testing in the United States and the costs of such testing. # CDC Priorities The Food Safety Initiative has enabled CDC to increase support for activities related to prevention of toxoplasmosis, with a special emphasis on preventing congenital toxoplasmosis.The NWTPCT has helped CDC to identify high-priority activities and to form important partnerships with other groups with similar goals. CDC is engaged in several activities to improve the ability to measure the burden of toxoplasmosis in the United States and to provide a baseline against which the impact of future prevention efforts can be measured.Epidemiologic staff are analyzing Toxoplasma IgG seroprevalence in samples collected in the nationally representative NHANES III (1 ) and preparing a document to disseminate the results.Plans are under way to conduct serologic testing of samples obtained as part of NHANES 2000 to evaluate trends in the prevalence of Toxoplasma infection and to assess the occurrence of acuteToxoplasma infections.In addition, CDC staff will examine national hospital discharge data and national death certificate data to monitor the annual number of cases of and deaths caused by toxoplasmosis, the proportion of toxoplasmosis associated with congenital infection, and the proportion associated with HIV infection.Other possible activities include a) examination of surveillance data (obtained from both educational and medical records) for multiple developmental disabilities (e.g., mental retardation, cerebral palsy, and hearing and vision impairment) and evidence of positive Toxoplasma tests and b) the designation by state health departments of congenital toxoplasmosis as a reportable infection.CDC is supporting a cost-effectiveness analysis of the New England Newborn Screening Program to provide background information for states considering newborn toxoplasmosis screening and reporting.One state has already received funding from CDC through the Emerging Infections Program and has begun toxoplasmosis-related activities.Minnesota is conducting active surveillance for toxoplasmosis using laboratories, ophthalmologists, infection-control practitioners, and other clinicians. CDC is conducting research on the genetic variation of Toxoplasma to develop tools that would enable molecular epidemiologic studies (e.g., to determine whether different strains have different characteristics and are more infectious or pathogenic for humans).The results of this research might help investigators describe the source and spread of Toxoplasma in outbreaks and differentiate between foodborne and cat feces or soilborne Toxoplasma infections.In addition, through FoodNet, CDC is querying laboratories in eight states about their diagnostic practices for toxoplasmosis. To help evaluate the accuracy of future commercial Toxoplasma antibody test kits, CDC created a Toxoplasma serum panel that contains known positive and negative sera.FDA now requires that any new commercial Toxoplasma test kit perform adequately based on results obtained using this panel.The panel is available for purchase through the CDC Technology Transfer Office. The American College of Obstetricians and Gynecologists, with assistance from CDC, is conducting a national survey of obstetricians to assess their knowledge about congenital toxoplasmosis and interpretation of related laboratory tests.The results of the survey will be used to identify ways to educate health-care providers about diagnosis and clinical management of pregnant women with suspected Toxoplasma infections. To # CONCLUSION Many cases of congenital toxoplasmosis in the United States can be prevented.Specific measures can be taken by women and their health-care providers to decrease the risk for infection during pregnancy and, if primary prevention fails and congenital infection occurs, to reduce the severity of infection in newborns.CDC is involved in efforts to improve measurement of the burden of toxoplasmosis in the United States, evaluate current prevention programs, train health-care providers, and educate women about toxoplasmosis.These efforts should allow CDC and state and local health departments to better monitor and reduce the impact of toxoplasmosis on pregnant women and their newborn infants. # MMWR March 31, 2000 # Exhibit Innovative and ambitious programs to prevent toxoplasmosis have been developed in the United States and in Europe, and the National Workshop on Toxoplasmosis: Preventing Congenital Toxoplasmosis (NWTPCT) provided a forum to compare current efforts.These programs involve three approaches: a) screening pregnant women (or all women of childbearing age) to detect as early as possible Toxoplasma infections (or susceptibility to such infections) that might indicate a risk for congenital infection, b) screening newborns to detect infections in infants as early as possible to enable early initiation of treatment, and c) educating women about preventing infection. # Screening Programs for Pregnant Women France In France, a screening program was implemented in 1976 to detect and treat Toxoplasma infection during pregnancy.The goal of this program is to institute preventive measures for seronegative women and to ensure early diagnosis and treatment of infection acquired during pregnancy.Since the beginning of the program, premarital and prenatal medical examinations for Toxoplasma antibodies have been performed.Premarital examinations are conducted to distinguish previously infected women from women who have not been previously infected.When a previously uninfected woman becomes pregnant, testing is conducted at her first prenatal examination during her first trimester and at six additional examinations conducted monthly during her second and third trimesters.In addition, women are educated about prevention methods during pregnancy (29 ).If these screening tests detect evidence of acute infection during pregnancy, treatment for the woman is initiated with spiramycin.If infection in the fetus is confirmed through fetal blood sampling and amniocentesis, pyrimethamine and sulfadiazine or sulfadoxine is added to the regimen (30)(31)(32). Even though coverage of the French program has been incomplete, the program has been associated with a decline in the incidence of congenital infection, as well as a decline in severe disease detected at birth.The proportion of the decline specifically attributable to the program or to the general decline in Europe in rates of seropositivity is difficult to determine because no unscreened group of women exists for comparison. # Austria Austria implemented a toxoplasmosis screening program in 1975.Nearly all women who become pregnant are serologically screened early in pregnancy and, if found to be negative initially, are tested again during the second and third trimesters.Women with Toxoplasma infections are treated as soon as infection is detected.Although seropositivity rates among pregnant Austrian women have declined from approximately 50.0% during the late 1970s to 36.7% during the early 1990s, the incidence of congenital Toxoplasma infection has declined even more, from 50-70 cases per 10,000 births before the program to 1 per 10,000 births during the early 1990s (33 ).As with the French program, the lack of an unscreened comparison group precludes determining the proportion of the decline attributable to the screening program, and lack of cost figures precludes costeffectiveness analyses. # European Research Network on Congenital Toxoplasmosis The European Research Network on Congenital Toxoplasmosis was established in 1993 and has sponsored several studies regarding public health interventions for congenital toxoplasmosis.Most recently, a multicenter study was conducted to evaluate the effectiveness of toxoplasmosis treatment administered during pregnancy in preventing transmission of maternal infection to the fetus.Pregnant women who visited one of five European university medical centers for prenatal care were screened for Toxoplasma antibodies at their first prenatal visit.Women who were seronegative were retested at least once every trimester in two centers and monthly in the other centers, until the birth of the infant.For women who seroconverted during pregnancy, prenatal antibiotic treatment was started, and their infants were followed for 1 year after birth.Treatment regimens consisted of spiramycin or a combination of pyrimethamine and sulfadiazine.If prenatal infection was confirmed with amniocentesis or cordocentesis, women were treated with pyrimethamine and sulfadiazine or sulfadoxine.Of women who screened positive and did not receive prenatal therapy, transmission from mother to infant occurred in 72% of the mother-infant pairs; of women who received prenatal therapy, transmission occurred in 39% of the mother-infant pairs.In addition, 20% of the untreated mothers gave birth to infants with severe sequelae, and 3.5% of the treated mothers gave birth to infants with severe sequelae.Furthermore, the earlier antibiotics were administered after infection, the less likely sequelae were detected in the infant (34 ). # Finland From January 1988 through June 1989, a cost-benefit analysis of Toxoplasma screening during pregnancy was conducted in a prospective study in Finland.The study compared costs of screening alternatives for primary infections during pregnancy with the costs of no screening.With screening, the annual costs of congenital toxoplasmosis were $95 US per pregnancy; without screening, annual costs were $128 US per pregnancy.Furthermore, screening along with health education was more beneficial than health education alone (35 ).The study findings suggest screening is beneficial in countries with low incidence of congenital toxoplasmosis, such as Finland.The findings of other studies suggest screening programs can also be beneficial in areas with high incidences of congenital toxoplasmosis (30,36,37 ). # NWTPCT's Assessment Although the findings of the European studies suggest Toxoplasma screening programs of women of childbearing age can prevent cases of congenital toxoplasmosis, several concerns could limit support for such programs in the United States.NWTPCT participants identified the need for cost-effectiveness studies to enable comparison of the benefits of expanded testing in the United States, the costs of such testing, and the unintended adverse consequences that might accompany such testing (e.g., inappropriately treating women with false-positive test results). # MMWR March 31, 2000 Screening Programs for Newborns # Denmark During June 1992-August 1996, researchers in Denmark conducted a newborn screening study for toxoplasmosis.The primary goal of this study was to determine the feasibility of screening newborn infants for congenital toxoplasmosis in an area with low prevalence; in Denmark, the seroprevalence of antibodies to Toxoplasma among women during this study was 28% (38,39 ).Approximately 90,000 infants were screened for Toxoplasma-specific IgG antibodies 5-10 days after birth.Infants born to mothers who seroconverted during pregnancy were subsequently examined physically and serologically for 1 year; for those with confirmed congenital infections, treatment was initiated with courses of pyrimethamine and sulfadiazine, alternating with spiramycin (38 ).During 1996, serum levels of Toxoplasma-specific IgM antibodies were also determined.The IgM test conducted within 10 days of birth resulted in a false-positive rate of 0.2 per 1,000 with no false-negatives.Results from this study indicated that a newborn screening program using a Toxoplasma-specific IgM antibody test exclusively could identify approximately 75% of infections in infants born to untreated mothers.In addition, the low rates of false-positives and false-negatives suggested this method would be feasible in large-scale newborn screening programs in areas with low seroprevalence rates of toxoplasmosis. # United States In the United States, the New England Newborn Screening Program tests newborn "filter-paper" specimens from all infants born in Massachusetts and New Hampshire for congenital toxoplasmosis by using a Toxoplasma-specific IgM antibody assay.If IgM antibodies are detected, an extensive clinical evaluation is performed, and a 1-year treatment regimen is initiated with a combination therapy of pyrimethamine and sulfadiazine (11 ).During 1986-1992, a total of 52 of the 635,000 infants screened had confirmed congenital infections; 50 appeared normal on routine neonatal examination and had toxoplasmosis diagnosed through screening alone.After more intensive examination, 19 (40%) of the 48 evaluated infants who appeared normal on routine examination had evidence of retinal or central nervous system disease.Treatment was provided for these infants, and compliance with therapy was observed.After 1 year of treatment, only one (2.2%) of 46 children had a neurologic deficit, and four (10.3%) of 39 had eye lesions that could have developed after birth.The findings of this program demonstrated that screening newborns for congenital toxoplasmosis is feasible in the United States.The laboratory and personnel costs of screening approximately 100,000 infants per year for Toxoplasma infection and following those who were infected totaled $220,000 or approximately $30,000 per infant identified.Costs were relatively low because the system used by the program to collect and process specimens was the same one already used for screening newborns for eight other diseases.On the basis of these preliminary cost estimates, this screening program appears to be a favorable alternative, considering the financial and social costs associated with raising a visually or mentally impaired child (40 ). # MMWR 73 NWTPCT's Assessment NWTPCT participants recognized the benefits of these newborn screening programs and discussed ways to evaluate the New England program to determine the benefit of using it as a model for developing additional programs in other areas of the United States.One specific recommendation was for CDC to support a detailed, costeffectiveness evaluation of the program. # Education Programs for Women The third approach to preventing toxoplasmosis focuses on educating women of childbearing age about minimizing their risk for infection with Toxoplasma.Education interventions assume that increased knowledge results in awareness, which consequently results in changes in risky behavior and declines in infection rates.Messages emphasize the importance of avoiding eating raw or undercooked meat, handling raw meat safely, and washing hands after gardening or changing cat litter boxes (37 ). # Canada A study conducted as part of prenatal classes at Canadian public health agencies evaluated the effect of a 10-minute teaching session on three behaviors: practices associated with cleaning the cat litter box and limiting the cat's diet to cooked food; safe food-handling practices; and handwashing after exposure to cat feces, garden soil, or raw meats.Among women in the classes, behavior improved regarding practices associated with cats; however, behavior regarding food-handling practices remained unchanged.In addition, improvement occurred in handwashing practices but only among professional women (41 ). # Belgium During 1979-1986, a Belgium study assessed the effectiveness of educational sessions held in hospital settings.Baseline data were collected during 1979-1982, when no education measures were in effect.
During 1983-1986, education sessions were provided to pregnant women.Although the intervention was associated with a 34% decrease in seroconversion rates, the decrease was not statistically significant (42 ). # NWTPCT's Assessment NWTPCT participants considered education programs to be a potentially powerful intervention because of their low cost and because pregnant women were highly motivated to protect the health of their babies.However, participants emphasized that the impact of educational programs was difficult to evaluate because of the limited number of comparative studies a) conducted with rigorous scientific methodology and b) of sufficient size to enable calculation of the effectiveness of the intervention compared with its cost. # MMWR March 31,2000 The material in this report was prepared for publication by: National # Professional Education and Training - Increase collaboration with professional groups that provide continuing education for their constituents to address breast and cervical cancer control issues in standardized curricula and training. - Continue to advocate for incorporation of breast and cervical cancer education in curricula for health professionals to facilitate a long-term effect on provider practice. # Partnerships - Continue to build partnerships with public health departments, tribes and tribal organizations, national and voluntary organizations, academic centers, and health-care purchasers through the following activities: implementing strategies communitywide to promote awareness and screening practices among all women; replicating and disseminating programmatic approaches that are proven effective in providing screening to priority populations (e.g., racial/ethnic minorities and women residing in rural or other hard-to-reach areas); cosponsoring conferences, workshops, and training related to breast and cervical cancer issues; and advocating for breast and cervical cancer control priorities (e.g., policies and standards) to ensure the quality of mammography and Pap screening delivered by all providers. # RESEARCH AGENDA To support the recommended priority activities for NBCCEDP, CDC has developed a research agenda comprising six priorities.This research will assist in improving cancer screening services provided to women enrolled in NBCCEDP and in developing new methods to recruit eligible women who have rarely or have never received breast or cervical cancer screening. - Priority: Determine effective strategies to communicate changes in NBCCEDP policy to cancer screening providers and women enrolled in the program.Emerging developments in cancer prevention and control occasionally require substantial changes in program policy (e.g., changing from annual to triennial cervical cancer screening among women with three previous normal Pap tests).Changes in program policy might require adapting the practice patterns of providers and modifying the expectations and behaviors of enrolled women.Research is needed to develop and evaluate effective public and provider education and materials for dissemination that will help translate policy changes into practice as rapidly as possible. - Priority: Identify effective strategies to increase the proportion of enrolled women who complete routine breast and cervical cancer rescreening according to NBCCEDP policy.Available data submitted twice a year to CDC by participating programs suggest that many women enrolled in NBCCEDP, regardless of their race/ethnicity, do not complete routine rescreening on schedule.Some research is under way in this area, but more is needed.A multiethnic, multicultural focus group study of the barriers to mammography rescreening among NBCCEDP enrollees in Texas ( 33) resulted in development of an ongoing retrospective cohort investigation among 2,500 randomly selected enrollees in Maryland, New York, Ohio, and Texas.Findings from this research that identify risk factors for failure to rescreen on schedule will be used to develop and test new interventions to increase routine rescreening; however, additional research is needed in this area. - Priority: Identify effective strategies to increase NBCCEDP enrollment among eligible women who have never received breast or cervical cancer screening. Data from the 1997 BRFSS suggest that substantial numbers of age-eligible, lowincome women have never received mammography or Pap smear screening (23 ).To develop effective outreach and enrollment strategies for women who have rarely or have never received cancer screening, participatory research methods that involve unscreened women and members of their communities in all phases of the research process might be particularly valuable.In addition, quantitative research designs might be necessary to test proposed interventions. Research initiatives related to this priority topic must address both missed screening opportunities in diverse provider settings and various cultural, language, and institutional barriers that might influence a woman's willingness to accept free or low-cost cancer screening when offered. - Priority: Evaluate variations in clinical practice patterns among providers of NBCCEDP screening services.Analyses of data submitted every 6 months to CDC by participating programs have identified several practice patterns that differ markedly across these programs.These variations raise concern regarding quality assessment.For example, an analysis of mammography results for 1991-1996 reported through the Breast Imaging Reporting and Data System (BI-RADS ® ) lexicon developed by the American College of Radiology (34 ) documented that the proportion of mammograms coded "probably benign, shortterm follow-up recommended" varied substantially across the state, territorial, and tribal programs (35 ).To understand the reasons for such variations and to develop appropriate provider education materials, where necessary, case studies and record linkage investigations within collaborating programs might be necessary.Such studies must be conducted within participating programs because data submitted to CDC cannot be linked with medical records, pathology laboratory reports, or cancer registries. - Priority: Determine optimal models for providing case-management services to women in NBCCEDP who have an abnormal screening result or a diagnosis of cancer.Without effective case management, some low-income women who need additional cancer testing or treatment will not receive the necessary care or will not receive it as rapidly as possible.Diverse case-management models have been developed for other public health concerns including tuberculosis control, adolescent prenatal care, and human immunodeficiency virus infection/acquired immunodeficiency syndrome.Research is needed to evaluate the applicability of these and other models to low-income, medically uninsured women who need additional cancer testing and treatment.Critical issues include determining how women will be selected for case management, how extensive case-management # ACCREDITATION Continuing Medical Education (CME).CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.CDC designates this educational activity for a maximum of 2.5 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 and awards 0.2 hour Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 2.9 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. # CE-2 # MMWR March 31, 2000 # GOALS AND OBJECTIVES This MMWR provides recommendations and other information to help health professionals improve skills in protecting the health of women.The articles in this MMWR were developed by CDC staff.This MMWR is intended to provide information to guide public health policy development, program management, and clinical care related to women's health.Upon completion of this educational activity, the reader should be able to develop strategies to reduce the risk for hip fractures, develop strategies to reduce the risk for exercise-related trauma, identify disease risk factors and prevention interventions for breast and cervical cancer, and develop strategies to reduce the risk for toxoplasmosis during pregnancy. To receive continuing education credit, please answer all of the following questions. # Detach or photocopy. Vol.49 / No.RR-2 # MMWR 3 The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy.To receive an electronic copy on Friday of each week, send an e-mail message to listserv@listserv.cdc.gov.The body content should read SUBscribe mmwr-toc.Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov.To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments.The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday.Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd.,N.E., Atlanta, GA 30333; telephone (888) 232-3228. 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. # IU.S. Government Printing Office: 2000-533-2206/08060 Region IV
Healthy eating patterns in childhood and adolescence promote optimal childhood health, growth, and intellectual development; prevent immediate health problems, such as iron deficiency anemia, obesity, eating disorders, and dental caries; and may prevent long-term health problems, such as coronary heart disease, cancer, and stroke.School health programs can help children and adolescents attain full educational potential and good health by providing them with the skills, social support, and environmental reinforcement they need to adopt long-term, healthy eating behaviors.This report summarizes strategies most likely to be effective in promoting healthy eating among school-age youths and provides nutrition education guidelines for a comprehensive school health program.These guidelines are based on a review of research, theory, and current practice, and they were developed by CDC in collaboration with experts from universities and from national, federal, and voluntary agencies.The guidelines include recommendations on seven aspects of a school-based program to promote healthy eating: school policy on nutrition, a sequential, coordinated curriculum, appropriate instruction for students, integration of school food service and nutrition education, staff training, family and community involvement, and program evaluation.#INTRODUCTION School-based programs can play an important role in promoting lifelong healthy eating.Because dietary factors "contribute substantially to the burden of preventable illness and premature death in the United States," the national health promotion and disease prevention objectives encourage schools to provide nutrition education from preschool through 12th grade (1 ).The U.S. Department of Agriculture's (USDA) Nutrition Education and Training (NET) Program urges "nutrition education be a major educational component of all child nutrition programs and offered in all schools, child care facilities, and summer sites" by the year 2000 (2 ).Because diet influences the potential for learning as well as health, an objective of the first national education goal is that children "receive the nutrition and health care needed to arrive at school with healthy minds and bodies" (3 ). The recommendations in this report are intended to help personnel and policymakers at the school, district, state, and national levels meet the national health objectives and education goals by implementing school-based nutrition education policies and programs.This report may also be useful to students, to parents, and to personnel in local and state health departments, community-based health and nutrition programs, pediatric clinics, and training institutions for teachers and public health professionals.These recommendations complement CDC guidelines for school health programs to prevent the spread of acquired immunodeficiency syndrome (AIDS) (4 ), to prevent tobacco use and addiction (5 ), and to promote physical activity (6 ). In this report, nutrition education refers to a broad range of activities that promote healthy eating behaviors.The nutrition education guidelines focus largely on classroom instruction, but they are relevant to all components of a comprehensive school health program-health education; a healthy environment; health services; counseling, psychological, and social services; integrated school and community efforts; physical education; nutrition services; and school-based health promotion for faculty and staff (7 ).Although the meals served by school food service programs are an important part of a school health program, this report does not provide specific recommendations related to purchasing and preparing food for school meals.Detailed information on this topic is available from many other publications (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and information sources (see Appendix A).These guidelines also do not address the specific nutrition education and counseling needs of pregnant adolescents (20,21 ) or young persons with special needs (22)(23)(24)(25)(26)(27)(28). These guidelines are based on a synthesis of research, theory, and current practice and are consistent with the principles of the national health education standards (29 ), the opportunity-to-learn standards for health education (29 ), the position papers of leading voluntary organizations involved in child nutrition (30 ), and the national action plan to improve the American diet (31 ).To develop these guidelines, CDC convened meetings of experts in nutrition education, reviewed published research, considered the recommendations of national policy documents (1,(32)(33)(34)(35), and consulted with experts from national, federal, and voluntary organizations. # EFFECTS OF DIET ON THE HEALTH, GROWTH, AND INTELLECTUAL DEVELOPMENT OF YOUNG PERSONS School-based nutrition education can improve dietary practices that affect young persons' health, growth, and intellectual development.Immediate effects of unhealthy eating patterns include undernutrition, iron deficiency anemia, and overweight and obesity. # Undernutrition Even moderate undernutrition can have lasting effects on children's cognitive development and school performance (36 ).Chronically undernourished children attain lower scores on standardized achievement tests, especially tests of language ability (37 ).When children are hungry or undernourished, they have difficulty resisting infection and therefore are more likely than other children to become sick, to miss school, and to fall behind in class (36,37 ); they are irritable and have difficulty concentrating, which can interfere with learning (38 ); and they have low energy, which can limit their physical activity (38 ).Some reports have estimated that millions of children in the United States experience hunger over the course of a year (39 ), but no scientific consensus currently exists on how to define or measure hunger (1 ). Skipping breakfast can adversely affect children's performance in problem-solving tasks (40)(41)(42).A study of low-income elementary school students indicated that those who participated in the School Breakfast Program had greater improvements in stand-ardized test scores and reduced rates of absence and tardiness than did children who qualified for the program but did not participate (43 ).Twelve percent of students reported skipping breakfast the day before one national survey was taken (44 ); 40% of 8th-and 10th-grade students in another study reported having eaten breakfast on ≤2 days the week before the survey (45 ).Strategies to encourage adequate nutrition among young persons include the following: - Promote participation in USDA food assistance programs (e.g., the School Breakfast Program and School Lunch Program, the Summer Food Service Program, and the Child and Adult Care Food Program). - Advise parents and guardians about community-based food supplementation programs (e.g., food stamps; local food pantries; and the Special Supplemental Nutrition Program for Women, Infants, and Children ). - Educate students and their families about the importance of eating breakfast. # Iron Deficiency Anemia Iron deficiency anemia is the most common cause of anemia in the United States (33 ).Iron deficiency hampers the body's ability to produce hemoglobin, which is needed to carry oxygen in the blood.This deficiency can increase fatigue, shorten attention span, decrease work capacity, reduce resistance to infection, and impair intellectual performance (33,46 ).Among school-age youths, female adolescents are at greatest risk for iron deficiency.Approximately 1% of elementary school-age children and 2%-4% of adolescent girls ages 12-19 years show evidence of iron deficiency anemia (47 ).To prevent iron deficiency, children and adolescents should eat adequate amounts of foods high in iron and in vitamin C, which helps the body absorb iron efficiently (33 ). # Overweight and Obesity* Overweight and obesity are increasing among children and adolescents in the United States (48)(49)(50)(51)(52).The prevalence of overweight among youths ages 6-17 years in the United States has more than doubled in the past 30 years; most of the increase has occurred since the late 1970s (52 ).Approximately 4.7 million, or 11%, of youths ages 6-17 years are seriously overweight (52 ).Obesity in young persons is related to elevated blood cholesterol levels (53)(54)(55)(56) and high blood pressure (57)(58)(59), and some very obese youths suffer from immediate health problems (e.g., respiratory disorders, orthopedic conditions, and hyperinsulinemia) (60 ).Being overweight during childhood and adolescence has been associated with increased adult mortality (61,62 ).Furthermore, obese children and adolescents are often excluded from peer groups and discriminated against by adults, experience psychological stress, and have a poor *Obesity refers to an excess of total body fat.Body fat content is usually estimated by one of two techniques, measuring skinfold thickness or computing the ratio of body weight to height.Researchers who use weight-to-height ratios tend to use the term "overweight" instead of "obesity."Although weight-to-height ratios correlate highly with body fat, they do not distinguish between body fat and lean body tissue: excess fat tissue is generally assumed to account for the additional weight, but excess weight can also include lean body mass or a large body frame (33 ). body image and low self-esteem (63,64 ).Increased physical activity and appropriate caloric intake are recommended for preventing and reducing obesity (35 ).CDC's guidelines for school and community health programs to promote physical activity among youths address strategies for increasing physical activity among young persons (6 ). # Unsafe Weight-Loss Methods Many young persons in the United States practice unsafe weight-loss methods.Deliberately restricting food intake over long periods can lead to poor growth and delayed sexual development (65 ).Data from one study indicated that the rate of smoking initiation is higher for adolescent girls who diet or who are concerned about their weight than for nondieters or girls having few weight concerns (66 ), and another study indicated that many white female high school students who smoke report using smoking to control their appetite and weight (67 ).Harmful weight loss practices have been reported among girls as young as 9 years old (68,69 ).Young persons involved in certain competitive sports and dancing are particularly at risk for unsafe weight control practices (70 ).A national survey of 8th-and 10th-grade students found that 32% skipped meals, 22% fasted, 7% used diet pills, 5% induced vomiting after meals, and 3% used laxatives to lose weight (45 ).Children and adolescents should learn about the dangers of unsafe weight-loss methods and about safe ways to maintain a healthy weight.The emphasis of society in the United States on thinness should be challenged, and young persons need to develop a healthy body image (71 ). # Eating Disorders Eating disorders (e.g., anorexia nervosa and bulimia nervosa) are psychological disorders characterized by severe disturbances in eating behavior.Anorexia nervosa is characterized by a refusal to maintain a minimally normal body weight, and bulimia nervosa is characterized by repeated episodes of binge eating followed by compensatory behaviors such as self-induced vomiting (72 ).Eating disorders often start in adolescence, and >90% of cases occur among females (72 ).Anorexia nervosa and bulimia nervosa affect as many as 3% of adolescent and young adult females, and the incidence of anorexia nervosa appears to have increased in recent decades (72 ).Compared with adolescents who have normal eating patterns, adolescents who have eating disorders tend to have lower self-esteem; a negative body image; and feelings of inadequacy, anxiety, social dysfunction, depression, and moodiness (73 ).Eating disorders can cause many severe complications, and mortality rates for these disorders are among the highest for any psychiatric disorder (74 ).Persons who have eating disorders should receive immediate medical and psychological treatment. # Dental Caries Dental caries is perhaps the most prevalent of all diseases (1 ).It affects 50.1% of youths ages 5-17 years and 84.4% of youths age 17 years (75 ).More than 50 million hours of school time are lost annually because of dental problems or dental visits (76 ) .Dental caries is a progressive disease, which, if left untreated, can result in acute infections, pain, costly treatment, and tooth loss.A strong link exists between sugar consumption and dental caries (33 ).To prevent dental caries, children and adolescents should drink fluoridated water, use fluoridated toothpaste, brush and floss their teeth regularly, have dental sealants applied to the pits and fissures of their teeth, and consume sugars in moderation (1 ). # EFFECTS OF CHILDHOOD EATING PATTERNS ON CHRONIC DISEASE RISKS OF ADULTS Nutrition education also should focus on preventing children and adolescents from developing chronic diseases during adulthood.Some of the physiological processes that lead to diet-related chronic disease begin in childhood.For example, autopsy studies have demonstrated that early indicators of atherosclerosis (the hardening of the arteries that is the most common cause of coronary heart disease ) begin in youth (77)(78)(79)(80)(81)(82)(83) and are related to blood cholesterol levels in young persons (79,(81)(82)(83).Unhealthy eating practices that contribute to chronic disease are established early in life; young persons having unhealthy eating habits tend to maintain these habits as they age (84 ).Thus, it is efficacious to teach persons healthy eating patterns when they are young; high-risk eating behaviors and physiological risk factors are difficult to change once they are established during youth. Diet-related risk factors for cardiovascular disease (e.g., high blood cholesterol level, high blood pressure, and overweight) are common in youths in the United States (34,52,(85)(86)(87)(88)(89)(90).Compared with their peers, children and adolescents who have high blood cholesterol (34,(91)(92)(93)(94)(95)(96), have high blood pressure (97,98 ), or are obese (91,(99)(100)(101)(102)(103) are more likely to have these risk factors during adulthood.Poor diet and inadequate physical activity together account for at least 300,000 deaths in the United States annually and are second only to tobacco use as the most prominent identifiable contributor to premature death (104 ).Interventions that promote healthy eating and physical activity behaviors during childhood and adolescence may not only prevent some of the leading causes of illness and death but also decrease direct health-care costs and improve quality of life. Diet is a known risk factor for the development of the nation's three leading causes of death: CHD, cancer, and stroke (33 ).Other health problems of adulthood associated with diet are diabetes, high blood pressure, overweight, and osteoporosis. # Coronary Heart Disease CHD kills more persons in the United States than any other disease does (1 ).Dietrelated risk factors for CHD include high blood cholesterol, high blood pressure, and obesity.These risk factors can be reduced by consuming less fat (particularly saturated fat) and cholesterol and by increasing physical activity (105 ). # Cancer One out of every five deaths in the United States is attributable to cancer (106 ).Dietary factors have been associated with several types of cancer, including colon, breast, and prostate (33 ).All cancer deaths in the United States might be reduced as much as 35% through dietary changes (107,108 ).The risk for some types of cancer may be reduced by maintaining a healthy weight; limiting consumption of fat, alcohol, and salt-cured, salt-pickled, or smoked foods; and eating more foods that protect the body against cancer (fruits, vegetables, whole grain cereals, and other high-fiber foods) (109 ).The National Cancer Institute advises eating at least five servings of fruits and vegetables each day (110 ). # Stroke Cerebrovascular disease, or stroke, is the third leading cause of death in the United States and a major cause of illness and disability (111 ).The most important risk factor for stroke is high blood pressure, which often can be controlled or prevented by adopting a healthy diet and maintaining a healthy weight (112 ).The risk for stroke can be reduced by consuming less sodium, increasing physical activity, and maintaining a healthy body weight. # Diabetes Diabetes is the seventh leading cause of death in the United States (104 ).CHD is two to four times more common and stroke is two to six times more common in persons who have diabetes than in persons who do not have diabetes (113 ).Diabetes can lead to blindness, kidney disease, and nerve damage (113 ).Non-insulin-dependent diabetes mellitus, which affects approximately 90% of persons who have diabetes, is often associated with obesity (114 ).Maintaining a desirable body weight through physical activity and modest caloric restriction is important in preventing diabetes and controlling its complications (114 ). # High Blood Pressure High blood pressure is a major cause of CHD, stroke, and kidney failure.About one in four adults in the United States has high blood pressure (115 ).Persons who have high blood pressure have three to four times the risk of developing CHD and as much as seven times the risk of stroke as do those who have normal blood pressure (116 ).Persons can reduce their risk for high blood pressure by consuming less sodium, increasing physical activity, and maintaining a healthy body weight.A diet high in potassium may help reduce the risk of high blood pressure (117 ). # Overweight In the United States, about one in three adults is overweight (118 ), and these persons are at increased risk for CHD, some types of cancer, stroke, diabetes mellitus, high blood pressure, and gallbladder disease (33 ).Overall risk for premature death is increased by excess weight; the risk increases as severity of overweight increases (33) .The best way to lose weight is to increase physical activity and control caloric intake, preferably by adopting a diet that is low in fat and high in vegetables, fruits, and grains (35 ). # Osteoporosis Osteoporosis is a decrease in the amount of bone so severe that the bone fractures easily.About 1.3 million bone fractures, including many fatal hip fractures, occur per year in persons ≥45 years of age (33 ).Low dietary calcium, a mineral essential for bone growth, may be associated with an increased risk for osteoporosis (33 ).For females especially, eating enough calcium is particularly important during childhood, adolescence, and young adulthood-when bones approach their maximum densityto reduce the risk for osteoporosis later in life (1,(119)(120)(121)(122).Regular weight-bearing exercises also can help prevent osteoporosis (33 ). # GUIDELINES FOR HEALTHY EATING To prevent certain diseases and to promote good health, persons >2 years of age should follow the seven recommendations that constitute the Dietary Guidelines for Americans (35 ).These guidelines are developed by the USDA and USDHHS and are published every 5 years.They are based on extensive reviews of hundreds of studies conducted over many years and represent the best current advice that nutrition scientists can give.
The guidelines are consistent with dietary recommendations made by major health promotion organizations, including the National Research Council (32 ), the National Cholesterol Education Program of the National Institutes of Health (34,105 ), the National Cancer Institute (109 ), the American Cancer Society (123 ), and the American Heart Association (124 ). The principles contained in the Dietary Guidelines for Americans should be the primary focus of school-based nutrition education.By enabling young persons to adopt practices consistent with the guidelines, schools can help the nation meet its health objectives (1 ), which were designed to guide health promotion and disease prevention policy and programs at the federal, state, and local level throughout the 1990s.Objective 2.19 is to "increase to at least 75 percent the proportion of the Nation's schools that provide nutrition education from preschool through 12th grade, preferably as part of quality school health education" (1 ).The six relevant dietary guidelines are (a) eat a variety of foods; (b) balance the food you eat with physical activity-maintain or improve your weight; (c) choose a diet with plenty of grain products, vegetables, and fruits; (d) choose a diet low in fat, saturated fat, and cholesterol; (e) choose a diet moderate in sugars; and (f) choose a diet moderate in salt and sodium. (The seventh recommendation concerns adults and alcoholic beverages.)Enabling children and adolescents to follow these guidelines can help the nation achieve these national health objectives for the year 2000 (1 ): 2.3 Reduce overweight to a prevalence of ≤20% among people aged 20 and older and ≤15% among adolescents aged 12 through 19. Reduce average dietary fat intake to ≤30% of calories and average saturated fat intake to ≤10% of calories among people aged two and older. # Increase complex carbohydrates and fiber-containing foods in the diets of adults to five or more daily servings for vegetables (including legumes) and fruits and to six or more daily servings for grain products. Increase to ≥50% the proportion of overweight people aged 12 and older who have adopted sound dietary practices combined with regular physical activity to attain an appropriate body weight.2.8 Increase calcium intake so ≥50% of youth aged 12 through 24 and ≥50% of pregnant and lactating women consume three or more servings daily of foods rich in calcium, and ≥50% of people aged ≥25 consume two or more servings daily. Decrease salt and sodium intake so that ≥65% of home meal preparers prepare foods without adding salt, ≥80% of people avoid using salt at the table, and ≥40% of adults regularly purchase foods modified or lower in sodium. The Food Guide Pyramid (Figure 1) was designed by the USDA and USDHHS to help persons follow the Dietary Guidelines for Americans.Schools can use the pyramid to illustrate the concepts of variety (eat different foods from among and within the food groups), moderation (limit the consumption of foods high in fat and added sugars), and proportionality (eat relatively greater amounts of foods from the groups that are lower in the pyramid: grains, vegetables, and fruits) (125 ).Other educational materials supplement the pyramid by listing low-fat choices within each food group (35 ). # EATING BEHAVIORS OF CHILDREN AND ADOLESCENTS IN THE UNITED STATES Many young persons in the United States do not follow the recommendations of the Dietary Guidelines for Americans or the Food Guide Pyramid.On average, children and adolescents consume too much fat, saturated fat, and sodium and not enough fruits, vegetables, or calcium (44,(126)(127)(128)(129) ; CDC, unpublished data).Children and adolescents obtain 33%-35% of their calories from fat and 12%-13% from saturated fat FIGURE 1.The Food Guide Pyramid -a guide to daily choices (above the recommended levels of 30% and 10%, respectively) (44,128,129 ).Only 16% of children ages 6-11 years and 15% of adolescents ages 12-19 years meet the recommendation for total fat intake; only 9% of children and 7% of adolescents meet the recommendation for saturated fat intake (130 ).Almost one-half of 8th-and 10thgrade students eat three or more snacks a day, and most of these snacks are high in fat, sugar, or sodium (45 ). Unpublished data from CDC's 1993 Youth Risk Behavior Survey indicated that, on the day before the survey, 41% of high school students in the United States ate no vegetables and 42% ate no fruits (127 ) (Appendix B).An analysis of a nationally representative sample of youths ages 2-18 years indicated that, over a 3-day period, the youths ate only 3.6 servings of fruits and vegetables daily and that fried potatoes accounted for a large proportion of the vegetables consumed, 20.4% of the youths ate the recommended five or more servings of fruits and vegetables daily, 50.8% ate fewer than one serving of fruit per day, and 29.3% ate fewer than one serving per day of vegetables that were not fried (131 ).Adolescent females eat considerably less calcium and iron than recommended by the Food and Nutrition Board of the National Research Council (126,129 ). Children and adolescents appear to be familiar with the general relationship between nutrition and health but are less aware of the relationship between specific foods and health.For example, young persons understand the importance of limiting fat, cholesterol, and sodium in one's diet, but they do not know which foods are high in fat, cholesterol, sodium, or fiber (45,132,133 ).One study indicated that adolescents were well-informed about good nutrition and health but did not use their knowledge to make healthy food choices (134 ). # THE NEED FOR SCHOOL-BASED NUTRITION EDUCATION Young persons need nutrition education to help them develop lifelong eating patterns consistent with the Dietary Guidelines for Americans and the Food Guide Pyramid.Schools are ideal settings for nutrition education for several reasons: - Schools can reach almost all children and adolescents. - Schools provide opportunities to practice healthy eating.More than one-half of youths in the United States eat one of their three major meals in school, and 1 in 10 children and adolescents eats two of three main meals in school (135 ). - Schools can teach students how to resist social pressures.Eating is a socially learned behavior that is influenced by social pressures.School-based programs can directly address peer pressure that discourages healthy eating and harness the power of peer pressure to reinforce healthy eating habits. - Skilled personnel are available.After appropriate training, teachers can use their instructional skills and food service personnel can contribute their expertise to nutrition education programs. - Evaluations suggest that school-based nutrition education can improve the eating behaviors of young persons (136)(137)(138). School-based nutrition education is particularly important because today's children and adolescents frequently decide what to eat with little adult supervision (139 ).The increase in one-parent families or families having two working parents and the availability of convenience foods and fast-food restaurants inhibit parents' monitoring of their children's eating habits. Young persons' food choices are influenced by television advertisements for lownutritive foods.Young persons see about one food advertisement for every 5 minutes of Saturday morning children's shows (140 ).Most of the foods advertised during children's programming are high in fat, sugar, or sodium; practically no advertisements are for healthy foods such as fruits and vegetables (140)(141)(142).Studies have indicated that, compared with those who watch little television, children and adolescents who watch more television are more likely to have unhealthy eating habits and unhealthy conceptions about food (143 ), ask their parents to buy foods advertised on television (144 ), and eat more fat (145 ).Some studies of young persons have found that television watching is directly associated with obesity (146)(147)(148)(149).Because youths in the United States spend, on average, more than 20 hours a week watching television (150 ) -more time over the course of the year than they are in school ( 141)-schoolbased programs should help counter the effect of television on young persons' eating habits. Schools are a critical part of the social environment that shapes young persons' eating behaviors and can therefore play a large role in helping improve their diet.However, schools cannot achieve this goal on their own when the cultural milieu has a large influence on food-related beliefs, values, and practices (30,138 ).Families, food stores, restaurants, the food industry, religious institutions, community centers, government programs, and the mass media must also support the principles of the Dietary Guidelines for Americans.The USDA's Team Nutrition (see Appendix A) seeks to gain the support of many sectors of society for improving the diet of young persons by creating innovative public and private partnerships that promote healthy food choices through the media, schools, families, and community (151 ). # PROMOTING HEALTHY EATING THROUGH A COMPREHENSIVE SCHOOL HEALTH PROGRAM In the school environment, classroom lessons alone might not be enough to effect lasting changes in students' eating behaviors (30 ); students also need access to healthy food and the support of persons around them (137 ).The influence of school goes beyond the classroom and includes normative messages from peers and adults regarding foods and eating patterns.Students are more likely to receive a strong, consistent message when healthy eating is promoted through a comprehensive school health program. A comprehensive school health program empowers students with not only the knowledge, attitudes, and skills required to make positive health decisions but also the environment, motivation, services, and support necessary to develop and maintain healthy behaviors (152 ).A comprehensive school health program includes health education; a healthy environment; health services; counseling, psychological, and social services; integrated school and community efforts; physical education; nutrition services; and a school-based health program for faculty and staff (7 ).Each compo-nent can contribute to integrated efforts that promote healthy eating.For example, classroom lessons on nutrition can be supported by - schools providing appealing, low-fat, low-sodium foods in vending machines and at school meetings and events; - school counselors and nurses providing guidance on health and, if necessary, referrals for nutritional problems; - community organizations providing counseling or nutrition education campaigns; - physical education instructors helping students understand the relationship between nutrition and physical activity; - school food service personnel serving healthy, well-balanced meals in the cafeteria; and - school personnel acting as role models for healthy eating (153 ). The USDA is promoting health-enhancing changes in the food service component of the school health program by requiring schools to serve meals that comply with the Dietary Guidelines for Americans (154 ) and by providing technical support to schools through Team Nutrition (151 ). # RECOMMENDATIONS FOR SCHOOL HEALTH PROGRAMS PROMOTING HEALTHY EATING Based on the available scientific literature, national nutrition policy documents, and current practice, these guidelines provide seven recommendations for ensuring a quality nutrition program within a comprehensive school health program.These recommendations address school policy on nutrition, a sequential, coordinated curriculum, appropriate and fun instruction for students, integration of school food service and nutrition education, staff training, family and community involvement, and program evaluation.Strategies that schools can use to achieve these recommendations are available (Appendix C).However, local school systems need to assess the nutrition needs and issues particular to their communities, and they need to work with key school-and community-based constituents, including students, to develop the most effective and relevant nutrition education plans for their communities.Vigorous, coordinated, and sustained support from communities, local and state education and health agencies, institutions of higher education, and national organizations also is necessary to ensure success (29 ). 1.Policy: Adopt a coordinated school nutrition policy that promotes healthy eating through classroom lessons and a supportive school environment.2.Curriculum for nutrition education: Implement nutrition education from preschool through secondary school as part of a sequential, comprehensive school health education curriculum designed to help students adopt healthy eating behaviors. # Instruction for students: # Rationale for the Policy A coordinated school nutrition policy, particularly as part of an overall school health policy, provides the framework for implementing the other six recommendations and ensures that students receive nutrition education messages that are reinforced throughout the school environment.For example, such a policy would address nutrition education classes; school lunch and breakfast; classroom snacks and parties; use of food to reward or discipline; and food sold in vending machines, at school stores, snack bars, sporting events, and special activities, and as part of fundraising activities.The school environment can powerfully influence students' attitudes, preferences, and behaviors related to food (137 ).Without a coordinated nutrition policy, schools risk negating the health lessons delivered in the classroom and cafeteria by allowing actions that discourage healthy eating behaviors. # Developing the Policy A school nutrition policy should be a brief document that incorporates input from all relevant constituents of the school community: students, teachers, coaches, staff, administrators, food service personnel, nurses, counselors, public health professionals, and parents.The policy should meet local needs and be adapted to the health concerns, food preferences, and dietary practices of different ethnic and socioeconomic groups.Technical assistance for assessing nutrition education needs is available through the state NET Program (155 ).Schools might consider using one or more of the following techniques to assess their particular needs: - Interview nutrition professionals to learn more about local eating habits and to identify materials and services available for youths and adults.Schools might interview representatives from the school food service program; the state NET Program; the nutrition unit within the State Department of Health; the district or state school health coordinator; the local WIC program and Cooperative Extension nutrition education program; the state or local chapters of the American Cancer Society, American Dietetic Association, and the American Heart Association; nutrition councils or coalitions; university research programs; organizations with special insights into the particular nutrition education needs of cultural and ethnic minorities; or businesses that offer nutrition-related services or food products. - Interview food service staff about students' eating practices in the school cafeteria. - Observe the school cafeteria, the teachers' lunchroom, and other areas in the school where food is available. - Review nutrition curricula used by teachers. - Survey teachers to determine how nutrition is taught, whether teachers use food for reward or punishment, and the level of interest of teachers in nutrition or wellness programs for themselves. - Survey students to determine their dietary preferences and what types of healthy changes in school food they most want. The policy plan should include means of obtaining follow-up input from all parties and means of revising the plan as needed.Student involvement is critical to the success of a nutrition policy.A nutrition advisory committee or a nutrition subcommittee of the school health advisory council having student members can develop and promulgate a coordinated school nutrition policy.Technical assistance in forming a school nutrition advisory committee is available from the American School Food Service Association (Appendix A).Successful implementation of a nutrition policy also requires the active support of school and district educational leadership. # Content of the Policy The written policy should describe the importance of the nutrition component within the comprehensive school health program.This section can briefly describe the role of good nutrition in promoting childhood growth, health, and learning; discuss the role of child and adolescent nutrition in reducing the risk for chronic diseases of adulthood; identify the importance of establishing a school environment that supports healthy eating choices by young persons; and generate support for the policy by identifying how improvements in student nutrition can satisfy the needs of different constituents of the school community (e.g., students, teachers, and food service personnel).An optimal policy on nutrition should publicly commit the school to providing adequate time for a curriculum on nutrition, serving healthy and appealing foods at school, developing food-use guidelines for teachers, supporting healthy school meals, and establishing links with nutrition service providers. Curriculum.Adequate time should be allocated for nutrition education throughout the preschool, primary, and secondary school years as part of a sequential, comprehensive school health education program.In addition, teachers should be adequately trained to teach nutrition and be provided with ongoing in-service training. Healthy † and appealing foods.Healthy and appealing foods should be available in meals, a la carte items in the cafeteria, snack bars, and vending machines (Exhibit 1); as classroom snacks; and at special events, athletic competitions, staff meetings, and parents' association meetings.In addition, schools should discourage the sale of foods high in fat, sodium, and added sugars (e.g., candy, fried chips, and soda) on school grounds and as part of fundraising activities.Although selling low-nutritive foods may provide revenue for school programs, such sales tell students that it is acceptable to compromise health for financial reasons (158 ).The school thereby risks contradicting the messages on healthy eating given in class.If schools contract with food service management companies to supply meals, the contractors should be required to serve appealing, low-fat, low-sodium meals that comply with the standards of the Dietary Guidelines for Americans. †As defined by the U.S. Food and Drug Administration (156,157 ) in its food label regulations, a "healthy" food must be low in fat (≤3 g per serving), be low in saturated fat (≤1 g per serving), contain limited amounts of cholesterol (≤60 mg per serving for a single-item food), and contain limited amounts of salt (≤480 mg per serving until 1998, when the criterion for a single-item food will decrease to ≤360 mg per serving).In addition, single-item foods that are not raw fruits or vegetables must provide ≥10% of the daily value of one or more of the following nutrients: vitamin A, vitamin C, iron, calcium, protein, and fiber.Criteria for products that include more than one type of food (e.g., macaroni and cheese) vary depending on the food. *These foods are appropriate if the vending machine is refrigerated. †Some schools might not want to offer these items because these foods can contribute to dental caries. §
Some schools might not want to offer peanut butter; although it is low in saturated fatty acids, peanut butter is high in total fat.Food use guidelines for teachers.Schools should discourage teachers from using food for disciplining or rewarding students.Some teachers give students low-nutritive foods, such as candy, as a reward for good behavior, and punish misbehaving students by denying a low-nutritive treat (159 ).These practices reinforce students' preferences for low-nutritive foods and contradict what is taught during nutrition education.Schools should recommend that both teachers and parents serve healthy party snacks and treats (160 ). Support for healthy school meals.Starting with the 1996-1997 school year, schools will be required to serve meals that comply with the standards of the Dietary Guidelines for Americans (154 ).To encourage students to participate in school meal programs and to make healthy choices in cafeterias, schools can use marketing-style incentives and promotions (13,14,135,161 ); use healthy school meals as examples in class; educate parents about the value of healthy school meals; involve students and parents in planning meals; and have teachers, administrators, and parents eat in the cafeteria and speak favorably about the healthy meals available there.Students should also be given adequate time and space to eat meals in a pleasant and safe environment (162 ). Links with nutrition service providers.Schools should establish links with qualified public health and nutrition professionals who can provide screening, referral, and counseling for nutritional problems (30,163 ); inform families about supplemental nutrition services available in the community, such as WIC ( 164), food stamps, local food pantries, the Summer Food Service Program, and the Child and Adult Care Food Program; and implement nutrition education and health promotion activities for school faculty, other staff, school board members, and parents.These links can help prevent and resolve nutritional problems that can impair a student's capacity to learn, demonstrate the value placed on good nutrition for the entire school community, and help adults serve as role models for school-age youths. # Recommendation 2.Curriculum for nutrition education: Implement nutrition education from preschool through secondary school as part of a sequential, comprehensive school health education curriculum designed to help students adopt healthy eating behaviors.Nutrition Education as Part of a Comprehensive School Health Education Program Nutrition education should be part of a comprehensive health education curriculum that focuses on understanding the relationship between personal behavior and health.This curriculum should give students the knowledge and skills they need to be "health literate," as delineated by the national health education standards (29 ) (Exhibit 2).The comprehensive health education approach is important to nutrition education because - unhealthy eating behaviors may be interrelated with other health risk factors (e.g., cigarette smoking and sedentary lifestyle) (165 ), - nutrition education shares many of the key goals of other health education content areas (e.g., raising the value placed on health, taking responsibility for one's health, and increasing confidence in one's ability to make health-enhancing behavioral changes), and - state-of-the-art nutrition education uses many of the social learning behavioral change techniques used in other health education domains. Therefore, nutrition education activities can reinforce, and be reinforced by, activities that address other health education topics as well as health in general. Linking nutrition and physical activity is particularly important because of the rising proportion of overweight youths in the United States.Nutrition education lessons should stress the importance of combining regular physical activity with sound nutrition as part of an overall healthy lifestyle.Physical education classes, in turn, should include guidance in food selection (6 ). # Sequential Lessons and Adequate Time Students who receive more lessons on nutrition have more positive behavioral changes than students who have fewer lessons (166,167 ).To achieve stable, positive changes in students' eating behaviors, adequate time should be allocated for nutrition education lessons.The curriculum should be sequential from preschool through secondary school; attention should be paid to scope and sequence.When designing the curriculum, schools should assess and address their students' needs and concerns.A curriculum targeted to a limited number of behaviors might make the most effective use of a scarce instructional time available for nutrition education (136 ). # EXHIBIT 2: National Health Education Standards (29 ) 1.Students will comprehend concepts related to health promotion and disease prevention.2.Students will be able to access valid health information and healthpromoting products and services.3.Students will be able to practice health-enhancing behaviors and reduce health risks.4.Students will analyze the influence of culture, media, technology, and other factors on health.5.Students will be able to use interpersonal communication skills to enhance health.6.Students will be able to use goal-setting and decision-making skills to enhance health.7.Students will be able to advocate for personal, family, and community health. To maximize classroom time, nutrition education can be integrated into the lesson plans of other school subjects; for example, math lessons could analyze nutrient intake or reading lessons could feature texts on nutrition (168 ).Little research on the integrated approach has been conducted ( 137), but embedding information on nutrition in other courses probably reinforces the goals of nutrition education.However, the exclusive use of an integrative approach might sacrifice key elements of an effective nutrition education program (e.g., adequate time, focusing on behaviors and skillbuilding, attention to scope and sequence, and adequate teacher preparation) (137 ).Therefore, integration into other courses can complement but should not replace sequential nutrition education lessons within a comprehensive school health education curriculum.Classroom time can be maximized also by having nutrition education lessons use skills learned in other classes (e.g., math or language arts) (169)(170)(171). Organizations and agencies can supply information on specific nutrition education curricula and materials (Appendix A).The USDA's NET Program provides technical assistance in school-based nutrition education (2,172 ).The Food and Nutrition Information Center of USDA's National Agricultural Library provides information on nutrition education evaluation and resources and serves as a national depository and lending library for NET materials.Nutritionists at some organizations can also answer specific nutrition content questions (Appendix A). # Focusing on Promoting Healthy Eating Behaviors The primary goal of nutrition education should be to help young persons adopt eating behaviors that will promote health and reduce risk for disease.Knowing how and why to eat healthily is important, but knowledge alone does not enable young persons to adopt healthy eating behaviors (137 ).Cognitive-focused curricula on nutrition education typically result in gains in knowledge but usually have little effect on behavior (173)(174)(175)(176)(177)(178). Behaviorally based education encourages specific healthy eating behaviors (e.g., eating less fat and sodium and eating more fruits and vegetables) (136,179 ); however, it does not detail the technical and scientific knowledge on which dietary recommendations are based and, therefore, might not fulfill science education requirements (180).The strategies listed in Appendix C can be used as central concepts in a behaviorally based nutrition education program. Several programs using a behavioral approach have achieved significant (p<0.05), positive changes in students' eating behaviors (167,(181)(182)(183)(184)(185)(186)(187)(188)(189)(190).Compared with students in control schools, students in some behaviorally based health and nutrition education programs had significant (p<0.05), favorable changes in serum cholesterol levels (167,188,191 ), blood pressure level (167,191 ), and body mass index (184 ).Although most of the behaviorally oriented programs did not achieve all their behavioral aims-perhaps because of the limited amount of curriculum time (136 )-current scientific knowledge indicates that a focus on behavior is a key determinant in the success of nutrition education programs (136)(137)(138). # Recommendation 3.Instruction for students: Provide nutrition education through developmentally appropriate, culturally relevant, fun, participatory activities that involve social learning strategies.Developmentally Appropriate and Culturally Relevant Activities Different educational strategies should be used for young persons at different stages of cognitive development.Regardless of the amount and quality of teaching they receive, young elementary schoolchildren might not fully understand abstract concepts (e.g., the nutrient content of foods or the classification of foods into groups) (192)(193)(194).Nutrition education for young children should focus on concrete experiences (e.g., increasing exposure to many healthy foods and building skills in choosing healthy foods) (169 ). More abstract associations between nutrition and health become appropriate as children approach middle school.By this age, children can understand and act on the connection between eating behaviors and health (137,194 ).Nutrition education for middle and high school students should focus on helping students assess their own eating behaviors and set goals for improving their food selection (138,195 ).Lessons for older children should emphasize personal responsibility, decision-making skills, and resisting negative social pressures (183,185,187,189 ). Nutrition education presents opportunities for young persons to learn about and experience cultural diversity related to food and eating.Students from different cultural groups have different health concerns, eating patterns, food preferences, and food-related habits and attitudes.These differences need to be considered when designing lesson plans or discussing food choices.Nutrition education can succeed only when students believe it is relevant to their lives. # Active Learning and an Emphasis on Fun The context in which students learn about healthy eating behaviors and the feelings students associate with healthy foods are key factors in determining their receptivity to nutrition education.Students are more likely to adopt healthy eating behaviors when - they learn about these behaviors through fun, participatory activities rather than through lectures (138,196,197 ); - lessons emphasize the positive, appealing aspects of healthy eating patterns rather than the negative consequences of unhealthy eating patterns; - the benefits of healthy eating behaviors are presented in the context of what is already important to the students; and - the students have repeated opportunities to taste foods that are low in fat, sodium, and added sugars and high in vitamins, minerals, and fiber during their lessons. § §When serving food, teachers must use hygienic food handling practices and consider possible food allergies and religious prohibitions; the food service director can help in this area. Computer-based lessons on nutrition can also be effective (198 ), especially when teacher time is limited or when student self-assessment is appropriate.Interactive, highly entertaining, and well-designed computer programs are now available to help young persons learn healthy food selection skills and assess their own diets (199,200).Computer-based lessons allow students to move at their own pace and can capture their attention. # Social Learning Techniques Most of the nutrition education programs that have resulted in behavioral change have used teaching strategies based on social learning theory (195,(201)(202)(203)(204)(205).In such lessons, increasing student knowledge is only one of many objectives.Social learning instruction also emphasizes - raising the value students place on good health and nutrition and identifying the benefits of adopting healthy eating patterns, including short-term benefits that are important to young persons (e.g., physical appearance, sense of personal control and independence, and capacity for physical activities); - giving students repeated opportunities to taste healthy foods, including foods they have not yet tasted; - working with parents, school personnel, public health professionals, and others to overcome barriers to healthy eating; - using influential role models, including peers, to demonstrate healthy eating practices; - providing incentives (e.g., verbal praise and small prizes) to reinforce messages; - helping students develop practical skills for and self-confidence in planning meals, preparing foods, reading food labels, and making healthy food choices through observation and hands-on practice; - enabling students to critically analyze sociocultural influences, including advertising, on food selection, to resist negative social pressures, and to develop social support for healthy eating; and - helping students analyze their own eating patterns, set realistic goals for changes in their eating behaviors, monitor their progress in reaching those goals, and reward themselves for achieving their goals. Nutrition education strategies include social learning techniques (Appendix C). # Recommendation 4.Integration of school food service and nutrition education: Coordinate school food service with nutrition education and with other components of the comprehensive school health program to reinforce messages on healthy eating. The school cafeteria provides a place for students to practice healthy eating.This experience should be coordinated with classroom lessons to allow students to apply critical thinking skills taught in the classroom (2,8,9,(11)(12)(13)(14)(15)18,169,178,206 ).School food service personnel can - visit classrooms and explain how they make sure meals meet the standards of the Dietary Guidelines for Americans, - invite classes to visit the cafeteria kitchen and learn how to prepare healthy foods, - involve students in planning the school menu and preparing recipes, - offer foods that reinforce classroom lessons (e.g., whole wheat rolls to reinforce a lesson on dietary fiber), - post in the cafeteria posters and fliers on nutrition, and - display nutrition information about available foods and give students opportunities to practice food analysis and selection skills learned in the classroom. In addition, classroom teaching can complement the goals of the school food service.For example, teachers can help food service managers by teaching students about the importance of nutritious school meals and getting feedback from students on new menu items developed to meet the goals set by USDA's School Meals Initiatives for Healthy Children (154 ). To ensure consistent nutrition messages from the school, food service personnel should work closely with those responsible for other components of the school health program.For example, the personnel can - help develop and implement school policies that make healthful foods available; - educate parents about the value of school meals (e.g., put health messages in monthly menus sent home to parents or make periodic presentations at parents' association meetings) (11,13 ); - help schools access and assess community public health and nutrition services; and - keep classroom teachers, physical education teachers, coaches, counselors, health-service providers, and other staff informed about the importance of healthy school meals. # Recommendation 5.Training for school staff: Provide staff involved in nutrition education with adequate preservice and ongoing in-service training that focuses on teaching strategies for behavioral change. Training in nutrition and health education can increase the extent to which teachers implement a curriculum (207)(208)(209), which in turn affects the likelihood that students' eating behaviors will change (167,207 ).All elementary school teachers as well as secondary school teachers in disciplines such as home economics, family and consumer sciences, language arts, physical education, and science should receive nutrition education training.State NET Programs can provide technical assistance for training teachers in nutrition education (Appendix A). Training should address content and teaching strategies.Because classroom teachers often need more help with innovative nutrition teaching techniques than with content (195,210 ), training should focus on giving teachers the skills they need to use the nonlecture, active learning methods discussed previously (195 ).Training programs are most effective if they - are designed to meet the specific needs of the teachers and are based on the teachers' level of nutrition knowledge and experience with the suggested teaching strategies, - model behavioral change techniques and give teachers practice in using them, - involve multiple sessions spaced across time so that teachers can try out the newly learned techniques in their classrooms and report on their experiences to the training group, and - provide posttraining sessions so that teachers can share experiences with their peers (211,212 ). Teachers should understand the importance of fully implementing the selected curriculum and become familiar with its underlying theory and concepts.Training should also help teachers assess and improve their own eating practices and make them aware of the behavioral messages they give as role models (213 ). Continuing education activities in nutrition education should be offered to food service personnel so this staff can reinforce classroom instruction through the school meal program and help shape the school's nutrition policy.State NET Programs and the National Food Service Management Institute provide technical assistance and training seminars for school nutrition professionals (see Appendix A).Administrative support is also critical to implementing a new program (214 ).Training for school administrators can help gain their support for nutrition education.Health promotion services for all school staff can positively affect their eating behaviors and their effectiveness in teaching healthy eating behaviors (180,215,216 ). # Recommendation 6.Family and community involvement: Involve family members and the community in supporting and reinforcing nutrition education. The attitudes and behaviors of parents and caretakers directly influence children's and adolescents' choice of foods (217,218 ).Parents control most of the food choices available at home, so changing parents' eating behaviors may be one of the most effective ways to change their children's eating behaviors.Involving parents in a nutrition education curriculum at the elementary school level can enhance the eating behaviors of both the students (181,(219)(220)(221) and the parents (181,219,222 ).Although parental involvement can enhance the effects of nutrition education programs at the elementary school level, it is not known whether involving parents at the secondary school level helps improve the students' eating behaviors.For older youths, self-assessment (185,189,198 ) and peer educators (187 ) might be more influential than parental involvement (137 ). Parents are usually more receptive to activities that can be done at home than to those that require their attendance at the school (223,224 ).To involve parents and other family members in nutrition education, schools can - send nutrition education materials and cafeteria menus home with students, - ask parents to send healthy snacks to school, - invite parents and other family members to periodically eat with their children in the cafeteria, - invite families to attend exhibitions of student nutrition projects or health fairs (217 ), - offer nutrition education workshops and screening services, and - assign nutrition education homework that students can do with their families (e.g., reading and interpreting food labels, reading nutrition-related newsletters, and preparing healthy recipes). Through school health advisory councils or through direct contact with community organizations, schools can engage community resources and services to respond to the nutritional needs of students (225,226 ).Schools can also participate in community-based nutrition education campaigns sponsored by public health agencies or voluntary organizations.
Students are most likely to adopt healthy eating behaviors if they receive consistent messages through multiple channels (e.g., home, school, community, and the media) and from multiple sources (e.g., parents, peers, teachers, health professionals, and the media) (225 ). # Recommendation 7.Program evaluation: Regularly evaluate the effectiveness of the school health program in promoting healthy eating, and change the program as appropriate to increase its effectiveness. Policymakers should regularly review the effectiveness of the school nutrition program.All groups affected by the program should have the opportunity to provide input.Assessment of nutrition programs and policies should include whether - a comprehensive school nutrition policy exists and is implemented as written; - nutrition education is provided throughout the preschool, primary, and secondary school years as part of comprehensive school health education; - teachers deliver nutrition education through developmentally appropriate, culturally relevant, fun, participatory activities that involve social learning strategies; - teachers and school food service personnel have undertaken joint project planning and action; - teachers have received curriculum-specific training; and - families and community organizations are involved in nutrition education. Schools might also consider measuring the effects of their programs and policies on self-reported eating behaviors; key variables that influence behavior, such as knowledge, attitudes, self-confidence, and behavioral intentions; and in-school eating behaviors that are easy to assess, such as participation in school food service programs and the number of students choosing healthy alternatives in the cafeteria (e.g., salad bars or low-fat milk). Schools can consult with the state NET Program or with evaluation specialists at universities, school districts, or the state departments of education or health to identify methods and materials for evaluating the effectiveness of their program (227,228).Valid evaluations can increase parent and community support for school programs, help schools reward teachers for exceptional work, and support grant applications for enhancing school health programs. # CONCLUSION To ensure a healthy future for our children, school-based nutrition education programs must become a national priority.These programs should be part of comprehensive school health programs and reach students from preschool through secondary school.School leaders, community leaders, and parents must commit to implementing and sustaining nutrition education programs within the schools.Such support is crucial to promoting healthy eating behaviors. The seven recommendations for school-based nutrition education presented in this report provide the framework for establishing such programs.By adopting these recommendations, schools can help ensure that all school-age youths attain their full educational potential and good health. # APPENDIX B: YOUTH RISK BEHAVIOR SURVEILLANCE SYSTEM AND SCHOOL HEALTH POLICIES AND PROGRAMS STUDY In 1990, CDC established the Youth Risk Behavior Surveillance System to help monitor progress in attaining national health and education objectives by periodically measuring the prevalence of behaviors in six health risk categories.These behaviors, which are usually established during youth, contribute to the leading causes of death and disease in the United States.Dietary behaviors are one of the six health risk categories.CDC conducts the Youth Risk Behavior Survey (YRBS) biennially in a national probability sample of high school students and enables interested state and local education agencies to conduct the survey in comparable probability samples in states and cities (127 ).The specific dietary behaviors and attitudes monitored by the YRBS include consumption of fruits and vegetables, consumption of foods high in fat, perceptions of body weight, and attempted weight loss and weight-loss techniques used.The YRBS also obtains information about specific physical activity behaviors. In 1994, CDC conducted the School Health Policies and Programs Study (SHPPS), which is a national study of school policies and programs at the school, district, and state levels that support comprehensive school health programs.The study also provides baseline data on national health and education objectives that can be attained through school health and physical education, school food service, and school health services and policies (229 ). SHPPS included a mail survey of local and state education agencies' policies related to school health in grades kindergarten through 12.The survey was conducted in all states and in a nationally representative sample of districts.The study also included on-site, structured interviews with school principals, health education teachers, physical education teachers, school food service directors, school nurses, counselors, and other personnel in a nationally representative sample of middle schools and high schools.The questionnaire included the following: school nutrition education requirements for students; the content of nutrition education curricula; training and joint activities of food service staff and teachers responsible for nutrition education; school policies related to foods sold in vending machines and for fundraising; food service practices related to purchasing and preparing food; involvement of parents, staff, and students in planning food service meals; and involvement of fast-food or food service management companies in school meals. -Teach the importance of balancing food intake and physical activity. - Identify healthy snacks (e.g., fruits, vegetables, and low-fat milk). - Increase students' confidence in their ability to make healthy eating choices by gradually building up their food selection and preparation skills and giving them practice. # Strategies to enhance behavioral capabilities that will support healthy eating - Provide many healthy foods for students to taste in an enjoyable social context. - Let students prepare simple snacks. - Have students try unfamiliar and culturally diverse foods that are low in fat, sodium, and added sugars. # For upper elementary students Strategies to make the food environment more health-enhancing - Make healthy foods (e.g., fruits, vegetables, and whole grains) widely available at school, and discourage the availability of foods high in fat, sodium, and added sugars. - Involve parents in nutrition education through homework. - Provide role models (e.g., teachers, parents, other adults, adolescents, and celebrities or fictional characters) for healthy eating. - Through class discussions and small-group exercises, provide social support for making healthy changes in eating and physical activity. - Provide cues, through posters and marketing-style incentives that students design, that encourage students to make healthy choices about eating and physical activity. - Use incentives, such as verbal praise or token gifts, to reinforce healthy eating and physical activity.Do not use food as a reward or punishment of any behavior. # Strategies to enhance personal characteristics that will support healthy eating - Explain the effects that diet and physical activity have on future health as well as on immediate concerns (e.g., current health, physical appearance, obesity, sense of well-being, and capacity for physical activity). - Teach the principles of the Dietary Guidelines for Americans and the Food Guide Pyramid.Instill pride in choosing to eat meals and snacks that comply with these principles. - Help students identify foods high and low in fat, saturated fat, cholesterol, sodium, added sugars, and fiber. - Teach the importance of balancing food intake and physical activity. - Teach the importance of eating adequate amounts of fruits, vegetables, and whole grains. - Help students increase the value they place on health and their sense of control over food selection and preparation. - Increase students' confidence in their ability to make healthy eating choices by gradually building up their food selection and preparation skills and giving them practice. - Have students analyze food preferences and factors that trigger eating behaviors. # Strategies to enhance behavioral capabilities that will support healthy eating - Provide opportunities for students to taste many healthy foods in an enjoyable social context. - Let students prepare healthy snacks or simple meals. - Encourage students to try unfamiliar and culturally diverse foods that are low in fat, sodium, and added sugars and that are high in fiber. - Have students select healthy foods from a fast-food restaurant menu. - Teach students how to recognize the fat, sodium, and fiber contents of foods by reading nutrition labels. - Help students record and assess their food intake. - Teach students how to use the Food Guide Pyramid to assess their diet for variety, moderation, and proportionality. - Have students set simple goals for changes in eating and physical activity, and devise strategies for implementing these changes and monitoring progress in reaching their goals. - When appropriate, let students practice (through role plays) encouraging parents to make healthy choices about eating and physical activity at home. - Have students examine media and social influences on eating and physical activity; teach students how to respond to these pressures. # Strategies to enhance behavioral capabilities that will support healthy eating - Let students plan and prepare healthy meals. - Have students select healthy foods from restaurant and cafeteria menus. - Teach students how to use nutrition labels to make healthy food choices. - Teach students ways to modify recipes and prepare foods to reduce fat and sodium content and to increase fiber content. - Help students identify incentives and reinforcements for their current eating and physical activity behaviors. - Have students examine media and social inducements to adopt unhealthy eating and physical activity patterns, teach them how to respond to these pressures, and let them use their new knowledge to identify their own resistance strategies. - Have students analyze environmental barriers to healthy eating and physical activity; explore strategies for overcoming these barriers. - When appropriate, give students practice in encouraging parents to make healthy choices about eating and physical activity at home. - Teach students to record their food intake, then have them assess and compare their diets with the standards set forth in the Dietary Guidelines for Americans and the Food Guide Pyramid.Have them assess and compare their intake of key nutrients (e.g., calcium and iron) with the intake recommended by the Public Health Service. - Have students set goals for healthy changes in eating and physical activity, identify barriers and incentives, and assess alternative strategies for reaching their goals and decide which to follow.Show students how to monitor their progress, revise their goals if necessary, and reward themselves for successfully attaining their goals. - Teach students how to evaluate nutrition claims from advertisements and nutrition-related news stories. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy.To receive an electronic copy on Friday of each week, send an e-mail message to lists@list.cdc.gov.The body content should read subscribe mmwr-toc.Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov.To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments.The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday.Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd.,N.E., Atlanta, GA 30333; telephone (404) 332-4555. 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. # 6U.S. Government Printing Office: 1996-733-175/47007 Region IV # APPENDIX A: NUTRITION EDUCATION RESOURCE LIST Nutrition education curricula and print, audiovisual, and computer-based materials are available from government agencies, voluntary organizations, corporations, and commodity organizations.State Nutrition Education and Training Program coordinators can help schools identify the most appropriate nutrition education curricula and materials.National clearinghouses that can help schools identify a wide range of nutrition education and school food service resources are sponsored by the U.S. Department of Agriculture's Food and Nutrition Information Center and the National Food Service Management Institute; the former also serves as a lending library. # APPENDIX C: SELECTED SCHOOL-BASED STRATEGIES TO PROMOTE HEALTHY EATING Different, developmentally appropriate activities are listed for lower elementary school, upper elementary school, and middle and high school students (194 ).This list is not intended to be comprehensive.However, it does include many of the concepts critical to improving the diet and health of young persons in this country.Schools should review these educational activities in relation to their students' needs and abilities to determine which activities are appropriate at each grade level. Interventions that promote healthy changes in eating behaviors need to target three interacting spheres of influence: (a) the environment, which influences the likelihood that healthy eating behaviors will be adopted through social norms, influential role models, cues to action, reinforcements, and opportunities for action; (b) personal characteristics (e.g., knowledge, attitudes, beliefs, values, confidence in one's ability to change eating behaviors, and expectations about the consequences of making those changes); and (c) behavioral skills and experience, which are related to selecting or preparing specific foods, dietary self-assessment, and decision-making (186,194,203,204 ). The strategies listed here require the involvement of teachers, administrators, food service personnel, other school staff, and parents (194 ).Classroom teachers play the lead role in most of these activities, but many activities would be most effective if they were reinforced by other persons; all adults in the school community can help by serving as role models.Each school or district should determine the policies it needs to guide its nutrition-related activities and who is responsible for the tasks. # For lower elementary students Strategies to make the food environment more health-enhancing - Make healthy foods (e.g., fruits, vegetables, and whole grains) widely available at school, and discourage the availability of foods high in fat, sodium, and added sugars. - Involve parents in nutrition education through homework. - Provide role models (e.g., teachers, parents, other adults, older children, and celebrities or fictional characters) for healthy eating. - Provide cues, through posters and marketing-style incentives, that encourage students to make healthy choices about eating and physical activity. - Use incentives, such as verbal praise or token gifts, to reinforce healthy eating and physical activity.Do not use food for reward or punishment of any behavior. # Strategies to enhance personal characteristics that will support healthy eating - Make basic connections between food and health (e.g., "You need food to feel good and to grow"). # For middle and high school students Strategies to make the food environment more health-enhancing - Make healthy foods (e.g., fruits, vegetables, and whole grains) widely available at school, and discourage the availability of foods high in fat, sodium, and added sugars. - Provide role models (e.g., teachers, parents, other adults, and celebrities) for healthy eating. - Use peers as role models, and use peer-led nutrition education activities. - Through class discussions and small-group exercises, provide social support for making healthy changes in eating and physical activity. - Provide cues, through posters and marketing-style incentives that students design, that encourage students to make healthy choices about eating and physical activity. # Strategies to enhance personal characteristics that will support healthy eating - Explain the effects that diet and physical activity have on future health as well as on immediate concerns (e.g., current health, physical appearance, obesity, eating disorders, sense of well-being, and capacity for physical activity). - Have students identify reasons to adopt healthy eating and physical activity patterns. - Teach the principles of the Dietary Guidelines for Americans.Instill in the students pride in choosing to eat meals and snacks that comply with these principles. - Teach students how to identify foods high and low in fat, saturated fat, cholesterol, sodium, and added sugars. - Teach students how to identify foods that are excellent sources of fiber, complex carbohydrates, calcium, iron, vitamin A, vitamin C, and folate. - Teach the importance of balancing food intake and physical activity. - Teach the effects of unsafe weight-loss methods and the characteristics of a safe weight-loss program. - Help students increase the value they place on health and their sense of control over food selection and preparation. - Increase students' confidence in their ability to eat healthily by gradually building up their skills and giving them practice. - Help students examine what motivates persons to adopt particular eating habits. Have students keep a food diary noting what cues their own eating behavior (e.g., mood, hunger, stress, or other persons).
will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available.#Chikungunya Virus There is no specific treatment for CHIKV infection, nor any commercially available vaccine to prevent it.Pending the development of a new vaccine, the only effective means of prevention are to protect individuals against mosquito bites.It should be noted, however, that the only available method for preventing an ongoing transmission of a possible CHIKV epidemic, namely the control of its vectors, has rarely been achieved and never has been sustained.Given these factors, the Pan American Health Organization (PAHO), with the support of the Division of Vector-borne Diseases of the United States Centers for Disease Control and Prevention (DVBD, CDC), created a working group and convened a meeting in Lima, Peru, on July 21−23, 2010, to discuss the threat this virus represents and to examine measures that might be taken to mitigate this vii threat (see Appendix I for additional details on the meeting).These preparedness guidelines are the result of this collaboration.These guidelines are intended to be adapted by each Member Country.They are designed to increase awareness about the threat and to provide the necessary tools to put in place the best possible strategies to prevent the importation of CHIKV into the Region, or to control it if introduced.These guidelines provide guidance on how to detect an outbreak of the disease, conduct pertinent epidemiological investigations, and prevent or mitigate the spread of the disease throughout the Region. We encourage everyone working to apply these guidelines to take into account all the knowledge available and their own country's capability to cope with the introduction of CHIKV.Steps should be taken now to put in place the necessary measures that will decrease the impact that this new arbovirus could have in our Region.The publication of these guidelines was possible thanks to funding from the U.S. Centers for Disease Control and Prevention. # ABBREviATiONS ANd ACRONymS Ae.Aedes # BACKGROUND AND RATIONALE Since 2004, Chikungunya virus (CHIKV) has been causing large epidemics of chikungunya fever (CHIK), with considerable morbidity and suffering.The epidemics have crossed international borders and seas, and the virus has been introduced into at least 19 countries by travelers returning from affected areas. Because the virus has been introduced into geographic locations where the appropriate vectors are endemic, the disease could establish itself in new areas of Europe and the Americas.The possibility that CHIKV could become established in the Americas has heightened awareness of the need to develop guidelines for the prevention and control of CHIK in PAHO's Member Countries.This document is meant to serve as a guideline that individual countries can use as the basis for their CHIKV surveillance, prevention, and control programs. # TA R G E T O F T H E S E G U I D E L I N E S : These guidelines are intended to be used by health workers, public health officials, and vector control specialists at the national, district, and sub-district levels. # O B J E C T I V E S : General objectives are the prevention, detection, and timely response to outbreaks of CHIK through surveillance, case detection, investigation, and the launching of public health actions. # EPidEmiOLOgy # BACkgROUNd CHIKV is an RNA virus that belongs to the Alphavirus genus in the family Togaviridae.The name chikungunya derives from a word in Makonde, the language spoken by the Makonde ethnic group living in southeast Tanzania and northern Mozambique.It roughly means "that which bends," describing the stooped appearance of persons suffering with the characteristic painful arthralgia. Epidemics of fever, rash, and arthritis resembling CHIK were reported as early as the 1770s.However, the virus was not isolated from human serum and mosquitoes until an epidemic in Tanzania in 1952−1953.1 Subsequent outbreaks occurred in Africa and Asia, many of them affecting small or rural communities. In Asia, however, CHIKV strains were isolated during large urban outbreaks in Bangkok, Thailand, in the 1960s and in Calcutta and Vellore, India, during the 1960s and 1970s.2,3 # Recent Outbreaks After the initial identification of CHIKV, sporadic outbreaks continued to occur, but little activity was reported after the mid-1980s.In 2004, however, an outbreak originating on the coast of Kenya subsequently spread to Comoros, La Réunion, and several other Indian Ocean islands in the following two years. From the spring of 2004 to the summer of 2006, an estimated 500,000 cases had occurred. The epidemic spread from the Indian Ocean islands to India, where large outbreaks occurred in 2006.Once introduced in India, CHIKV spread to 17 of the country's 28 states, infecting more than 1.39 million people before the end of the year.The outbreak in India continued into 2010, with new cases appearing in areas that had not been affected in the epidemic's early phase. Viremic travelers also spread outbreaks from India to the Andaman and Nicobar Islands, Sri Lanka, the Maldives, Singapore, Malaysia, Indonesia.Concern over the spread of CHIKV peaked in 2007, when the virus was found to be spreading autochthonously (human-to-mosquito-to-human) in northern Italy after being introduced by a viremic traveler returning from India.4 The attack rates in communities that have been affected in the recent epidemics ranged from 38%−63%, and in many of these countries cases continue to be reported, albeit at reduced levels.In 2010, the virus continued to cause illness in India, Indonesia, Myanmar, Thailand, and the Maldives; it also has resurged in La Réunion.In 2010, imported cases also were identified in Taiwan, France, and the United States.These cases were infected viremic travelers returning from Indonesia, La Réunion, and India, respectively. During the recent outbreaks, individuals viremic with CHIKV were found in the Caribbean (Martinique), the United States, and French Guiana.5 All of them had returned from areas with endemic or epidemic CHIKV transmission; thus, these cases were not due to autochthonous transmission.All of these areas have competent mosquito vectors and naïve hosts, however, and thus could support endemic transmission of CHIKV in the Americas.Given these factors, CHIKV has the capacity to emerge, re-emerge, and quickly spread in novel areas, which makes heightened surveillance and preparedness a priority. # EPidEmiOLOgy # Tr a n s m i s s i o n D y n a m i c s # Vectors There are two main vectors of CHIKV, Aedes aegypti and Ae.albopictus.Both mosquito species are widely distributed throughout the tropics with Ae.albopictus also present at more temperate latitudes.Given the vectors' distribution throughout the Americas, the entire Region is susceptible to the virus' invasion and spread. # Reservoirs Humans serve as the primary CHIKV reservoir during epidemic periods.During inter-epidemic periods, several vertebrates have been implicated as potential reservoirs, including non-human primates, rodents, birds, and some small mammals. # Incubation Periods Mosquitoes acquire the virus from a viremic host.Following an average extrinsic incubation of 10 days, the mosquito is then able to transmit the virus to a naïve host, such as a human.In humans bitten by an infected mosquito, disease symptoms typically occur after an average intrinsic incubation period of threeto-seven days (range: 1−12 days) (Figure 1). # Susceptibility and Immunity All individuals not previously infected with CHIKV (naïve individuals) are at risk of acquiring infection and developing disease.It is believed that once exposed to CHIKV, individuals will develop long lasting immunity that will protect them against reinfection. # EPidEmiOLOgy # Mosquito refeeds / acquires virus Viremia # Summary of Epidemiology Section - CHIKV is an RNA virus that belongs to the Alphavirus genus in the family Togaviridae. - The attack rates in communities that have been affected in the recent epidemics ranged from 38%−63%. - The two major vectors of CHIKV are Ae.aegypti and Ae.albopictus; both mosquitoes are widely distributed throughout the tropics and Ae.albopictus is present at more temperate latitudes. - CHIK is not known to be circulating in the Americas; however, the risk of introduction is high due to travel importation, competent vectors (same vectors as dengue), and population susceptibility. # CLiNiCAL # 3A. Clinical Presentation of Acute disease Following the bite of a mosquito infected with CHIKV, most individuals will present with symptomatic disease after an incubation period of three to seven days (range: 1−12 days).Not all individuals infected with the virus develop symptoms, however.Serosurveys indicate that between 3% and 28% of persons with antibodies to CHIKV have asymptomatic infections.6−7 Individuals acutely infected with CHIKV, whether clinically apparent or asymptomatic, can contribute to the spread of the disease if the vectors that transmit the virus are present and active in the same location. CHIKV can cause acute, subacute, and chronic disease.Acute disease is most often characterized by sudden onset of high fever (typically greater than 102°F ) and severe joint pain.8−10 Other signs and symptoms may include headache, diffuse back pain, myalgias, nausea, vomiting, polyarthritis, rash, and conjunctivitis (Table 1).11 The acute phase of CHIK lasts for 3−10 days. # CLiNiCAL - Fever typically lasts from several days up to a week.The fever can be continuous or intermittent; a drop in temperature is not associated with worsening of symptoms, however.Occasionally, the fever may be associated with relative bradycardia. - Joint symptoms are usually symmetric and occur most commonly in hands and feet, but they can affect more proximal joints.Swelling can also be seen and is often associated with tenosynovitis.Patients are often severely incapacitated due to pain, tenderness, swelling, and stiffness.Many patients cannot perform normal tasks or go to work, and many will be confined to bed due to these symptoms. - Rash usually occurs two to five days after onset of fever in approximately half of all patients.It is typically maculopapular, involving the trunk and extremities, but can also include palms, soles, and face.The rash can also present as a diffuse erythema that blanches with pressure.In infants, vesiculobullous lesions are often the most common skin manifestation. There are no significant pathognomonic hematologic findings seen with CHIKV infections.Abnormal laboratory findings can include mild thrombocytopenia (>100,000/mm 3 ), leukopenia, and elevated liver function tests.Erythrocyte sedimentation rate and C-reactive protein are usually elevated. Rarely, severe forms of the disease can occur with atypical manifestations (see Section 3B).Fatalities related to CHIKV infection are thought to be uncommon. # 3B. Atypical manifestations Although most CHIKV infections result in fever and arthralgias, atypical manifestations can occur (Table 2).These manifestations can be due to the direct effects of the virus, immunologic response to the virus, or drug toxicity.Some of the atypical manifestations are more in common in certain groups. For instance, meningoencephalitis and vesiculobullous dermatosis are observed more frequently in children and infants, respectively . .21,22 3C. High-risk groups CHIKV can affect women and men of all ages.Clinical presentation is thought to vary by age, however, with the very young (neonates) and the elderly being at greater risk for more severe disease. In addition to age, comorbidities (underlying diseases) have also been identified as a risk factor for poor disease outcome.8,23,24,27 Most CHIKV infections that occur during pregnancy will not result in the virus being transmitted to the fetus.25,28 There have been rare reports of spontaneous abortions following CHIKV infection in the mother, however.26 The highest transmission risk appears to be when women are infected during the intrapartum period .29 The vertical transmission rate is as high as 49% during this period. Infants are typically asymptomatic at birth and then develop fever, pain, rash, and peripheral edema.Those infected during the intrapartum period may also develop neurologic disease (e.g., meningoencephalitis, white matter lesions, brain swelling, and intracranial hemorrhage), hemorrhagic symptoms, and myocardial disease.30 Laboratory abnormalities included raised liver function tests, reduced platelet and lymphocyte counts, and decreased prothrombin levels.Neonates who suffer from neurologic disease often develop long-term disabilities.31 There is no evidence that the virus is transmitted through breast milk.25 Older adults are more likely to suffer from severe atypical disease and death. Individuals >65 years had a 50-fold higher mortality rate when compared to younger adults (<45 years old).23 Although it is unclear why older adults are at increased risk for more severe disease, it may be due to the frequency of concomitant underlying diseases or decreased immunlogic response.23 # 3d.differential diagnosis Fever with or without arthralgia is a very common manifestation of several other diseases.CHIK may not have the typical manifestations or it may coexist with other infectious diseases such as dengue fever or malaria.Diseases that can be considered in the differential diagnoses may vary based on pertinent epidemiologic features such as place of residence, travel history, and exposure (Table 3). # Disease or agent Presentation Post-infectious arthritis (including rheumatic fever) Arthritis of one or more, typically larger joints due to an infectious disease such as Chlamydia, shigella, and gonorrhea. Rheumatic fever is seen more commonly in children as migratory polyarthritis predominantly affecting large joints.CHIK has to be distinguished from dengue fever, which has the potential for much worse outcomes, including death.The two diseases can occur together in the same patient.Observations from previous outbreaks in Thailand and India have characterized the principal features distinguishing CHIK from dengue fever.In CHIK, shock or severe hemorrhage is very rarely observed; the onset is more acute and the duration of fever is much shorter.In CHIK, maculopapular rash also is more frequent than in dengue fever (Table 4).Although people may complain of diffuse body pain, the pain is much more pronounced and localized to the joints and tendons in CHIK, in comparison of dengue fever. (Cont.) # CLiNiCAL # 3E. Subacute and Chronic disease After the first 10 days, most patients will feel an improvement in their general health and joint pain.Following this period, however, a relapse of symptoms can occur, with some patients complaining of various rheumatic symptoms, including distal polyarthritis, exacerbation of pain in previously injured joints and bones, and subacute hypertrophic tenosynovitis in wrists and ankles.This is most common two to three months after their illness onset.Some patients can also develop transient peripheral vascular disorders, such as Raynaud's syndrome. In addition to physical symptoms, the majority of patients will complain of depressive symptoms, general fatigue, and weakness.13 Chronic disease is defined by symptoms that persist for more than three months. The frequency of persons reporting persistent symptoms varies substantially by study and the time that had elapsed between symptom onset and follow-up. Studies from South Africa note that 12%−18% of patients will have persistent symptoms at 18 months and up to 2 to 3 years later.35,36 From more recent studies in India, the proportion of patients with persistent symptoms at 10 months was 49%.37 Data from La Réunion have found that as many as 80%−93% of patients will complain of persistent symptoms 3 months after disease onset; this decreases to 57% at 15 months and to 47% at 2 years 38,39 (F. Simone, Dept of Infectious Diseases and Tropical Medicine, Laveran Military Hospital, Marseilles, France, personal communication). The most common persistent symptom is inflammatory arthralgias in the same joints that were affected during the acute stages.Usually, there is no significant change in laboratory tests and x-rays of the affected areas.However, some individuals will go onto develop destructive arthropathy/arthritis resembling rheumatoid or psoriatic arthritis.40 Other symptoms or complaints of the chronic phase of the disease can include fatigue and depression.6 Risk factors for nonrecovery are older age (> 45 years), pre-existing joint disorders, and more severe acute disease.38,41 # Summary of Clinical Section - Acute stage is symptomatic in most people and causes acute fever, distal polyarthralgias, and occasional rash. - Severe and lethal forms are more frequent among patients older than 65 years and/or with underlying chronic diseases. - Maternal-fetal transmission is possible among pregnant women, with the highest risk for severe infection in the neonates during the antepartum period. - Most patients initially will have severe and incapacitating joint symptoms; many will go on to develop long-lasting rheumatism, fatigue, and depression resulting in an impaired quality of life for months to years. # Collection of samples for serology, isolation and molecular diagnosis: Sample: Serum Time of collection: Acute, within the first eight days of illness; convalescent, 10−14 days after acute specimen collection. To collect serum: - Aseptically collect 4−5 ml of venous blood in a tube or a vial. - Allow blood to clot at room temperature, centrifuge at 2,000 rpm to separate serum.Collect the serum in a clean dry vial. - All clinical samples should be accompanied by their clinical and epidemiological information. # Other types of specimens for laboratory investigation: Specimens: - CSF in meningo-encephalitis cases. - Synovial fluid in arthritis with effusion. - Autopsy material -serum or available tissues. Transportation of Samples: - Transport specimens to the laboratory at 2°−8°C (icebox) as soon as possible. - Do not freeze whole blood, as hemolysis may interfere with serology test results. - If a delay greater than 24 hours is expected before specimens can be submitted to the laboratory, the serum should be separated and stored at refrigerated temperature. - Serum samples for virus isolation and molecular diagnosis should be stored frozen (at −20°C for short-term storage or at −70°C for long-term storage). # 4B. Laboratory Surveillance Prior to identification of CHIKV in a country, laboratory surveillance should be conducted on three sets of samples, as follows: 1) dengue-negative specimens where the patient exhibits severe joint pain; 2) samples with clinically compatible illness from new geographic areas without active dengue circulation; 3) clusters of febrile illness with severe joint pain.The following table (Table 5) outlines the ideal tests to be performed in various epidemiological settings.
# During the initial introduction of CHIKV into a new region, comprehensive testing should be completed to confirm that CHIKV is the etiological agent. After CHIKV has been identified, limited testing (not testing all specimens or performing fewer assay types) can be considered depending upon the capacity of the lab and the epidemiological situation. # 4C. interpretation and Reporting of Results Figure 2 shows typical viremia and antibody response in humans and Table 6 describes the typical results of testing samples at various time points.The following laboratory test results would confirm a recent CHIKV infection: - Isolation of CHIKV, including confirmatory identification (either IFA, RT-PCR, or sequencing). - Detection of CHIKV RNA by real time RT-PCR. - Identification of a positive IgM result in a patient with acute symptoms of CHIK, followed by the demonstration of CHIKV-specific antibody determined by PRNT with viruses in the SFV serogroup. - Demonstration of seroconversion or a four-fold rise in PRNT, HI, or ELISA titers (again using other SFV serogroup viruses) between acute and convalescent specimens. Autochthonous cases should be reported to WHO, in collaboration with an epidemiologist, according to International Health Regulations (IHR) (see section 6F). # 4d.Laboratory Network for diagnosing CHikv Currently DVBD, CDC can provide diagnostic testing for CHIKV infection. Reagents and consultations can also be provided by CDC and the Public Health Agency of Canada.Depending on the availability of resources and the epidemiologic situation, PAHO and CDC will be working together in the near future to improve CHIKV detection in the Region by providing training and reagents to existing dengue (RELDA) and other arbovirus laboratories in the Americas.Furthermore, proficiency testing is planned to ensure testing quality in the Region.A contingency plan will be developed to ensure that all laboratories capable of performing testing in the Americas have an adequate supply of reagents and protocols. # Summary of Laboratory Section - Both molecular and serologic techniques are available for the laboratory diagnostic evaluation of CHIKV infection. - During an outbreak, laboratories will need to develop, with other public health partners, sample triage plans to avoid laboratory overload. - Laboratories have a key role in the surveillance for CHIKV introduction and spread; ongoing training of laboratories for CHIK detection is needed throughout the Region. - Collaboration is important, in order for network partner (public health) labs to be able to share materials. - Reference laboratories in the Region will play a significant role in reagent production and in providing laboratory confirmation of suspected CHIK cases. # LABORATORy # CASE mANAgEmENT 5A. Treatment There is no specific antiviral drug treatment for CHIK.Symptomatic treatment is recommended after excluding more serious conditions like malaria, dengue, and bacterial infections. # A c u t e D i s e a s e Treatment is symptomatic or supportive, comprised of rest and the use of acetaminophen or paracetamol to relieve fever, and ibuprofen, naproxen, or another non-steroidal anti-inflammatory agent (NSAID) to relieve the arthritic component of the disease.Using aspirin is not advised because of the risk of bleeding in small number of patients and the risk of developing Reye's syndrome in children younger than 12 years of age.In patients with severe joint pains that are not relieved by NSAID, narcotics (e.g., morphine) or short-term corticosteroids can be used after evaluating the risk-benefit of these treatments. Patients should be advised to drink plenty of fluids to replenish fluid lost from sweating, vomiting, and other insensible losses. # S u b a c u t e a n d C h r o n i c D i s e a s e While recovery from CHIK is the expected outcome, convalescence can be prolonged (sometimes up to a year or even more) and persistent joint pain may require pain management, including long-term anti-inflammatory therapy. Although an older study suggested that chloroquine phosphate offered some benefit, 45 a recent double-blind, placebo-controlled randomized trial found it to be of no real value treating joint symptoms.46 Disabling peripheral arthritis that has a tendency to persist for months, if refractory to other agents, may occasionally respond to short-term corticosteroids.38 To limit the use of oral corticosteroids, local injections (intra-articular) of corticosteroids or topical NSAID therapy can be used.In patients with refractory joint symptoms, alternative therapies such as methotrexate can be evaluated.In addition to pharmacotherapy, cases that have prolonged arthralgia and joint stiffness may benefit from a program of graduated physiotherapy.Movement and mild exercise tend to improve morning stiffness and pain, but heavy exercise may exacerbate symptoms. # 5B. Patient isolation Recommendations To prevent the infection of others in the household, the community, or the hospital, a patient with acute CHIK should avoid being bitten by Ae.aegypti or Ae.albopictus mosquitoes during the viremic phase, which is usually the first week of illness.As these mosquitoes bite during daytime, from dawn to dusk or even after dark in the presence of artificial light, staying under an insecticide-treated (IT) bednet or remaining in place with intact screens is highly recommended. Furthermore, physicians or health care workers who visit CHIK-infected patients at home should take care to avoid being bitten by mosquitoes by using insect repellent and wearing long sleeves and pants. # CASE mANAgEmENT One hospital-associated infection of CHIK has been identified in a healthcare provider who had an accidental needle stick from a patient with CHIK.47 Several laboratory workers also have contracted CHIKV infection after handling infected blood.48 These exposures indicate that direct contact transmission can occur.However, other modes of transmission, such as through respiratory droplets or particles, have not been documented. # 5C. Health Care and Hospital Surge Capacity At the peak of one recent outbreak, 47,000 suspected cases were identified in a single week among a population of 766,000.27 There also can be an accumulation of patients with symptoms who seek more long-term care.With that potential volume of cases per week, huge demands are likely to be placed on the health care system during outbreaks of the disease.A number of steps similar to those for pandemic influenza preparedness should be considered by health care - Develop and implement methods for identifying and investigating potential introduction of CHIKV within existing surveillance systems (e.g., surveillance system for dengue). - Inform health care providers and public health officials about the potential threat of CHIKV, and educate them about the clinical presentation, diagnosis, and management of cases at health care facilities. - Develop planning and decision-making structures for responding to a potential outbreak at health care facilities. - Develop institutional plans to address disease surveillance, hospital communications, education and training, triage and clinical evaluation, facility access, occupational health, surge capacity (beds and access to care), supply chain, and access to critical inventory needs. Following the introduction of CHIKV into an area, health care facilities should: - Activate institutional plans with assistance from the Ministry of Health. - Ensure rapid and frequent communication within health care facilities and between health care facilities and health departments. - Implement surge-capacity plans that address staffing, bed capacity, consumable and durable supplies, and continuation of essential medical servic- # es (see section on Health care Planning in the PAHO and HHS Pandemic Influenza Plan for further considerations 49,50 ). Effective triage systems at various levels of health care may help to decrease the potential burden of a CHIK outbreak on the health care system.Regardless of the level of medical care available at the triage location, a key measure that needs to be considered at all levels of health care is the institution of appropriate mosquito control measures in the immediate area.If this is not done, patients acutely ill with CHIK can serve as a source of subsequent infections for other patients and for health care workers via mosquito transmission.Furthermore, consideration should be given to establishing areas where patients with suspected CHIK infection are seen and, if necessary, hospitalized (e.g., establish CHIK wards with screens and/or bednets).Finally, consideration should be given to the safety of health care workers.During a previous outbreak, up to one-third of health care workers became infected, further taxing already overburdened and stretched resources.9 'Guiding principles for managing acute stage of the disease' has been previously described in detail in WHO's "Guidelines on Clinical Management of Chikungunya Fever".51 Key information, including triage considerations, from that document is summarized here. # Who should seek medical care? - Anyone with neurologic signs or symptoms including irritability, drowsiness, severe headaches, or photophobia. - Anyone with chest pain, shortness of breath, or persistent vomiting. - Anyone with a fever persisting for more than five days (indicative of another illness like dengue). - Anyone who develops any of the following, especially once the fever subsides: -intractable severe pain, -dizziness, extreme weakness, or irritability, -cold extremities, cyanosis, -decreased urine output, and -any bleeding under the skin or through any orifice. - Women in the last trimester of pregnancy, newborns, and persons with chronic underlying disease, as they or their offsprings are at risk for more severe disease. # Triage at point of first contact (Primary or ambulatory/urgent care) - Rule out other illnesses by history, clinical examination, and basic laboratory investigations, including but not limited to complete blood count (CBC), liver function tests, and electrolytes.Be careful to evaluate if patient has warning signs for severe dengue or malaria.If these signs are present, refer patient immediately to a hospital. - Assess for dehydration and provide proper rehydration therapy as needed. - Evaluate hemodynamic status and stabilize and immediately refer patients with delayed capillary refill, narrow pulse pressure, hypotension, oliguria, altered sensorium, or bleeding manifestations. - Treat symptomatically (paracetamol/acetaminophen). - For those with prolonged joint pain (after three days of symptomatic treatment) consider more aggressive pain management, such as morphine and short-term corticosteroids. - Consider referral for patients with increased risk of a poor outcome (persons older than 60 years, those with chronic disease, pregnant women, and newborns). # Triage at the secondary level (district or local hospital) - Treat symptomatically (according to previous treatments). - Investigate person for renal failure, neurologic signs and symptoms, hepatic insufficiency, cardiac illness, thrombocytopenia, and malaria. - Evaluate hemodynamic status and assess for dehydration; provide proper supportive care and rehydration therapy as needed. - Consider cerebral spinal tap if meningitis is suspected. - Collect blood for serologic testing of CHIK and other diseases in the differential diagnosis (e.g., dengue). - Review history of present illness and evaluate if patient has warning signs for severe dengue.If present, administer supportive care in a unit that can monitor vital signs on an hourly basis during the critical phase. - Refer patients with any of the following conditions to a higher level health center: pregnancy, oliguria/anuria, refractory hypotension, significant clinical bleeding, altered sensorium, meningoencephalitis, persistent fever of more than one week's duration, and signs of decompensation of underlying diseases. # Triage at the tertiary care level (advanced care centers or centers with infectious disease specialists) - Ensure that all the above-mentioned procedures have been completed and that a comprehensive medical team is available to assist in managing patients with severe or atypical disease. - Collect blood sample for serology and/or RT-PCR (see Laboratory section for more specific on CHIK testing). - Consider the possibility of other rheumatic (e.g., rheumatoid arthritis, gout, rheumatic fever) or infectious diseases (e.g., viral or bacterial meningoencephalitis). - Treat serious complications (e.g., bleeding disorder with blood components, acute renal failure with dialysis). - Assess disability and recommend rehabilitative procedures. - Given the severity of the pain and the potential long-term pain with CHIK, pain management and psychological assistance should be made available and consideration given to develop chronic pain management protocols, teams, and centers.Autopsies should be considered on all deceased patients, with involvement of pathologists. # 5d.Blood, Organ, and Tissue Safety Blood-borne transmission is possible.There are documented cases that include infection of laboratory personnel handling infected blood and of a health care worker drawing blood from an infected patient.47,48 These cases support the belief that CHIKV is able to be transmitted through blood products. To determine the impact of CHIKV on blood supply safety consider: 1) incidence of viremia among blood donors (which may vary depending on the time of the outbreak); 2) clinical impact on transfusion recipients who become infected; 3) availability of measures to reduce transfusion transmission (e.g., nucleic acid amplification testing (NAT) or photochemical pathogen inactivation treatment); 4) availability of an alternative blood supply (from non-affected areas); and 5) the cost incurred by adopting these measures.52 # CASE mANAgEmENT In addition to asking the local health-care community to promote optimal use of blood components, possible considerations for blood safety in areas with CHIKV introduction could include: 53 - Continue to obtain blood donations from local persons until an unacceptable incidence or prevalence a of infection is reached in the community. - Screen blood donors for symptoms prior to donation. - Asking donors to report any illness they experience after donating blood, while holding on to the blood donations for several days (e.g, 2-5 days) prior to releasing it. - If feasible, cease all blood donations in an area of known CHIKV infections and import blood products from uninfected areas. - Institute screening (e.g., NAT) of the blood supply for CHIKV.This will require a preexisting platform and regulatory clearance, and is unlikely to be available in most areas. Similar measures should be considered for organ and tissue (grafts) transplantations. # CASE mANAgEmENT a To be determined by blood banks and public health officials in the area. # Summary of Case Management Section - Treatment for CHIK is supportive, using anti-pyretics, optimal analgesics, and fluids. - Acutely infected patients need to be protected against mosquito bites to prevent further disease spread at home, in the community, and in the health care facility. - Because CHIK will place a large burden on the community, including on all levels of the health care system, well-established protocols and plans need to be developed in advance to assist in the triage, care, and rehabilitation of patients. # SURvEiLLANCE ANd OUTBREAk RESPONSE T he main objective of surveillance is to detect, in a timely manner, cases of CHIK in the Americas.Early detection will allow for proper response and characterization of the outbreak and identification of the viral strains circulating. # 6A. modes of Surveillance Multiple modes of surveillance can be considered to determine if CHIK may have been introduced to an area, to track the disease once introduced, or to follow the disease once it has been established. # .P r e p a r e d n e s s p h a s e Reinforce existing febrile syndromic surveillance sentinel sites so they can detect CHIK cases.A percentage of patients presenting with fever and arthralgia or fever and arthritis with no known etiology (e.g., negative test for malaria or dengue), should be tested for CHIK at the national reference laboratory (See Section 4 for more details on proposed laboratory surveillance testing).To ensure adequate laboratory testing and surveillance capacity, laboratories should be aware of the laboratory network set up for testing and eventual distribution of supplies. # Introduction Once an autochthonous case of CHIK is detected, an in-depth epidemiologic investigation must be conducted to: - Track viral spread. - Monitor for possible introduction into surrounding areas. - Describe key epidemiologic and clinical features. - Assess clinical severity and impact on society (e.g., days missed from work, school closures, etc.). - Identify risk factors for infection or severe disease. - Identify circulating CHIKV lineages. These efforts will be the basis for developing effective control measures. Active, passive, and laboratory surveillance should be used to calculate and monitor indicators such as: incidence, rate of spread, rate of hospitalization (per infections), proportion of severe disease, mortality ratios, and disability rates. # Sustained transmission Once the virus has been identified throughout a country, scaling back of the level of testing and active surveillance can be considered (e.g., testing only a fraction of suspect cases or testing severe or atypical cases, newborns, cases identified in new regions) to avoid unnecessary costs in resource-limited settings. However, ongoing surveillance should be continued to monitor changes in the epidemiology and ecology of CHIKV transmission.Any changes in surveillance at the national level should be readily communicated to other surveillance and prevention partners, such as vector control specialists, to ensure the quality and uniformity of the data collected.Public health authorities should be alerted to small clusters of disease (fever and arthralgia or arthritis) associated with a traveler returning from a CHIK endemic area or an increase in the number of hospital visits for fever and arthralgia or arthritis occurring in a localized area in a short time. # 6B. Case detection # 6C. Case definition Suspect case: a patient with acute onset of fever >38.5ºC (101.3ºF) and severe arthralgia or arthritis not explained by other medical conditions, and who resides or has visited epidemic or endemic areas within two weeks prior to the onset of symptoms. Confirmed case: a suspect case with any of the following CHIK specific tests: - Viral isolation. - Detection of viral RNA by RT-PCR. - Detection of IgM in a single serum sample (collected during acute or convalescent phase). - Four-fold increase in CHIKV-specific antibody titers (samples collected at least two to three weeks apart). During an epidemic, all patients need not be subjected to confirmatory tests as above. An epidemiologic link can be sufficient. An evaluation of the sensitivity and specificity for clinical criteria for CHIKV infection was done during a large outbreak of the disease.54 The combination of fever and polyarthralgias had the best sensitivity and specificity at 84% and 89%, respectively, and allowed for the correct classification 87% of individuals with serologically confirmed CHIKV infection. # 6d.Case Reporting CHIK is not a notifiable disease in most countries.
However, depending on the epidemiologic situation, each country must determine independently when CHIK should be a disease of mandatory reporting.Occurrence of suspect cases could indicate a possible outbreak and, therefore, should be immediately reported to the nearest health authority in accordance with the IHR guidelines. Prior to the introduction of CHIK into an area, clinicians should report any suspect or confirmed travel-related cases to local public health officials who, in turn, should report them to a regional level and then on to a national level, where the information should be summarized and shared with stakeholders (Figure 3).In addition, other key partners, such as vector control management teams, should be notified. # 6E. Epidemiologic Reports Ideally, epidemiologic reporting should be established at the national level, with the support of local and regional public health officials.The types and number of epidemiologic reports will likely evolve during the course of the outbreak to reflect the types of surveillance that are performed in an area.terms of presenting and closing the data on a daily basis.In addition to case count by location and timing, reporting on disease severity (hospitalization, mortality), number of hospital beds occupied per day, and trends in cases based on syndromic surveillance can be considered as ways to present the data.The national level data should be communicated back to the collecting districts, as well as to the press and other public health and partner agencies that participate in the control efforts (see Section 8, "Risk and Outbreak Communication" for more detail).Once a country has identified autochthonous transmission within its borders, it should activate its emergency operations center ("sala de situación") to serve as a source for rapid communication and decision making. # 6F. international Health Regulations and Border measures I n t e r n a t i o n a l H e a l t h R e g u l a t i o n s A single imported case (i.e., a traveler) of CHIKV into the Americas would not necessarily constitute a public health emergency of international concern (PHEIC) under IHR, 55 although this case should be thoroughly investigated to minimize the risk of CHIK establishment in the country.However, suspicion of autochthonous CHIKV transmission in the Americas will meet PHEIC criteria and should be reported per IHR (see Appendix E for an example).Such an event would have a serious public health impact because of its potential to cause an epidemic with high attack rates among an immunologically naïve population, and because vectors are sufficiently abundant to potentially support permanent establishment of the virus and year-round transmission.The event would also be unusual for the Americas, since it would signal the appearance of a previously absent pathogen and a significant risk of international spread given the amount of travel between countries in the Region.Although CHIKV does not have a high mortality rate, it has high morbidity rates associated with persistent arthralgias that can lead to disability and a reduction in productivity. Even disregarding the issue of cost and complexity of implementation, port of entry screening activities are unlikely to prevent or delay the importation of CHIKV. There is no evidence to support that requiring pilots or ship captains to complete health declarations, asking passengers to complete screening questionnaires, taking temperature measurements and engaging in other entry screening modalities effectively prevent CHIKV introduction and spread into the Americas.Member Countries should use their scarce public health resources on activities more likely to achieve intended results, including implementing sustainable vector control efforts, enhancing clinical surveillance for CHIKV disease, educating the public, and considering assisting affected Member Countries.For similar reasons, exit screening is not recommended if Member Countries in the Americas confront CHIKV outbreaks within their borders. Some jurisdictions outside the Americas have instituted mosquito abatement activities at international airports and spraying adulticides in the passenger cabins of arriving international flights as part of efforts aimed at preventing dengue importation.However, virus-infected mosquitoes arriving in passenger aircraft are not considered as significant sources of most arboviral importations. For arboviruses with a human-mosquito-human transmission cycle, the most important source of viral importation is the viremic traveler.In a region like the Americas, where competent vectors are already present in the majority of countries, mosquito abatement and vector surveillance efforts predominantly focused on international airports and seaports can be implemented by national authorities to prevent CHIKV importation, but PAHO does not recommend them. The exception would be if cases were being detected close to an international airport or seaport, or if suspected cases worked in or around these ports of entry. Routine vector control efforts consistent with IHR Article 22, which calls for eliminating vectors at facilities used by travelers at points of entry, should be implemented, but are not intended as a principal means of preventing CHIKV importation. Similarly, in the presence of CHIK cases and local virus transmission, there is no need to place any restrictions on baggage, cargo, containers, goods, or postal parcels beyond usual practices; this will avoid unnecessary interference with international traffic in the absence of any identified public health benefit. It is advisable, however, to establish communications between public health authorities and conveyance operators (sea and air, cargo and passenger) and other port-based organizations, in case there is a need to implement a CHIKV communication campaign. Countries may elect to distribute Travel Health Alert Notices (THANs) to international travelers if there is concern that CHIKV transmission is likely or if ongoing transmission has been detected.This information would offer guidance to travelers on how to reduce their risk of contracting CHIKV, steps to take for reducing the likelihood that they will be bitten by mosquitoes, or seeking early diagnosis if they develop signs and symptoms compatible with CHIK fever. These messages could be relayed through online reservation systems, travelers' health clinics, travelers' health Web sites, and postings at international ports when outbreaks are occurring. It will be important to monitor air travel patterns between countries where CHIKV is circulating and every other country or area in the Americas, in order to identify locations most at risk to virus introduction.In a preliminary analysis that was limited exclusively to direct flight data, scheduled commercial flight data shows that countries importing CHIKV had 23 times more total scheduled passenger seats originating from countries with CHIKV activity than did nonimporting countries (CDC, unpublished).Subsequent analyses using passengerspecific data, which includes travel connections and actual passenger volume, could provide more accurate information on which to base a risk assessment of CHIKV importation. # Summary of Surveillance and Outbreak # Response Section - Epidemiological surveillance is key to the timely detection of cases and appropriate and rapid response with active participation from all stakeholders. - CHIK surveillance should be built upon existing dengue surveillance (highlighting differences in clinical presentation). - If autochthonous transmission of CHIK is identified, it must be reported immediately as a PHEIC under IHR. # vECTOR SURvEiLLANCE ANd CONTROL I n the absence of an effective CHIKV vaccine, the only tool available to prevent infection is reduction of human-vector contact.The primary vectors of CHIKV are Ae.aegypti and Ae.albopictus.Ae.aegypti is the principal vector in areas of Africa where the virus is considered to be endemic.However, Ae.albopictus was incriminated during recent epidemics, following introduction of the virus into temperate Europe 17 and some tropical areas of the Indian Ocean .27, 57 These outbreaks were associated with an adaptation of CHIKV strains to Ae.albopictus.58,59 Both Ae.aegypti and Ae.albopictus are present in the Americas (Figures 4 and 5).Ae.aegypti will likely be the most important vector in urban areas, and Ae.albopictus will likely play a more significant role in There are some significant differences between Ae.aegypti and Ae.albopictus that must be considered in developing surveillance and control procedures. Ae.aegypti is more closely associated with humans and their homes, and feeds preferentially on humans.Adult Ae.aegypti rest indoors, and its larval habitats are most frequently containers on the household premises.Ae.albopictus feeds readily on humans, but also utilizes a broader range of bloodmeal hosts; 62 its larvae occur in peridomestic habitats as well as surrounding natural habitats. Ae.albopictus can overwinter in the egg stage and, therefore, can occupy more temperate climates 63 than Ae.aegypti.These species have distinct morphological features, and the identification of specimens collected during surveillance and control programs in the Americas can be readily accomplished.64,65 An effective, operational dengue control program provides the basis for CHIKV preparedness, because the biology and control procedures for Ae.aegypti are similar to those for Ae.albopictus.Surveillance and control recommendations developed for dengue management 66 as a component of the Integrated Management Strategy for Dengue Prevention and Control (IMS-Dengue) may be utilized and intensified in order to respond to a CHIKV introduction. Successful control programs require well trained professional and technical staff and sufficient funding.In addition, an independent quality assurance program should be incorporated into the integrated vector management (IVM) scheme. To be successful, the CHIKV IVM program must include intersectoral participation (collaboration) at all levels of government and among health, education, environment, social development, and tourism agencies.IVM programs also benefit from participation of non-governmental organizations (NGOs) and private organizations.CHIKV control program must communicate with and mobilize the entire community.67 In fact, the community's participation is an essential component of IVM.68 To be effective, an IVM strategy must be developed and in place before CHIKV is introduced. # vECTOR # 7A. Reducing the Risk of CHikv Components of an IVM program to reduce CHIKV risk include: # Vector Surveillance and Identification of High Risk Areas In areas where dengue is endemic, a retrospective analysis of Dengue virus transmission during previous years should be conducted during the CHIKV planning phase to indicate the areas where CHIKV is expected to circulate (given the similarity in transmission cycles of these viruses).Areas can be stratified in terms of risk of transmission.69 Stratification is then used to assign resources and priorities.For example, controlling or preventing CHIKV transmission in neighborhoods that traditionally have produced many cases of dengue should inhibit virus amplification and virus spread to nearby neighborhoods. The program must have the ability to systematically collect surveillance data on relative densities of Ae.aegypti and Ae.albopictus.Surveillance methods for Ae.aegypti and Ae.albopictus are varied and include methods to monitor egg production, larval sites, pupal abundance, and adult abundance.These methods are reviewed in Chapter 5 of the WHO Dengue Guidelines.66 New traps and sampling methods are being developed that may provide more accurate surveillance data.70,71 Programs must be able to detect and identify hidden and difficult to control larval sites (e.g., cryptic locations such as septic tanks, storm drains, sump pumps, and vacant lots) and other productive sites, as well as the readily identified and commonly found larval habitats. # Personal Protection Individuals may reduce the likelihood of infection by the use of personal repellents on skin or clothing.DEET (N,N-diethyl-m-toluamide) and picaridin (also known as KBR3023 or Bayrepel™) are effective repellents widely available in the Americas.Infants and others sleeping or resting during the day should use bednets to avoid infection from Ae.aegypti and Ae.albopictus, both of which are day biting mosquitoes.It is of particular importance that individuals who are vECTOR potentially infected with CHIKV during an outbreak rest beneath an IT bednet to avoid mosquito bites and further spread of infection.Use of IT bednets has the additional benefit of killing mosquitoes that come into contact with the net, which may reduce vector-human contact for other household members.72 A number of pesticide products may be used to safely treat bednets (Table 6), or long-lasting pretreated nets can be obtained commercially. # Household Prevention The use of intact screens on windows and doors will reduce entry of vectors into the home, and mosquito proofing water storage vessels will reduce oviposition sites and local production.Within a household, use of IT bednets 72 and IT curtains 73 also reduce vector-human contact. The number of adult mosquitoes in a home may be reduced by using commercially available pyrethroid-based aerosol sprays and other products designed for the home, such as mosquito coils and electronic mat vaporizers.Aerosol sprays may be applied throughout the home, but areas where adult mosquitoes rest (dark, cooler areas) must be targeted, including bedrooms, closets, clothing hampers, etc.Care should be taken to emphasize proper use of these products when advocating their application to the public, in order to reduce unnecessary exposure to pesticides. # Neighborhood and Community Prevention Neighborhood and community prevention for a CHIKV introduction in the Americas should be based on methods developed for dengue control, utilizing effective strategies to reduce the densities of vector mosquitoes.66 A fully operational dengue control program will reduce the probability that a viremic human arriving in the Americas will be fed upon by Ae.aegypti or Ae. albopictus mosquitoes, thereby leading to secondary transmission and potential establishment of the virus. Dengue programs for controlling Ae.aegypti have traditionally focused on control of immature mosquitoes, often through the community's involvement in environmental management and source reduction.It is essential that community involvement be incorporated into an IVM program.74,75 # Ve c t o r C o n t r o l P r o c e d u r e s The WHO Dengue Guidelines 66 provide information on the main methods of vector control, and they should be consulted when establishing or improving existing programs.The program should be managed by experienced professional vector control biologists to assure that the program uses current pesticide recommendations, incorporates new methods of vector control, and includes resistance testing.Prevention programs should utilize the methods of vector control found in Appendix F, as appropriate.66, 74 # 7B. Response to CHikv introduction Immediately upon confirmation of the first autochthonous CHIKV case, the health department should inform the IVM program regarding the onset date and location of the case.Vector control procedures must be intensified to effectively reduce the abundance of infected vectors in order to halt transmission in the areas of the case(s). vECTOR Simultaneously, emergency response committees at local and national levels should be informed of the situation and activated.Initial efforts should focus on containing virus transmission and preventing expansion (Appendix G).If virus containment fails, or if cases are not detected until the outbreak has spread over a large geographic area, intensive vector control efforts will need to be expanded to a larger scale program. # Summary of Vector Surveillance and Control Section - Epidemiological surveillance is key to the timely detection of cases Early detection of disease will increase the likelihood of containing transmission of CHIKV in the area. - Successful IVM for CHIKV requires trained experts in medical entomology and vector control, sufficient resources, and a sustained commitment. - Current dengue control programs in the Region should be utilized and improved to prevent CHIKV transmission. - Vector surveillance and control activities and methodologies must be validated and continually evaluated to measure efficacy.As CHIKV is new to the Americas, the media, the public, and many officials will need to be educated about the disease, its mode of transmission, the lack of specific therapeutic treatment, means of symptomatic and supportive treatment, and the adoption of control measures. Risk communication messaging can emphasize that the risk of CHIKV infection can be reduced, and that it is typically a self-limiting disease. # 8B. Risk Communication Strategies by Phase and Target Audience Appendix H gives an example of a model risk communication plan with strategies organized by preparedness, response, and recovery phases of an emergency.The plan defines various target audiences that should be considered in developing a country-specific risk communication plan. Risk communication should be organized across multiple agencies and should target the media, the public health community, community-based organizations, the private sector, and civil society institutions. # S t r u c t u r e a n d C o o r d i n a t i o n Ideally, an emergency response to a CHIKV outbreak will use an Incident Command System that provides structure for collaboration.In Latin America, the equivalent is the Emergency Operational Committee (or COE in Spanish). A key component in emergency operations is the establishment of a Joint Lack of coordination on these points will help create confusion and undermine confidence in the management of the response. # S t r a t e g i e s b y P h a s e : P r e p a r e d n e s s P h a s e The primary activities during the preparedness phase are to develop a communications plan and to create strategic partnerships.During this phase, potential activities may include: - Informing key stakeholders about preparedness materials, such as these guidelines. - Developing basic response materials, such as fact sheets and frequently asked questions, will facilitate a rapid response to a CHIKV introduction and reduce misinformation.Information channels may include printed materials, websites and other electronic and social media, the mass media, short message service (SMS) text messages, inter-personal communication through group meetings, schools, and utilization of traditional or folk media. - Working with partners to develop strategies to guide care seeking, travel (national and international), and prevention/risk reduction. - Communication with journalists and news agencies to provide baseline information on CHIKV and on the national preparedness and response plan. - Networking with key personnel at potential information points, such as arrivals and departure locations (airports, ports, borders) and public facilities (health care facilities, educational centers, workplaces, nursing homes, shopping malls, churches, public transport sites, stadiums, among others). - Anticipating sensitive issues can allow for preemptive preparation of responses and strategies.
Sensitive topics related to CHIKV may include concern over safety of community and household pesticide use, any restrictions involved in a containment response, large numbers of persons seeking care at health care facilities, and the cost of control measures. # S t r a t e g i e s by P h a s e : T h e R e s p o n s e P h a s e During the response phase, the communication plan is put into action; in particular, communications with the mass media, health care providers, and other key audiences are intensified. # The Mass Media Effective communication through the mass media can help maintain clear information regarding the outbreak and the public health response.Information should be communicated via an appropriate, trained national-level spokesperson. Use of a consistent spokesperson can build trust and avoid the release of potentially conflicting messages from various sources.Information in the mass media can also reinforce the key behavioral outcomes that can help reduce risk during an outbreak.Content in the electronic and print media should be regularly monitored (on a daily basis during an intense outbreak), in order to make any necessary adjustments to the strategies and messages conveyed to the population. # 8C. Specific Behavioral Strategies for CHikv Risk Reduction Specific strategies for effective personal, household, and community primary Advance research into knowledge, attitudes, and practices regarding repellent and household control measures may yield benefits in understanding barriers to use and potential for misapplication.Even if it is not feasible to conduct this research in advance, rapid qualitative assessment in affected areas can yield insights to increase the effectiveness of prevention messages. Communication on prevention should target specific behaviors that offer the best likelihood of reducing risk.Feasible strategies will vary by location, depending on a given community's resources, attitudes, control program capacity, and ecology.Key messages for personal and household prevention can include: C o m m u n i t y S t r a t e g i e s - Encouraging support of and compliance with governmental control efforts such as environmental sanitation, larviciding and adulticiding. - Advocacy for household and neighborhood source reduction (e.g., trash clean-up, control of water storage, etc.). -Use of personal prevention such as clothing, repellents, and insecticidetreated materials: -Encouraging the use of long sleeves and pants may be reasonable in areas where temperatures are moderate, particularly during evening when Aedes mosquitoes are often still seeking a bloodmeal.This recommendation may be less practical in tropical zones. -Repellents for use on skin and clothing are now sold widely throughout the Americas.A significant outbreak may increase interest in these tools, and authorities should be prepared to provide guidance and to rely on creative strategies to increase use. - Methods to reduce human-vector contact include use of household insecticides and installation of screening.Where feasible, screening material can be installed over windows even without the use of expensive frames (stapling in place or using wooden frames). - It may be useful to specify active ingredients or even brand names for recommended repellent and/or household insecticides, as a way to reduce use of ineffective and possibly dangerous materials. # Summary of Risk and Outbreak Communication Section - Communications are an integrated, coordinated effort involving all disciplines and components for preparation and response. - Timely communication with stakeholders is crucial for enlisting the community's participation and to avoid confusion and misinformation. - As CHIKV is novel in the Americas, the media, the public and many officials will need to be educated about the disease, the mode of transmission, the lack of specific therapeutic treatment, means of symptomatic and supportive treatment, and effective control measures. # CONCLUSiON C urrently, CHIKV is not known to be circulating in the Americas.The risk of introduction is high, however, due to travel importation, competent vectors (same vectors as dengue), and population susceptibility.Given the likelihood that CHIKV will be introduced in the Region, advance preparation is essential.The timely detection of cases and an appropriate and rapid response with active participation of all stakeholders will be necessary to minimize the risk of importation and sustained transmission in the Region. These guidelines for the preparedness and response CHIKV introduction in the Americas were developed to increase awareness of the disease and to provide the necessary information to institute the most appropriate strategies to prevent the importation and spread of CHIKV in the Region.Each Member Country is encouraged to use and adapt these guidelines to detect an outbreak of the disease early, to conduct pertinent epidemiologic investigations, and to prevent or mitigate the expansion of the disease in the Americas. # APPENdiCES # Introduction The optimal method for determining specific etiology of an arbovirus infection requires isolation of the virus from a specimen obtained from the patient during the acute stage of the disease and the demonstration of a rise in titer of an antibody to the isolate during convalescence.For a number of reasons, the successful isolation of most arboviruses from patient specimens is the exception, whether because the specimen to be examined is not collected early enough, is not properly handled, or is not expeditiously transmitted to the virus laboratory for inoculation.The viremia for many arbovirus infections in humans, if detectable at any stage, ceases by the time of or soon after onset of symptoms⎯a stage when antibody is often demonstrable.Because some circulating virus # Introduction For isolation from brain, samples should be taken from several areas, including the cortex, brain nuclei, cerebellum, and brain stem.Neurotropic arboviruses sometimes can be isolated from CSF obtained by lumbar puncture during the acute stages of encephalitis or aseptic meningitis.Alphaviruses, like CHIKV, have been isolated from joint fluid of patients with acute polyarthritis.Under certain circumstances arboviruses have been recovered from urine, milk, semen, and vitreous fluid. # Principle Susceptible cell culture systems are available for the attempted isolation of the presumed etiologic agent of an illness or disease.Following successful isolation, the isolate may be positively identified and an antigen prepared from this isolate or the virus itself may be used to test the patient's serum for the presence of antibodies to the viral isolate.If antibodies are detected, this exercise confirms that the isolate was the causative agent of the illness or disease.In certain instances, serum from a patient may not be available.Under those circumstances, one relies on reisolation of the causative virus from the same original specimen.Reisolation should always be attempted, however, whether serum is available from the patient or not. # Materials and Reagents Vero cell culture monolayers or other suitably susceptible cell cultures C6/36 cell cultures-cloned Ae.albopictus mosquito cell. # Procedure Available tissues or fluids should be divided for viral isolation, electron microscopy, and for immunohistochemical examination.Tissues should be collected aseptically and rapidly transported to the laboratory in viral transport. The aliquot for viral isolation should be immediately frozen at −70° C in a mechanical freezer or stored on dry ice.Samples for viral isolation should be kept frozen continuously, avoiding freeze-thaw cycles that inactivate virus. Appendix A. Viral Isolation Protocol (for Cell Culture) (Cont.) # Procedure The aliquot for electron microscopy should be minced and place directly in glutaraldehyde.Autolytic changes occur rapidly and tissues should be fixed as quickly as possible.A portion of the sample should be fixed in buffered formalin or, preferably, embedded in freeze-media and frozen, to prepare sections for immunohistochemical examination.Processed specimens should be inoculated into cell cultures with a minimum of delay.Sera from patients with acute febrile illnesses can be used undiluted for virus isolation or at dilutions of 1:10 and 1:100 in a protein containing diluent.It is important to inoculate unknown specimens at two or preferably more dilutions (undiluted to 10-2 ).Shell vial cultures or 25cm 2 flask cultures of Vero are inoculated and observed for the production of CPE during 10−14 days.For shell vials, a total volume of 400 µl is inoculated, followed by centrifugation at 100 x g for one hour at 37°C.A portion of the cell supernatant can be collected and tested for the presence of virus by either targeted RT-PCR or consensus RT-PCR assays.Alternatively cells are harvested and spot slides are prepared for IFA examination using monoclonal dengue type-specific antibodies. # Controls Uninoculated Vero and C6/36 cells # Interpretation Positive virus isolation, reisolation, and definitive identification define the etiologic agent of the patient's illness. If paired sera or a convalescent serum from that patient are available, the identified viral isolate is tested serologically with the patient's sera to verify antibody response to that virus. RNase free water Prepare a reagent "master mix" according to the number of reactions desired.The master mix should be prepared in a "clean room" that is physically separated from all other laboratory activities and that has dedicated reagents and equipment (e.g., pipettes).For 10 samples make a 10X master mix (see above) by multiplying the volumes of all individual reagents by 10.Combine the reagents in the above order in an RNase free centrifuge tube on ice.Divide the master mix into 10 portions of 40 µl each into either 0.Master mix production. - Utilize dedicated or separate equipment within pre-and post-amplification areas, especially pipets and centrifuges. - Always wear gloves, even when handling unopened tubes. - Quickly open and close tubes and avoid touching any inside portion. - Use RNase free plastic disposable tubes and pipet tips. - Use aerosol block pipet tips. - Use RNase free water. - Prepare all reagents on ice.1.Solid phase samples (mosquitoes or tissues) are first homogenized in an isotonic buffer to produce a liquid homogenate.RNA is extracted from liquid specimens (CSF or serum) without any pre-treatment as described below.Tissue specimens ( ) are homogenized in 1 ml of BA-1 diluent using TenBroeck tissue grinders.Mosquito specimens are homogenized in TenBroeck tissue grinders or by using the copper clad steel bead (BB) grinding technique.With both techniques the homogenates are clarified by centrifugation in a microcentrifuge (e.g., Eppendorf) at maximum speed for 5 minutes to pellet any particulate material. (Continued) # Introduction Assays that detect viral specific immunoglobulin M (IgM) are advantageous because they detect antibodies produced during the first few days after onset of clinical symptoms in a primary infection.This obviates the need for convalescent-phase specimens in many cases.IgM capture is the optimal approach to IgM detection: it is simple, sensitive, and is applicable to serum and cerebrospinal fluid (CSF) samples from a variety of animal species (e.g., human, equine, avian).False-positive reactions due to rheumatoid factor are minimized. # Principle IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) provides a useful alternative to immunofluorescence for documentation of a serologic response.ELISA is less subjective than immunofluorescence and large numbers of samples can be processed.The principle of ELISA is similar to that of immunofluorescence.Anti-IgM (the capture antibody) is coated on 96-well plates in the Arboviral Diagnostic Laboratory at DVBD, CDC.This is followed sequentially by the patient's serum, then known non-infectious viral antigen.The presence of antigen is detected by using enzyme-conjugated anti-viral antibody, and a colorimetric result is generated by the interaction of the enzyme and a chromogenic substrate.This constitutes the MAC-ELISA. # Safety The procedure should be performed under laboratory safety conditions that take into consideration the potential infectious nature of the serum specimens involved.Lab coat, gloves, and a laminar flow hood is recommended. # Materials and Reagents Incubator Single and multi-channel pipettors Reagent reservoirs Ziploc bags, paper towels Clinical specimens Acute and convalescent human serum and/or cerebrospinal fluid (CSF) specimens Previously tested antibody-positive and antibody-negative human sera for controls Note: Store all diagnostic specimens at 4°C prior to testing, and -20°C after all anticipated testing has been completed.Avoid repeated freeze-thaw cycles. # Procedure Note: The following procedure includes information on quality control and interpretation.Each serum specimen is tested in triplicate on both viral and normal antigens.Eight test specimens can be analyzed per plate.CSF specimens are usually tested only singly. 1.Using a fine-tipped permanent marker, number and label the plates.Identify the location of each clinical specimen (S1−S8) by using the appropriate laboratory code number.To keep timing of reagent addition consistent, process plates in the order that they are numbered during all steps of the procedure.Plates should be kept in an enclosed, humidified environment during all incubation times with the exception of the coating step.A large ziploc bag containing a moist paper towel works well for this purpose.Procedure 9.Add 50µl per well of horseradish peroxidase-conjugated monoclonal antibody, broadly cross-reactive for the appropriate viral antigenic group, diluted in blocking buffer, according to a previous titration. # Incubate for -ne hour at 37°C in a humid chamber.10.Turn on plate reader to warm up, and remove TMB-ELISA from refrigerator.11.Wash plates 5X twice.Turn the plates 180 o in the washer after the first series of five cycles.This promotes consistent results. 12.While the plate is at room temperature, add 75µl per well of TMB substrate to all wells.Immediately cover plates to block out light.Incubate at room temperature for 10 minutes.A blue color will develop in antibody-positive wells. 13.Add 50µl per well of stop solution to all wells, including the outer rows of wells on the plate (the plate reader itself should be set to zero on some of these wells).The wells that were blue will now change to a yellow color.Allow plates to sit at room temperature for one minute.Read plates in microtiter plate reader by using a 450 nm filter. C for an undefined period of time. 4.Test and control sera can be diluted to the working dilutions and refrigerated one day prior to use.Antigens and conjugate must be diluted to the working dilutions immediately prior to use. The MAC-ELISA should be restandardized periodically.This should occur when new lot numbers of reagents are introduced, and at the very least, once a year.It is recommended that the mean optical density of the positive control serum reacted on the viral antigen be set to approximately at 1.0.The normal control serum reacted on the viral antigen should be around 0.2 (this varies).The standardization of reagents is normally achieved via titration, always comparing the optical densities of the reagents when reacted on viral and normal antigen. # Results Before the results can be calculated for each clinical specimen, the test must be determined to be valid.For a valid test the following must be true: # Results Mean OD of the positive control serum reacted on viral antigen (P) Mean OD of the negative control serum reacted on viral antigen (N) must be greater than or equal to 2.0.This is the P/N of the positive control. Test validity must be determined for each plate.Results for the clinical specimens may only be determined if the test is valid.If the test is not valid, then that plate must be repeated.If the test still fails after a repeat, then one or more of the reagent or test parameters was likely in error, and troubleshooting should be performed. To determine whether the clinical specimens (S1−S8) contain IgM to the viral antigen (which would indicate recent infections with that virus) the following must be calculated: Mean OD of the test specimen reacted on viral antigen (P) Mean OD of the negative control serum reacted on viral antigen (N) This is the P/N of the test specimen.For a specimen to be considered IgM-positive to the test virus, the P/N must be greater than or equal to 2.0.In addition the value of P for the test specimen must be greater than or equal to twice the mean OD of the test specimen reacted on normal antigen.If this requirement is not met, non-specific background is being generated, and the result must be reported as uninterpretable. # Interpretation It is further recommended that for sera, all positive results should be confirmed by titration using 6, 2-fold dilutions of the serum specimens compared to a similar titration of the negative control serum.Linear curves indicate true seropositivity.Flat or undulating titration curves indicate false-positive results. # Procedure Note: The following procedure includes information on quality control and interpretation.Each serum specimen is tested in triplicate on both viral and normal antigens.Eight test specimens can be analyzed per plate. 1.Using a fine-tipped permanent marker, number and label the plates.Identify the location of each clinical specimen (S1−S8) by using the appropriate laboratory code number.To keep timing of reagent addition consistent, process plates in the order that they are numbered during all steps of the procedure.Plates should be kept in an enclosed, humidified environment during all incubation times with the exception of the coating step.A large ziploc bag containing a moist paper towel works well for this purpose. 2.Coat the inner 60 wells of 96 well plates with 75µl/well of the appropriate group-reactive monoclonal antibody diluted in coating buffer according to prior titration.Incubate at 4°C overnight. 3.Dump out the coating antibody and blot plates on paper towels.Block plates with 200µl blocking buffer per well. Incubate at room temperature for 30 minutes. 4.Wash wells 5X with wash buffer by using an automatic plate washer.Wells should be filled to the top each cycle.5.Dilute viral antigen in wash buffer according to a previous titration.Add 50µl per well to the left three wells of each serum block.To the right three wells of each block, add 50µl per well of normal antigen diluted in wash buffer to the same concentration as the viral antigen. Incubate overnight at 4°C in a humidified chamber. 6.Wash 5X. 10.Turn on plate reader to warm up and dissolve substrate tablets in tris buffer about 15 minutes prior to adding it to the plates.
# Wash plates 5X twice.Turn the plates 180 o in the washer after the first series of five cycles.This promotes consistent results. 12.While the plate is at room temperature, add 75µl per well of Sigma 104 substrate to all wells.Immediately cover plates to block out light.Incubate at room temperature for 30 minutes.A yellow color will develop in antibody-positive wells. 13.Add 35µl per well of stop solution to all wells, including the outer rows of wells on the plate (the plate reader itself should be set to zero on some of these wells).Reactive wells will remain a yellow color.Allow plates to sit at room temperature for one minute.Read plates in microtiter plate reader by using a 405 nm filter. Practical considerations 1.Plates can be coated and kept at 4 o C for up to a week. C for an undefined period of time. 4.Test and control sera can be diluted to the working dilutions and refrigerated one day prior to use.Antigens and conjugate must be diluted to the working dilutions immediately prior to use. The IgG-ELISA should be restandardized periodically.This should occur when new lot numbers of reagents are introduced, and at the very least, once a year.It is recommended that the mean optical density of the positive control serum reacted on the viral antigen be set to approximately.1.0.The normal control serum reacted on the viral antigen should be around 0.2 (this varies).The standardization of reagents is normally achieved via titration, always comparing the optical densities of the reagents when reacted on viral and normal antigen. # Results Before the results can be calculated for each clinical specimen, the test must be determined to be valid.For a valid test the following must be true: Mean OD of the positive control serum reacted on viral antigen (P) Mean OD of the negative control serum reacted on viral antigen (N) must be greater than or equal to 2.0.This is the P/N of the positive control. Appendix C. IgM and IgG Serologic Assay Protocols (Cont.) # IgG ENZYME-LINKED IMMUNOSORBENT ASSAY PROTOCOL # Results Test validity must be determined for each plate.Results for the clinical specimens may only be determined if the test is valid.If the test is not valid, then that plate must be repeated.If the test still fails after a repeat, then one or more of the reagent or test parameters was likely in error, and troubleshooting should be performed. To determine whether the clinical specimens (S1-S8) contain IgG to the viral antigen (which would indicate either recent or past infections with that virus) the following must be calculated: Mean OD of the test specimen reacted on viral antigen (P) Mean OD of the negative control serum reacted on viral antigen (N) This is the P/N of the test specimen.For a specimen to be considered IgG-positive to the test virus, the P/N must be greater than or equal to 2.0.In addition the value of P for the test specimen must be greater than or equal to twice the mean OD of the test specimen reacted on normal antigen.If this requirement is not met, non-specific background is being generated, and the result must be reported as uninterpretable. # NOTIFICATION_____________Region______________ A Note: The immediate notification must include whatever is possible to complete the learning of the outbreak.Once investigated, it is sent back the full format to regional World Health Organization office. # Appendix E. Report for an Event or Outbreak of Public Health Importance There are a number of vector control procedures that should be considered to mitigate the risk of CHIKV expansion in an area (Table F1). Appendix F. Vector Control Procedures C h e m i c a l C o n t r o l o f L a r v a l H a b i t a t s If potable water vessels cannot be screened or covered, they should be cleaned regularly or treated to stop larval production according to WHO Pesticide Evaluation Scheme (WHOPES) recommended practices for potable water.66 Potential larval habitats that do not contain water intended for human consumption may be treated with larvicides listed in Table F2. Adapted from: Pesticides and their application for the control of vectors and pests of public health importance.77 Label instructions must always be followed when using insecticides. b The strength of the finished formulation when applied depends on the performance of the spraying equipment used.Traditionally, Indoor Residual Sprays (IRS) have been used most successfully against malaria vectors (Table F4).IRS treatment should be effective against Ae. aegypti, which rests indoors, though it may be difficult to apply operationally. Generally, all interior walls and ceilings of a house are treated.For control of Ae.aegypti, it is important to treat bedrooms, closets, the undersides of beds, and other dark areas where Ae.aegypti adults rest before and after taking a bloodmeal.Residents should be informed that IRS are safe when applied according to the label, but that individuals with health concerns, such as those with asthma or allergies, should take measures to reduce or eliminate exposure during the application process. # R e s i s t a n c e Te s t i n g Frequent application of the same insecticide or class of insecticide may select for individual mosquitoes that are able to survive pesticide applications.78 Resistance is a heritable change in the sensitivity of a mosquito population to an insecticide that may lead to failure of the pesticide to yield the expected degree of control. The insecticides available for use as adulticides are limited, and fall into three chemical classes: organophosphates, carbamates, and pyrethroids.Some products for larviciding have different modes of actions, such as insect growth regulators and microbials tools.78 However, the most commonly used product for controlling larvae of Ae.aegypti in containers is the organophosphate temephos.Resistance to temephos has been detected in multiple Ae.aegypti populations in the Americas 79,80 and poses a serious threat to Ae.aegypti control.Little information is available about resistance in Ae.albopictus populations in the Region. Control programs must include a resistance monitoring program 81−83 (additional references are available at / en/) to assess efficacy and to establish a pesticide rotation plan to mitigate the development of resistance.5.Monitor houses and buildings in the neighborhoods that are being treated and implement special control rounds after working hours, weekends, and holidays to assure that nearly 100% of homes and businesses are treated. # O u t b r e a k I n t e r v e n t i o n Controlling an epidemic of CHIKV or a series of outbreaks over a larger geographic scale requires the following: 1.Activating a command center (Emergency Operations Center), either physical or virtual, where epidemiologists, entomologists and vector control specialists, educators, media communicators, etc.,can jointly plan, work, and evaluate progress throughout the epidemic.Epidemiological services need to be organized so that daily, detailed reports are sent to all authorized personnel in the affected areas (states, municipalities).To be successful, it will be necessary to establish an efficient system of communications, allowing for feed-back reports and the receipt of acknowledgements (by e-mail, fax, telephone, etc.). Orienting the population at large through the media on the possibility of resulting infection with CHIKV and on how families and communities can contribute to the abatement of the epidemic.Educational materials on specific actions to prevent or control CHIKV transmission should be elaborated and distributed by various media (TV, radio, newspapers, local organizations, schools, clinics, etc.).It is important to report daily (to the press) which communities or neighborhoods are being affected by CHIKV, so that residents and local authorities are aware of imminent risk of infection and can take appropriate actions (e.g., proper use of repellents, elimination of all standing water, organizing clean-up campaigns, etc.).Dissemination of this information needs to be done in a way that no personal information or identifiers are released to the public at any time. 3.Ensuring that infected and febrile persons are protected from mosquito bites by using bednets at home and in hospitals. # Orienting vector control operations through real-time epidemiological and entomological assessments of CHIKV transmission, indicating the specific areas that need to be treated.In areas where dengue is endemic, knowledge from a retrospective analysis of dengue virus transmission or previous experience with dengue viruses should be used to guide vector control operations. 5.Applying effective vector control measures.An epidemic is generally a series of smaller outbreaks occurring simultaneously in several different places within a country (neighborhoods, cities, municipalities, states), where the number of disease cases is unusually large.This means that epidemic control measures may need to be applied concurrently in several locations. Large-area control of mosquito populations over short periods by spraying insecticides from truck-or aircraft-mounted equipment has not proven effective in reducing dengue transmission.Large-scale outdoor application of pesticides may be beneficial when used in conjunction with other control measures as part of an integrated mosquito control program.76 Therefore, effective vector control measures to be applied during an epidemic are similar to those recommended for area-wide CHIKV containment (above) and dengue virus outbreaks.66 The main difference is that they should be simultaneously applied in many areas to abate individual outbreaks. a. Geo-reference each CHIKV case to the level of operational control areas. In the case of endemic areas, conduct the retrospective epidemiological study at this level, so that stratification serves operational purposes. Use Geographical Information System (GIS) to map operational units, make and distribute maps of disease incidence, and spatially monitor the epidemic. b. Divide the target area (e.g., state, municipality) into relatively uniform areas (operational control areas) that will be treated using an area-wide approach (neighborhoods with 2,000−5,000 persons; census areas, zip-codes, etc.).All premises, businesses and other areas (parks, cemeteries, abandoned lots, areas along creeks, illegal dumps, etc.)will be simultaneously treated within a few days.This operational division of the space should be conducted well in advance of an eventual introduction of CHIKV. c. Area-wide vector control measures imply having sufficiently trained personnel, equipment, and supplies to treat the environment where Aedes mosquitoes are being produced.By significantly reducing mosquito adults (using adulticides) and the production of new adult mosquitoes (source reduction and elimination, larvicides) in a particular area, the transmission cycle could be interrupted, and CHIKV could be driven to extinction.This scenario is possible only if the number of biting mosquitoes is dramatically reduced for the length of time it takes for humans and vectors to become clear of CHIKV.For this reason, vector control measures need to achieve a very high efficiency, as measured by the elimination of an extremely large proportion of vector mosquitoes. # L i m i t a t i o n s o f Ve c t o r C o n t r o l Vector population reduction and the associated reduction of vector-human contact should be correlated with reduced virus transmission and reduced human disease.In order to interrupt an outbreak, however, vector population reduction must be immediate, substantial, and sustained.Adult mosquitoes will continue to emerge and replace adult mosquitoes killed by adulticides. Therefore, it is essential to maintain IVM programs with complete coverage and repeated treatments.In addition to the presence of mosquito control professionals and an active IVM program, it is important to maintain the support and cooperation of all members of society.67 # Medical personnel - Develop and provide information via websites, booklets, pamphlets, and pocket guides. - Participate in conferences addressing risk factors, case presentations, diagnostics, and risk factors. - Develop frequently addressed questions (FAQs) addressing differences between CHIKV and dengue, if applicable. - Establish hotline infrastructure for clinical support. - Implement response plan(s). - Provide updated, easy-toaccess information concerning epidemiology of outbreak, risk factors, case definition, diagnostics, etc. - Update information flow as necessary. - Activate and staff an information hotline for clinical support. -Continue to provide updates. - Continue to support the clinical hotline. - Provide information concerning sequelae. - Evaluate communication with the clinical community; gather "lessons learned". - Provide final response report. -Continue to gather information from laboratories. - Gather "lessons learned". (Continued) Local and regional health department personnel; epidemiologists - Health department staff, epidemiologists, and communicators work together to develop and provide information to be used by public health partners and the media to address the surveillance methods, analysis of data, and development of messages for the general population. - Activate information channels for the timely gathering of information to support decision cycles at the operational level, including the health care services. -Evaluate communications with health departments and epidemiologists. - Gather "lessons learned". (Continued) Travelers associations, businesses, and organizations - Outreach to those traveling to regions at risk for CHIKV, describing symptoms and prevention of the disease, using official and business websites and factsheets, and other means (such as closed circuit TV, message boards, and public service announcements). -Request travel and tourism industry operators to intensify the communication activities included in the travelers information plan. - Provide updates concerning disease status and preventive and protective actions. - Evaluate the timeliness of response by the travel industry. - Gather "lessons learned". Maritime, land, and air transportation industry and authorities (ports) - Develop THANs before the event for use by port authorities, customs and transportation security agencies. - Provide the industry and authorities with information concerning IHR requirements. -Request maritime, land, and air industry and port representatives to intensify their communications activities as appropriate for the response. - Provide updates concerning disease status and preventive and protective actions. - Evaluate the timeliness of response by the travel industry. - Gather "lessons learned". General population - Use multiple channels to inform the general public of the potential for CHIKV risk and means of prevention and protection. - Plan for use of hotlines; support local hotlines as appropriate. - Develop health education materials, such as website pages, posters, pamphlets, handbills, billboards, SMS text messaging and social media, and on-line social networking. - Consider the use of interpersonal communication through group meetings, in schools; make optimal use of traditional/folk media. - Special campaigns may be carried out via the mass media, including in local newspapers/ magazines, radio, and TV, as well as through outdoor publicity, such as billboards. - Monitor communication channels.Assess delivery of the messages. - Increase efforts to garner support of insecticide use and other control measures, as needed. - Develop location-specific messaging and update as appropriate. - Open hotlines, and support local hotlines as appropriate. (Continued) Faith-based communities - Develop and provide information for use within religious media networks, during services, and among outreach groups. - Collaborate with leadership to advance protection and prevention efforts and vector management.addressing protection and prevention efforts and vector management. - Provide updates to the private sector concerning the response. - Evaluate involvement of private sector in the communication plan for preparation and response to CHIKV. - Gather "lessons learned". Real time RT-PCR can be performed using a number of commercially available kits.Either the BioRad iScript 1 Step RT-qPCR (#170-8895) or the QIAGEN QuantiTect Probe RT-PCR kit (#204443) is currently used by the Arboviral Diagnostic Laboratory at DVBD, CDC.The two kits are nearly identical in the reaction setup, with one exception: the volume of enzyme used in the QIAGEN kit is 0.5 µl per reaction, instead of 1.0 µl; the volume of water in the master mix is adjusted by 0.5 µl to account for this.The setup shown below is for the QIAGEN kit.Note also that the volume of RNA added per reaction below is 10 µl but can be increased or decreased with the appropriate adjustment of total volume with water. # Component Vol.per reaction Appendix B. Real-Time Reverse Transcriptase-Polymerase Chain Reaction Protocol (Cont.) # Interpretation The following algorithm is used by the Arboviral Diagnostic Laboratory at DVBD, CDC to evaluate the TaqMan results. Positive: - Cutoff (Ct) value 38 in duplicate wells Equivocal: - Ct value 38 in one of two wells Negative: - Ct values >38 in duplicate wells All positive and equivocal samples are repeated with a second set of primer/probes for confirmation.A positive result in any of the negative controls invalidates the entire run.Failure of the positive control to generate a positive result also invalidates the entire run. Appendix B. Real-Time Reverse Transcriptase-Polymerase Chain Reaction Protocol (Cont.) 2.Extract RNA from 140 µl of the liquid specimen (CSF, serum, or clarified homogenate) using the QiAmp viral RNA kit (QIAGEN part # 52904).Follow the manufacturer's protocol exactly. # NOTE: For mosquito specimens add one additional wash with AW1.Extract at least two negative controls and two positive controls along with the test specimens.The positive controls should differ in the amount of target RNA present (i.e., a pre-determined high positive and a low positive). The volume of sample extracted can be greater or less than the standard volume stated in the QIAGEN protocol (140 µl) with the appropriate adjustments to all other volumes in the protocol.4.Wash wells 5X with wash buffer by using an automatic plate washer.Wells should be filled to the top each cycle.5.Add 50µl per well of the patient's serum (S) diluted 1:400 in wash buffer to a block of six wells, or add patient's CSF undiluted to two wells only, so that the CSF will be tested singly against the viral and normal antigens.Note: CSF can be diluted to a maximum of 1:5 in wash buffer if necessary.Add positive control human serum (Ref) diluted in wash buffer according to a previous titration, and a negative human serum control (N) diluted 1:400 in wash buffer to a block of six wells each.Incubate plates for 1 hour at 37°C in a humidified chamber. 6.
Wash 5X. 7.Dilute viral antigen in wash buffer according to a previous titration.Add 50µl per well to the left three wells of each serum block.To the right three wells of each block, add 50µl per well of normal antigen diluted in wash buffer to the same concentration as the viral antigen. Incubate overnight at 4°C in a humidified chamber. 8.Wash 5X. Appendix C. IgM and IgG Serologic Assay Protocols (Cont.) # IgM ANTIBODY CAPTURE ENZYME-LINKED IMMUNOSORBENT ASSAY PROTOCOL Interpretation All patient P/N values greater than or equal to 2.0 should be reported as presumptive IgM-positive (see paragraph below), as long as they meet the requirements listed above.In the event that an early acute CSF or serum is negative by this test, a convalescent serum specimen must be requested and tested before that patient is reported as negative for serological evidence of recent viral infection.Without testing of a convalescent specimen, a negative result may reflect testing of an acute-phase specimen obtained before antibody has risen to detectable levels.In most patients, IgM is detectable eight days post-onset of symptoms from an alpha-, flavi-, or California group virus infection.IgM persists for at least 45 days, and often for as long as 90 days.The positive P/N cut-off value of 2.0 is empirical, based on experience and convention.P/N values that lie between 2.0 and 3.0 should be considered suspect false-positives.Further tests should be performed to determine the status of these specimens. It should be stressed that the P/N value for a specimen at the screening dilution of 1:400 is not an indication of absolute antibody concentration, i.e., the P/N value is not quantitative. # Principle The IgG-ELISA provides a useful alternative to immunofluorescence for identification of a viral isolate or documentation of a serologic response.IgG-ELISA is less subjective than immunofluorescence and large numbers of samples can be processed.Viral group-reactive monoclonal antibody is coated on a 96-well plate, followed sequentially by known viral antigen, patient serum, enzyme-conjugated human IgG, and lastly substrate for the conjugate used.This constitutes the IgG-ELISA used at the Arboviral Diagnostic Laboratory, DVBD, CDC. # Safety The procedure should be performed under laboratory safety conditions that take into consideration the potential infectious nature of the serum specimens involved.Lab coat, gloves, and a laminar flow hood is recommended. # Materials and Reagents A negative IgG-ELISA result plus a negative MAC-ELISA result indicates the lack of any recent or past infections with the test virus if the sample was collected >7 days post illness onset.These results on a more acute sample cannot rule out the infection as the antibody response may not have had time to form. The positive P/N cut-off value of 2.0 is empirical, based on experience and convention.P/N values that lie between 2.0 and 3.0 should be considered suspect false-positives.Further tests should be performed to determine the status of these specimens. It should be stressed that the P/N value for a specimen at the screening dilution of 1:400 is not an indication of absolute antibody concentration, i.e., the P/N value is not quantitative. -Train spokespersons on this subject. # Appendix D. Example of a Case Report Form - Develop a plan for risk and crisis communication. -Provide the associations with FAQ sheets. - Work with associations to provide prevention messages to the general population. - Intensify communication with the medical sciences and health-professional associations with respect to health care services and look for disease patterns and trends. - Evaluate the timeliness of information provided to the associations, as well as the timeliness of transfer of the information to the association's membership. Appendix H. Model of Risk and Outbreak Communication Plan (Cont.) # Target audience # Preparation phase Response phase # Recovery phase Vector control personnel - Vector control personnel and communicators work together to develop and provide information concerning possible CHIKV vectors and integrated vector management, in both electronic and hardcopy formats via video conferences, workshops, etc. -Activate communication plan with health professionals and other entities. - Gather information concerning the effectiveness of ongoing integrated vector management activities, if appropriate. - Provide updated information to health professionals concerning protection and prevention. -Evaluate communications actions for vector control and gather "lessons learned". - Gather information concerning best practices for vector management. Appendix H. Model of Risk and Outbreak Communication Plan (Cont.) # Target audience # Preparation phase Response phase # Recovery phase Blood banks - Provide information to blood bank managers concerning risks associated with CHIKV. - Develop and provide information concerning blood-product management and risks, as well as preparation for donor shortages. - Develop donor screening guidelines and procedures. - Develop fact sheets for donors and prospective donors for distribution in the blood banks. -Establish active communication with blood banks to address shortages of supplies and of donors within restricted areas, in order to inform the general population as well as the media. - Coordinate with implementation of donor screening guidelines and procedures in areas affected by CHIKV emergence. - Evaluate the effectiveness of recommendations that blood banks provide to blood donors. - Develop a communications plan to support lifting of restrictions for donations within a previously restricted area. Appendix H. Model of Risk and Outbreak Communication Plan (Cont.) # Target audience # Preparation phase Response phase # Recovery phase Civil authorities, government officials - Engage in advocacy to gain the support needed for effective preparation and response. - Keep channels open with local, regional, and national levels of government. - Designate and train spokespersons, providing function-specific information appropriate for the level of responsibility. -Implement the communications plan with the other government authorities, updating spokespersons information. - Include appropriate representatives in the JIC. -Evaluate the effectiveness of preparation and response communications activities conducted with authorities and officials. - Gather "lessons learned". Appendix H. Model of Risk and Outbreak Communication Plan (Cont.) # Target audience # Preparation phase Response phase # Recovery phase The media - Develop and maintain relationships with the media that will support communications activities. - Provide training, participate in interviews, and develop public service announcements to advice media partners and prepare them for potential CHIKV activity. - Prepare spokespersons.Spokespersons must be technically and politically credible and willing to interact with the press on short notice. - Establish a permanent channel of information with the media for regular communications, including briefings and interviews. - Disseminate regular reports from the JIC concerning the status of outbreak to provide a consistent message. - Monitor press reports and coverage.Conduct analysis of reports for appropriateness and relevance and adjust messaging/ strategies accordingly. - Continue to provide updates to the media, including appropriate messaging as the risk of transmission is reduced. # O b j e c t i v e s The aim of this meeting was to assemble a technical advisory group to review and adapt a preliminary draft of "Preparedness and Response for Chikungunya Virus Introduction in the Americas".The technical advisory group included experts in various fields from the Americas, including epidemiologists, clinicians, entomologists, laboratory personnel, and communication specialists. After discussing the document's various chapters, these experts submitted changes, additions, and rewrites that they considered appropriate to make the guidelines factual and relevant to all countries in the Region.The guidelines are meant to be a useful tool that can be adapted and applied by each Member Country in establishing the most appropriate strategies for the prevention and control of Chikungunya virus in the Americas.-Communications (Communications Chapter) 16:15 -17:45 Groups meet to decide on approach (Coordinator, Presenter)
# PURPOSE This position statement is based on scientific reviews prepared for a Flour Fortification Initiative (FFI) technical workshop held in Stone Mountain, GA, USA in 2008 where various organizations actively engaged in the prevention and control of vitamin and mineral deficiencies and various other relevant stakeholders met and discussed specific practical recommendations to guide flour fortification efforts being implemented in various countries by the public, private and civic sector.This joint statement reflects the position of the World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO), The United Nations Children's Fund (UNICEF), Global Alliance for Improved Nutrition (GAIN), The Micronutrient Initiative (MI) and Flour Fortification Initiative (FFI).It is intended for a wide audience including food industry, scientists and governments involved in the design and implementation of flour fortification programs as public health interventions. The World Health Organization and the Food and Agriculture Organization of the United Nations published in 2006 the Guidelines on Food Fortification with Micronutrients (WHO/FAO, 2006).These general guidelines, written from a nutrition and public health perspective are a resource for governments and agencies implementing or considering food fortification, and a source of information for scientists, technologists and the food industry.Some basic principles for effective fortification programs along with fortificants' physical characteristics, selection and use with specific food vehicles are described.Fortification of widely distributed and consumed foods has the potential to improve nutritional status of a large proportion of the population, and neither requires changes in dietary patterns nor individual decision for compliance.Technological issues to food fortification need to be fully resolved especially with regards to appropriate levels of nutrients, stability of fortificant, nutrient interactions, physical properties and acceptability by consumers (WHO/FAO, 2006).Worldwide, more than 600 million metric tons of wheat and maize flours are milled annually by commercial roller mills and consumed as noodles, breads, pasta, and other flour products by people in many countries.Fortification of industrially processed wheat and maize flour when appropriately implemented, is an effective, simple, and inexpensive strategy for supplying vitamins and minerals to the diets of large segments of the world's population.It is estimated that the proportion of industrial-scale wheat flour being fortified is 97% in the Americas, 31% in Africa, 44% in Eastern Mediterranean , 21% in South-East Asia , 6% in Europe, and 4% in the Western Pacific regions in 2007 (FFI, 2008). Nearly 100 leading nutrition, pharmaceutical and cereal scientists and milling experts from the public and private sectors from around the world met on March 30 to April 3, 2008 in Stone Mountain, GA, USA to provide advice for countries considering national wheat and/or maize flour fortification.This Second Technical Workshop on Wheat Flour Fortification: Practical Recommendations for National Application was a follow up to a Flour Fortification Initiative, the US Centers for Disease Control and Prevention (CDC) and the Mexican Institute of Public Health, first technical workshop entitled "Wheat Flour Fortification: Current Knowledge and Practical Applications," held in Cuernavaca, Mexico in December 2004 (FFI, 2004).The purpose of this second workshop was to provide guidance on national fortification of wheat and maize flours, milled in industrial roller mills (i.e. >20 metric tons (MT)/day milling capacity), with iron, zinc, folic acid, vitamin B12 and vitamin A and to develop guidelines on formulations of premix based on common ranges of flour consumption.A secondary aim was to agree on the best practices guidelines for premix manufactures and millers.Expert work groups prepared technical documents reviewing published efficacy and effectiveness studies as well as the form and levels of fortificants currently being added to flour in different countries.. The full reviews will be published in a supplement of Food and Nutrition Bulletin in 2009 and the summary recommendations of this meeting can be found in http:// www.sph.emory.edu/wheatflour/atlanta08/ (FFI, 2008). Wheat and maize flour fortification is a preventive food-based approach to improve micronutrient status of populations over time that can be integrated to other interventions in the efforts to reduce vitamin and mineral deficiencies when identified as public health problems.However, fortification of other appropriate food vehicles with the same and/or other nutrients should also be considered when feasible.Wheat and maize flour fortification should be considered when industrially produced flour is regularly consumed by large population groups in a country.Wheat and maize flour fortification programmes could be expected to be most effective in achieving a public health impact if mandated at the national level and can help achieve international public health goals.Decisions about which nutrients to add and the appropriate amounts to add to fortify flour should be based on a series of factors including the nutritional needs and deficiencies of the population; the usual consumption profile of "fortifiable" flour (i.e., the total estimated amount of flour milled by # THE FFI SECOND TECHNICAL WORKSHOP ON WHEAT FLOUR FORTIFICATION RECOMMENDATIONS FOR WHEAT AND MAIZE FLOUR FORTIFICATION BACKGROUND industrial roller mills, produced domestically or imported, which could in principle be fortified); sensory and physical effects of the fortificant nutrients on flour and flour products; fortification of other food vehicles; population consumption of vitamin and mineral supplements; and costs.Flour fortification programs should include appropriate Quality Assurance and Quality Control (QA/QC) programs at mills as well as regulatory and public health monitoring of the nutrient content of fortified foods and assessment of the nutritional/health impacts of the fortification strategies.Though the wheat and maize flours can be fortified with several micronutrients, the technical workshop focused on iron, folic acid, vitamin B 12 , vitamin A and zinc, which are five micronutrients recognized to be of public health significance in developing countries. # IRON 1. The suggested levels for fortification of wheat flour with iron were reviewed by experts from published efficacy and effectiveness studies with various ironfortified foods (Hurrell R et al, 2009).The authors estimated the daily amounts of selected iron compounds including NaFeEDTA, ferrous sulphate, ferrous fumarate and electrolytic iron that have been shown to improve iron status in populations.The selection of the type and quantity of vitamins and minerals to add to flour, either as a voluntary standard or a mandatory requirement, lies with national decision makers in each country and therefore the choice of compounds as well as quantities should be viewed in the context of each country's situation.Based on available data from the Food Balance Sheets of the Food and Agriculture Organization (FAO) and World Bank-supported Household Income and Expenditure Survey (HIES) it was proposed that four wheat flour average consumption ranges were considered in designing flour fortification programs: >300 g/d, 150-300 g/d, 75-150 g/d and <75 g/d . # FOLIC ACID 2. Well conducted studies from the United States (Williams LJ et al, 2002), Canada (De Wals P et al, 2007), and Chile (Hertrampf E & Cortes F, 2004) have documented decreases of 26%, 42%, and 40%, respectively, in the rate of neural tube defects (NTD) affected births after implementation of national regulations mandating wheat-flour fortification with folic acid.Wheat and maize flour fortification with folic acid increases folate intake by women and can reduce the risk of neural tube and other birth defects. # VITAMIN B 3.12 An unpublished pilot study testing the feasibility of adding B-complex vitamins and iron to flour in Israel showed that vitamin B 12 added to flour was stable during baking, did not affect the quality of the bread, and increased plasma B 12 concentrations slightly within six months (Allen L et al, 2008).However, evidence is still lacking about population impact of fortification of wheat flour with vitamin B 12 to improve vitamin B 12 status.Nevertheless, fortifying flours with vitamin B 12 could be a feasible approach to improve vitamin B 12 intake and status of populations as there are no known adverse consequences of vitamin B 12 fortification, and there are no known adverse effects of high intakes of the vitamin. # VITAMIN A 4. Wheat and maize flour can technically be fortified with vitamin A as vitamin A is stable in flour without producing organoleptic changes.As is the case for some other vitamins, high humidity and high temperatures can adversely affect vitamin A content during preparation of wheat and maize flour products.These estimated levels consider only wheat flour as main fortification vehicle in a public health program.If other mass-fortification programs with other food vehicles are implemented effectively, these suggested fortification levels may need to be adjusted downwards as needed.Experience with vitamin A fortification of wheat and maize flour in developing countries is increasing.Although vitamin A is most often used in oils and fats fortification, currently 11 countries are fortifying or propose to fortify wheat and/or maize flour with this vitamin.Two published efficacy trials have reported the impact of vitamin A fortified wheat flour on vitamin A nutritional status but there are no published studies that have evaluated the effectiveness of this intervention on a national scale (West KP et al, 2009).Wheat and, more broadly, other cereal grain flour (e.g., maize) can be considered as a vehicle for delivery of vitamin A to populations at risk of vitamin A deficiency. # ZINC 5. Unpublished results from a trial of wheat flour fortification in China suggests that zinc fortified flour could improve zinc status in women of childbearing age (Brown K et al, 2009).Fortification of other foods with zinc has proven that zinc intake and absorption increase when some zinc fortified foods are consumed but the impact as a public health intervention remains unknown.More research on efficacy and effectiveness of large scale zinc fortification programs is needed.The levels of nutrients to consider adding to fortified wheat flour based on extraction, fortificant compound, and estimated per capita flour availability are presented in the Table 1.These levels and compounds could theoretically improve the nutritional status in the populations consuming the fortified wheat flour regularly in different preparations. This statement was prepared by the core group from the World Health Organization's Department of Nutrition for Health and Development in close collaboration with the Food and Agriculture Organization of the United Nations (FAO), the nutrition section of UNICEF, the Global Alliance for Improved Nutrition (GAIN), the Micronutrient Initiative (MI) and the Flour Fortification Initiative (FFI).The core group members were: Dr. Francesco Branca (WHO), Dr. Juan Pablo Pena-Rosas (WHO), Dr. Brian Thompson (FAO), Mr. Arnold Timmer, (UNICEF), Dr. Regina Moench-Pfanner (GAIN), Dr. Annie Wesley (MI) and Dr. Glen Maberly (FFI).The core group evaluated the commissioned scientific reviews prepared by international nutrition, pharmaceutical and cereal scientists and milling experts from the public and private sector working in the area of micronutrients, milling and food fortification, as well as the summary of discussions and conclusions from the consultation.This position statement is based on these documents and was initiated at WHO headquarters and further discussed and reviewed by members of the core group who provided technical and editorial advice.This statement contains all the consensus recommendations of the core group. All members of the core group were asked to submit and sign Declaration of Interest statements which are on file.There are no known conflicts of interest disclosed among the core group members developing this statement. It is anticipated that the recommendations in this position statement will remain valid until December 2010.The Department of Nutrition for Health and Development at WHO headquarters in Geneva will be responsible for initiating a review following formal WHO Handbook for Guideline Development procedures at that time. # PLANS FOR UPDATE # CONFLICTS OF INTEREST
Drafts of this document have been reviewed by leaders of numerous medical, scientific, public health, and labor organizations and others expert in tuberculosis, acquired immunodeficiency syndrome, infection control, hospital epidemiology, microbiology, ventilation, industrial hygiene, nursing, dental practice, or emergency medical services.We thank the many organizations and individuals for their thoughtful comments, suggestions, and assistance.#Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Facilities, 1994 # Executive Summary This document updates and replaces all previously published guidelines for the prevention of Mycobacterium tuberculosis transmission in health-care facilities.The purpose of this revision is to emphasize the importance of a) the hierarchy of control measures, including administrative and engineering controls and personal respiratory protection; b) the use of risk assessments for developing a written tuberculosis (TB) control plan; c) early identification and management of persons who have TB; d) TB screening programs for health-care workers (HCWs); e) HCW training and education; and f) the evaluation of TB infection-control programs. Transmission of M. tuberculosis is a recognized risk to patients and HCWs in healthcare facilities.Transmission is most likely to occur from patients who have unrecognized pulmonary or laryngeal TB, are not on effective anti-TB therapy, and have not been placed in TB isolation.Several recent TB outbreaks in health-care facilities, including outbreaks of multidrug-resistant TB, have heightened concern about nosocomial transmission.Patients who have multidrug-resistant TB can remain infectious for prolonged periods, which increases the risk for nosocomial and/or occupational transmission of M. tuberculosis.Increases in the incidence of TB have been observed in some geographic areas; these increases are related partially to the high risk for TB among immunosuppressed persons, particularly those infected with human immunodeficiency virus (HIV).Transmission of M. tuberculosis to HIV-infected persons is of particular concern because these persons are at high risk for developing active TB if they become infected with the bacteria.Thus, health-care facilities should be particularly alert to the need for preventing transmission of M. tuberculosis in settings in which HIV-infected persons work or receive care. Supervisory responsibility for the TB infection-control program should be assigned to a designated person or group of persons who should be given the authority to implement and enforce TB infection-control policies.An effective TB infection-control program requires early identification, isolation, and treatment of persons who have active TB.The primary emphasis of TB infection-control plans in health-care facilities should be achieving these three goals by the application of a hierarchy of control measures, including a) the use of administrative measures to reduce the risk for exposure to persons who have infectious TB, b) the use of engineering controls to prevent the spread and reduce the concentration of infectious droplet nuclei, and c) the use of personal respiratory protective equipment in areas where there is still a risk for exposure to M. tuberculosis (e.g., TB isolation rooms).Implementation of a TB infectioncontrol program requires risk assessment and development of a TB infection-control plan; early identification, treatment, and isolation of infectious TB patients; effective engineering controls; an appropriate respiratory protection program; HCW TB training, education, counseling, and screening; and evaluation of the program's effectiveness. Although completely eliminating the risk for transmission of M. tuberculosis in all health-care facilities may not be possible at the present time, adherence to these guidelines should reduce the risk to persons in these settings.Recently, nosocomial TB outbreaks have demonstrated the substantial morbidity and mortality among patients and HCWs that have been associated with incomplete implementation of CDC's Guidelines for Preventing the Transmission of Tuberculosis in Health-Care Facilities, with Special Focus on HIV-Related Issues published in 1990.- Follow-up investigations at some of these hospitals have documented that complete implementation of measures similar or identical to those in the 1990 TB Guidelines significantly reduced or eliminated nosocomial transmission of M. tuberculosis to patients and/or HCWs. # I. Introduction # A. Purpose of Document In April 1992, the National MDR-TB Task Force published the National Action Plan to Combat Multidrug-Resistant Tuberculosis (1 ).The publication was a response to reported nosocomial outbreaks of tuberculosis (TB), including outbreaks of multidrug-resistant TB (MDR-TB), and the increasing incidence of TB in some geographic areas.The plan called for the update and revision of the guidelines for preventing nosocomial transmission of Mycobacterium tuberculosis published December 7, 1990 (2 ). These recommendations update and replace all previously published CDC recommendations for TB infection control in health-care facilities (2,4 ).The recommendations in this document are applicable primarily to inpatient facilities in which health care is provided (e.g., hospitals, medical wards in correctional facilities, nursing homes, and hospices).Recommendations applicable to ambulatory-care facilities, emergency departments, homehealth-care settings, emergency medical services, medical offices, dental settings, and other facilities or residential settings that provide medical care are provided in separate sections, with cross-references to other sections of the guidelines if appropriate. Designated personnel at health-care facilities should conduct a risk assessment for the entire facility and for each area- and occupational group, determine the risk for nosocomial or occupational transmission of M. tuberculosis, and implement an appropriate TB infection-control program.The extent of the TB infection-control program may range from a simple program emphasizing administrative controls in settings where there is minimal risk for exposure to M. tuberculosis, to a comprehensive program that includes administrative controls, engineering controls, and respiratory protection in settings where the risk for exposure is high.In all settings, administrative measures should be used to minimize the number of HCWs exposed to M. tuberculosis while still providing optimal care for TB patients.HCWs providing care to patients who have TB should be informed about the level of risk for transmission of M. tuberculosis and the appropriate control measures to minimize that risk. In this document, the term "HCWs" refers to all the paid and unpaid persons working in health-care settings who have the potential for exposure to M. tuberculosis.This may include, but is not limited to, physicians; nurses; aides; dental workers; technicians; workers in laboratories and morgues; emergency medical service (EMS) personnel; students; part-time personnel; temporary staff not employed by the health-care facility; and persons not involved directly in patient care but who are potentially at risk for occupational exposure to M. tuberculosis (e.g., volunteer workers and dietary, housekeeping, maintenance, clerical, and janitorial staff). Although the purpose of this document is to make recommendations for reducing the risk for transmission of M. tuberculosis in health-care facilities, the process of implementing these recommendations must safeguard, in accordance with applicable state and federal laws, the confidentiality and civil rights of persons who have TB. # B. Epidemiology, Transmission, and Pathogenesis of TB The prevalence of TB is not distributed evenly throughout all segments of the U.S. population.Some subgroups or persons have a higher risk for TB either because they are more likely than other persons in the general population to have been exposed to and infected with M. tuberculosis or because their infection is more likely to progress to active TB after they have been infected (5 ).In some cases, both of these factors may be present.Groups of persons known to have a higher prevalence of TB infection include contacts of persons who have active TB, foreign-born persons from areas of the world with a high prevalence of TB (e.g., Asia, Africa, the Caribbean, and Latin America), medically underserved populations (e.g., some African-Americans, Hispanics, Asians and Pacific Islanders, American Indians, and Alaskan Natives), homeless persons, current or former correctional-facility inmates, alcoholics, injecting-drug users, and the elderly.Groups with a higher risk for progression from latent TB infection to active disease include persons who have been infected recently (i.e., within the previous 2 years), children <4 years of age, persons with fibrotic lesions on chest radiographs, and persons with certain medical conditions (i.e., human immunodeficiency virus infection, silicosis, gastrectomy or jejuno-ileal bypass, being ≥10% below ideal body weight, chronic renal failure with renal dialysis, diabetes mellitus, immunosuppression resulting from receipt of high-dose corticosteroid or other immunosuppressive therapy, and some malignancies) (5 ). M. tuberculosis is carried in airborne particles, or droplet nuclei, that can be generated when persons who have pulmonary or laryngeal TB sneeze, cough, speak, or sing (6 ).The particles are an estimated 1-5 µm in size, and normal air currents can keep them airborne for prolonged time periods and spread them throughout a room or building (7 ).Infection occurs when a susceptible person inhales droplet nuclei containing M. tuberculosis, and these droplet nuclei traverse the mouth or nasal passages, upper respiratory tract, and bronchi to reach the alveoli of the lungs.Once in the alveoli, the organisms are taken up by alveolar macrophages and spread throughout the body.Usually within 2-10 weeks after initial infection with M. tuberculosis, the immune response limits further multiplication and spread of the tubercle bacilli; however, some of the bacilli remain dormant and viable for many years.This condition is referred to as latent TB infection.Persons with latent TB infection usually have positive purified protein derivative (PPD)-tuberculin skin-test results, but they do not have symptoms of active TB, and they are not infectious. In general, persons who become infected with M. tuberculosis have approximately a 10% risk for developing active TB during their lifetimes.This risk is greatest during the first 2 years after infection.Immunocompromised persons have a greater risk for the progression of latent TB infection to active TB disease; HIV infection is the strongest known risk factor for this progression.Persons with latent TB infection who become coinfected with HIV have approximately an 8%-10% risk per year for developing active TB (8 ). HIV-infected persons who are already severely immunosuppressed and who become newly infected with M. tuberculosis have an even greater risk for developing active TB (9)(10)(11)(12). The probability that a person who is exposed to M. tuberculosis will become infected depends primarily on the concentration of infectious droplet nuclei in the air and the duration of exposure.Characteristics of the TB patient that enhance transmission include a) disease in the lungs, airways, or larynx; b) presence of cough or other forceful expiratory measures; c) presence of acid-fast bacilli (AFB) in the sputum; d) failure of the patient to cover the mouth and nose when coughing or sneezing; e) presence of cavitation on chest radiograph; f) inappropriate or short duration of chemotherapy; and g) administration of procedures that can induce coughing or cause aerosolization of M. tuberculosis (e.g., sputum induction).Environmental factors that enhance the likelihood of transmission include a) exposure in relatively small, enclosed spaces; b) inadequate local or general ventilation that results in insufficient dilution and/or removal of infectious droplet nuclei; and c) recirculation of air containing infectious droplet nuclei.Characteristics of the persons exposed to M. tuberculosis that may affect the risk for becoming infected are not as well defined.In general, persons who have been infected previously with M. tuberculosis may be less susceptible to subsequent infection.However, reinfection can occur among previously infected persons, especially if they are severely immunocompromised.Vaccination with Bacille of Calmette and Guérin (BCG) probably does not affect the risk for infection; rather, it decreases the risk for progressing from latent TB infection to active TB (13 ).Finally, although it is well established that HIV infection increases the likelihood of progressing from latent TB infection to active TB, it is unknown whether HIV infection increases the risk for becoming infected if exposed to M. tuberculosis. # C. Risk for Nosocomial Transmission of M. tuberculosis Transmission of M. tuberculosis is a recognized risk in health-care facilities (14)(15)(16)(17)(18)(19)(20)(21)(22).The magnitude of the risk varies considerably by the type of healthcare facility, the prevalence of TB in the community, the patient population served, the HCW's occupational group, the area of the health-care facility in which the HCW works, and the effectiveness of TB infection-control interventions.The risk may be higher in areas where patients with TB are provided care before diagnosis and initiation of TB treatment and isolation precautions (e.g., in clinic waiting areas and emergency departments) or where diagnostic or treatment procedures that stimulate coughing are performed.Nosocomial transmission of M. tuberculosis has been associated with close contact with persons who have infectious TB and with the performance of certain procedures (e.g., bronchoscopy , endotracheal intubation and suctioning , open abscess irrigation , and autopsy ).Sputum induction and aerosol treatments that induce coughing may also increase the potential for transmission of M. tuberculosis (23,24 ).Personnel of health-care facilities should be particularly alert to the need for preventing transmission of M. tuberculosis in those facilities in which immunocompromised persons (e.g., HIV-infected persons) work or receive care-especially if cough-inducing procedures, such as sputum induction and aerosolized pentamidine treatments, are being performed. Several TB outbreaks among persons in health-care facilities have been reported recently (11,(24)(25)(26)(27)(28) ; CDC, unpublished data).Many of these outbreaks involved transmission of multidrug-resistant strains of M. tuberculosis to both patients and HCWs.Most of the patients and some of the HCWs were HIV-infected persons in whom new infection progressed rapidly to active disease.Mortality associated with those outbreaks was high (range: 43%-93%).Furthermore, the interval between diagnosis and death was brief (range of median intervals: 4-16 weeks).Factors contributing to these outbreaks included delayed diagnosis of TB, delayed recognition of drug resistance, and delayed initiation of effective therapy-all of which resulted in prolonged infectiousness, delayed initiation and inadequate duration of TB isolation, inadequate ventilation in TB isolation rooms, lapses in TB isolation practices and inadequate precautions for cough-inducing procedures, and lack of adequate respiratory protection.Analysis of data collected from three of the health-care facilities involved in the outbreaks indicates that transmission of M. tuberculosis decreased significantly or ceased entirely in areas where measures similar to those in the 1990 TB Guidelines were implemented (2,(29)(30)(31)(32).However, several interventions were implemented simultaneously, and the effectiveness of the separate interventions could not be determined. # D. Fundamentals of TB Infection Control An effective TB infection-control program requires early identification, isolation, and effective treatment of persons who have active TB.The primary emphasis of the TB infection-control plan should be on achieving these three goals.In all health-care facilities, particularly those in which persons who are at high risk for TB work or receive care, policies and procedures for TB control should be developed, reviewed periodically, and evaluated for effectiveness to determine the actions necessary to minimize the risk for transmission of M. tuberculosis.The second level of the hierarchy is the use of engineering controls to prevent the spread and reduce the concentration of infectious droplet nuclei.These controls include a) direct source control using local exhaust ventilation, b) controlling direction of airflow to prevent contamination of air in areas adjacent to the infectious source, c) diluting and removing contaminated air via general ventilation, and d) air cleaning via air filtration or ultraviolet germicidal irradiation (UVGI). The first two levels of the hierarchy minimize the number of areas in the health-care facility where exposure to infectious TB may occur, and they reduce, but do not eliminate, the risk in those few areas where exposure to M. tuberculosis can still occur (e.g., rooms in which patients with known or suspected infectious TB are being isolated and treatment rooms in which cough-inducing or aerosol-generating procedures are performed on such patients).Because persons entering such rooms may be exposed to M. tuberculosis, the third level of the hierarchy is the use of personal respiratory protective equipment in these and certain other situations in which the risk for infection with M. tuberculosis may be relatively higher. Specific measures to reduce the risk for transmission of M. tuberculosis include the following: - Assigning to specific persons in the health-care facility the supervisory responsibility for designing, implementing, evaluating, and maintaining the TB infection-control program (Section II.A). - Conducting a risk assessment to evaluate the risk for transmission of M. tuberculosis in all areas of the health-care facility, developing a written TB infection-control program based on the risk assessment, and periodically repeating the risk assessment to evaluate the effectiveness of the TB infection-control program (Section II.B). - Developing, implementing, and enforcing policies and protocols to ensure early identification, diagnostic evaluation, and effective treatment of patients who may have infectious TB (Section II.C; Suppl.2). - Providing prompt triage for and appropriate management of patients in the outpatient setting who may have infectious TB (Section II.D). - Promptly initiating and maintaining TB isolation for persons who may have infectious TB and who are admitted to the inpatient setting (Section II.E; Suppl.1). - Effectively planning arrangements for discharge (Section II.E). - Developing, installing, maintaining, and evaluating ventilation and other engineering controls to reduce the potential for airborne exposure to M. tuberculosis (Section II.F; Suppl.3). - Developing, implementing, maintaining, and evaluating a respiratory protection program (Section II.G; Suppl.4). - Using precautions while performing cough-inducing procedures (Section II.H; Suppl.3). - Educating and training HCWs about TB, effective methods for preventing transmission of M. tuberculosis, and the benefits of medical screening programs (Section II.I). - Developing and implementing a program for routine periodic counseling and screening of HCWs for active TB and latent TB infection (Section II.J; Suppl.2). - Promptly evaluating possible episodes of M. tuberculosis transmission in health-care facilities, including PPD skin-test conversions among HCWs, epidemiologically associated cases among HCWs or patients, and contacts of patients or HCWs who have TB and who were not promptly identified and isolated (Section II.K). - Coordinating activities with the local public health department, emphasizing reporting, and ensuring adequate discharge follow-up and the continuation and completion of therapy (Section II.L). # II.Recommendations # A. Assignment of Responsibility - Supervisory responsibility for the TB infection-control program should be assigned to a designated person or group of persons with expertise in infection control, occupational health, and engineering.These persons should be given the authority to implement and enforce TB infectioncontrol policies. - If supervisory responsibility is assigned to a committee, one person should be designated as the TB contact person.Questions and problems can then be addressed to this person. 1, Figure 1).
Appropriate infection-control interventions can then be developed on the basis of actual risk.Risk assessments should be performed for all inpatient and outpatient settings (e.g., medical and dental offices). # B. Risk - Regardless of risk level, the management of patients with known or suspected infectious TB should not vary.However, the index of suspicion for infectious TB among patients, the frequency of HCW PPD skin testing, the number of TB isolation rooms, and other factors will depend on whether the risk for transmission of M. tuberculosis in the facility, area, or occupational group is high, intermediate, low, very low, or minimal. - The risk assessment should be conducted by a qualified person or group of persons (e.g., hospital epidemiologists, infectious disease specialists, pulmonary disease specialists, infection-control practitioners, health-care administrators, occupational health personnel, engineers, HCWs, or local public health personnel). - The risk assessment should be conducted for the entire facility and for specific areas within the facility (e.g., medical, TB, pulmonary, or HIV wards; HIV, infectious disease, or pulmonary clinics; and emergency departments or other areas where TB patients might receive 1.Review the community TB profile (from public health department data). 2.Review the number of TB patients who were treated in each area of the facility (both inpatient and outpatient). (This information can be obtained by analyzing laboratory surveillance data and by reviewing discharge diagnoses or medical and infectioncontrol records.) 3.Review the drug-susceptibility patterns of TB isolates of patients who were treated at the facility. 4.Analyze purified protein derivative (PPD)-tuberculin skin-test results of health-care workers (HCWs), by area or by occupational group for HCWs not assigned to a specific area (e.g., respiratory therapists). 5.To evaluate infection-control parameters, review medical records of a sample of TB patients seen at the facility. Calculate intervals from: - admission until TB suspected; - admission until TB evaluation performed; - admission until acid-fast bacilli (AFB) specimens ordered; - AFB specimens ordered until AFB specimens collected; - AFB specimens collected until AFB smears performed and reported; - AFB specimens collected until cultures performed and reported; - AFB specimens collected until species identification conducted and reported; - AFB specimens collected until drug-susceptibility tests performed and reported; - admission until TB isolation initiated; - admission until TB treatment initiated; and - duration of TB isolation. Obtain the following additional information: - Were appropriate criteria used for discontinuing isolation? - Did the patient have a history of prior admission to the facility? - Was the TB treatment regimen adequate? - Were follow-up sputum specimens collected properly? - Was appropriate discharge planning conducted? No TB patients in facility or community. -Classification of risk for a facility, for a specific area, and for a specific occupational group should be based on a) the profile of TB in the community; b) the number of infectious TB patients admitted to the area or ward, or the estimated number of infectious TB patients to whom HCWs in an occupational group may be exposed; and c) the results of analysis of HCW PPD test conversions (where applicable) and possible person-to-person transmission of M. tuberculosis (Figure 1). # Minimal risk - All TB infection-control programs should include periodic reassessments of risk.The frequency of repeat risk assessments should be based on the results of the most recent risk assessment (Table 2, Figure 1). - The "minimal-risk" category applies only to an entire facility.A "minimal-risk" facility does not admit TB patients to inpatient or outpatient areas and is not located in a community with TB (i.e., Area: a structural unit (e.g., a hospital ward or laboratory) or functional unit (e.g., an internal medicine service) in which HCWs provide services to and share air with a specific patient population or work with clinical specimens that may contain viable M. tuberculosis organisms.The risk for exposure to M. tuberculosis in a given area depends on the prevalence of TB in the population served and the characteristics of the environment. †With epidemiologic evaluation suggestive of occupational (nosocomial) transmission (see Problem Evaluation section in the text). §Cluster: two or more PPD skin-test conversions occurring within a 3-month period among HCWs in a specific area or occupational group, and epidemiologic evidence suggests occupational (nosocomial) transmission. ¶For example, clusters of M. tuberculosis isolates with identical DNA fingerprint (RFLP) patterns or drug-resistance patterns, with epidemiologic evaluation suggestive of nosocomial transmission (see Problem Evaluation section in the text).Does not include patients identified in triage system and referred to a collaborating facility or patients being managed in outpatient areas. † †To prevent inappropriate management and potential loss to follow-up of patients identified in the triage system of a very low-risk facility as having suspected TB, an agreement should exist for referral between the referring and receiving facilities. § §Or, for occupational groups, exposure to fewer than six TB patients for HCWs in the particular occupational group during the preceding year. ¶ ¶Or, for occupational groups, exposure to six or more TB patients for HCWs in the particular occupational group during the preceding year. See Problem Evaluation section in the text. † † †Occurrence of drug-resistant TB in the facility or community, or a relatively high prevalence of HIV infection among patients or HCWs in the area, may warrant a higher risk rating. § § §For outpatient facilities, if TB cases have been documented in the community but no TB patients have been examined in the outpatient area during the preceding year, the area can be designated as very low risk. Because very low-risk facilities do not admit patients who may have active TB to inpatient areas, most HCWs in such facilities do not need routine follow-up PPD screening after baseline PPD testing is done.However, those who are involved in the initial assessment and diagnostic evaluation of patients in the ambulatory-care, emergency, and admitting departments of such facilities or in the outpatient management of patients with active TB could be exposed potentially to a patient who has active TB.These HCWs may need to receive routine periodic PPD screening.Similarly, these HCWs may need to be included in a respiratory protection program. †Because very low-risk facilities do not admit patients suspected of having active TB, review of TB patient medical records is not applicable.However, follow-up of patients who were identified during triage as possibly having active TB and referred to another institution for further evaluation and management may be useful in evaluating the effectiveness of the triage system. §Some minimal or very low-risk facilities may elect to use engineering controls (e.g., booths for cough-inducing procedures, portable high-efficiency particulate filtration units, ultraviolet germicidal irradiation units) in triage/waiting areas.In such situations, appropriate protocols for maintaining this equipment should be in place, and this maintenance should be evaluated periodically. ¶The criteria used in clinical prediction rules will probably vary from facility to facility depending on the prevalence of TB in the population served by the facility and on the clinical, radiographic, and laboratory characteristics of TB patients examined in the facility.The protocols should be consistent with CDC/American Thoracic Society recommendations (33 ). † † Protocols for referring patients who require specialized treatment (e.g., patients with multidrug-resistant TB) may be appropriate. § §Based on maximum daily number of patients requiring TB isolation for suspected or confirmed active TB.Isolation rooms should meet the performance criteria specified in these guidelines. ¶ ¶If such procedures are used in the triage protocol(s) for identifying patients who may have active TB. Minimal-risk facilities do not need to maintain an ongoing PPD skin-testing program.However, baseline PPD testing of HCWs may be advisable so that if an unexpected exposure does occur, conversions can be distinguished from positive PPD test results caused by previous exposures. counties or communities in which TB cases have not been reported during the previous year).Thus, there is essentially no risk for exposure to TB patients in the facility.This category may also apply to many outpatient settings (e.g., many medical and dental offices). - The "very low-risk" category generally applies only to an entire facility.A very low-risk facility is one in which a) patients with active TB are not admitted to inpatient areas but may receive initial assessment and diagnostic evaluation or outpatient management in outpatient areas (e.g., ambulatory-care and emergency departments) and b) patients who may have active TB and need inpatient care are promptly referred to a collaborating facility.In such facilities, the outpatient areas in which exposure to patients with active TB could occur should be assessed and assigned to the appropriate low-, intermediate-, or high-risk category.Categorical assignment will depend on the number of TB patients examined in the area during the preceding year and whether there is evidence of nosocomial transmission of M. tuberculosis in the area.If TB cases have been reported in the community, but no patients with active TB have been examined in the outpatient area during the preceding year, the area can be designated as very low risk (e.g., many medical offices). The referring and receiving facilities should establish a referral agreement to prevent inappropriate management and potential loss to follow-up of patients suspected of having TB during evaluation in the triage system of a very low-risk facility. In some facilities in which TB patients are admitted to inpatient areas, a very low-risk protocol may be appropriate for areas (e.g., administrative areas) or occupational groups that have only a very remote possibility of exposure to M. tuberculosis. The very low-risk category may also be appropriate for outpatient facilities that do not provide initial assessment of persons who may have TB, but do screen patients for active TB as part of a limited medical screening before undertaking specialty care (e.g., dental settings). - "Low-risk" areas or occupational groups are those in which a) the PPD test conversion rate is not greater than that for areas or groups in which occupational exposure to M. tuberculosis is unlikely or than previous conversion rates for the same area or group, b) no clusters- of PPD test conversions have occurred, c) person-to-person transmission of M. tuberculosis has not been detected, and d) fewer than six TB patients are examined or treated per year. - "Intermediate-risk" areas or occupational groups are those in which a) the PPD test conversion rate is not greater than that for areas or groups in which occupational exposure to M. tuberculosis is unlikely or than previous conversion rates for the same area or group, b) no clusters of PPD test conversions have occurred, c) person-to-person transmission of M. tuberculosis has not been detected, and d) six or - "High-risk" areas or occupational groups are those in which a) the PPD test conversion rate is significantly greater than for areas or groups in which occupational exposure to M. tuberculosis is unlikely or than previous conversion rates for the same area or group, and epidemiologic evaluation suggests nosocomial transmission; or b) a cluster of PPD test conversions has occurred, and epidemiologic evaluation suggests nosocomial transmission of M. tuberculosis; or c) possible person-to-person transmission of M. tuberculosis has been detected. - If no data or insufficient data for adequate determination of risk have been collected, such data should be compiled, analyzed, and reviewed expeditiously. b. Community TB profile - A profile of TB in the community that is served by the facility should be obtained from the public health department.This profile should include, at a minimum, the incidence (and prevalence, if available) of active TB in the community and the drug-susceptibility patterns of M. tuberculosis isolates (i.e., the antituberculous agents to which each isolate is susceptible and those to which it is resistant) from patients in the community. # c. Case surveillance - Data concerning the number of suspected and confirmed active TB cases among patients and HCWs in the facility should be systematically collected, reviewed, and used to estimate the number of TB isolation rooms needed, to recognize possible clusters of nosocomial transmission, and to assess the level of potential occupational risk.The number of TB patients in specific areas of a facility can be obtained from laboratory surveillance data on specimens positive for AFB smears or M. tuberculosis cultures, from infectioncontrol records, and from databases containing information about hospital discharge diagnoses. - Drug-susceptibility patterns of M. tuberculosis isolates from TB patients treated in the facility should be reviewed to identify the frequency and patterns of drug resistance.This information may indicate a need to modify the initial treatment regimen or may suggest possible nosocomial transmission or increased occupational risk. # d. Analysis of HCW PPD test screening data - Results of HCW PPD testing should be recorded in the individual HCW's employee health record and in a retrievable aggregate data-base of all HCW PPD test results.Personal identifying information should be handled confidentially.PPD test conversion rates should be calculated at appropriate intervals to estimate the risk for PPD test conversions for each area of the facility and for each specific occupational group not assigned to a specific area (Table 2).To calculate PPD test conversion rates, the total number of previously PPDnegative HCWs tested in each area or group (i.e., the denominator) and the number of PPD test conversions among HCWs in each area or group (the numerator) must be obtained. - PPD test conversion rates for each area or occupational group should be compared with rates for areas or groups in which occupational exposure to M. tuberculosis is unlikely and with previous conversion rates in the same area or group to identify areas or groups where the risk for occupational PPD test conversions may be increased.A low number of HCWs in a specific area may result in a greatly increased rate of conversion for that area, although the actual risk may not be significantly greater than that for other areas.Testing for statistical significance (e.g., Fisher's exact test or chi square test) may assist interpretation; however, lack of statistical significance may not rule out a problem (i.e., if the number of HCWs tested is low, there may not be adequate statistical power to detect a significant difference).Thus, interpretation of individual situations is necessary. - An epidemiologic investigation to evaluate the likelihood of nosocomial transmission should be conducted if PPD test conversions are noted (Section II.K.1). - The frequency and comprehensiveness of the HCW PPD testing program should be evaluated periodically to ensure that all HCWs who should be included in the program are being tested at appropriate intervals.For surveillance purposes, earlier detection of transmission may be enhanced if HCWs in a given area or occupational group are tested on different scheduled dates rather than all being tested on the same date (Section II.J.3). e. Review of TB patient medical records - The medical records of a sample of TB patients examined at the facility can be reviewed periodically to evaluate infection-control parameters (Table 1).Parameters to examine may include the intervals from date of admission until a) TB was suspected, b) specimens for AFB smears were ordered, c) these specimens were collected, d) tests were performed, and e) results were reported.Moreover, the adequacy of the TB treatment regimens that were used should be evaluated. - Medical record reviews should note previous hospital admissions of TB patients before the onset of TB symptoms.Patient-to-patient transmission may be suspected if active TB occurs in a patient who had a prior hospitalization during which exposure to another TB patient occurred or if isolates from two or more TB patients have identical characteristic drug-susceptibility or DNA fingerprint patterns. - Data from the case review should be used to determine if there is a need to modify a) protocols for identifying and isolating patients who may have infectious TB, b) laboratory procedures, c) administrative policies and practices, or d) protocols for patient management. f. Observation of TB infection-control practices - Assessing adherence to the policies of the TB infection-control program should be part of the evaluation process.This assessment should be performed on a regular basis and whenever an increase occurs in the number of TB patients or HCW PPD test conversions. Areas at high risk for transmission of M. tuberculosis should be monitored more frequently than other areas.The review of patient medical records provides information on HCW adherence to some of the policies of the TB infection-control program.In addition, work practices related to TB isolation (e.g., keeping doors to isolation rooms closed) should be observed to determine if employers are enforcing, and HCWs are adhering to, these policies and if patient adherence is being enforced.If these policies are not being enforced or adhered to, appropriate education and other corrective action should be implemented. # g. Engineering evaluation - Results of engineering maintenance measures should be reviewed at regular intervals (Table 3).Data from the most recent evaluation and from maintenance procedures and logs should be reviewed carefully as part of the risk assessment. # Development of the TB Infection-Control Plan - Based on the results of the risk assessment, a written TB infectioncontrol plan should be developed and implemented for each area of the facility and for each occupational group of HCWs not assigned to a specific area of the facility (Table 2; Table 3). - The occurrence of drug-resistant TB in the facility or the community, or a relatively high prevalence of HIV infection among patients or HCWs in the community, may increase the concern about transmission of M. tuberculosis and may influence the decision regarding which protocol to follow (i.e., a higher-risk classification may be selected). - Health-care facilities are likely to have a combination of low-, intermediate-, and high-risk areas or occupational groups during the same time period.The appropriate protocol should be implemented for each area or group. - Areas in which cough-inducing procedures are performed on patients who may have active TB should, at the minimum, implement the intermediate-risk protocol.
# Periodic Reassessment - Follow-up risk assessment should be performed at the interval indicated by the most recent risk assessment (Figure 1; # Characteristics of an effective TB infection-control program -Continued the results of the follow-up assessment, problem evaluation may need to be conducted or the protocol may need to be modified to a higher-or lower-risk level. - After each risk assessment, the staff responsible for TB control, in conjunction with other appropriate HCWs, should review all TB control policies to ensure that they are effective and meet current needs. # Examples of Risk Assessment Examples of six hypothetical situations and the means by which surveillance data are used to select a TB control protocol are described as follows: The low-risk protocol will be followed in all areas. Hospital A. Hospital B. The overall HCW PPD test conversion rate in the facility is 1.8%.The PPD test conversion rate for the medical intensive-care unit rate is significantly higher than all other areas in the facility.The problem identification process is initiated (Section II.K).It is determined that all TB patients have been isolated appropriately.Other potential problems are then evaluated, and the cause for the higher rate is not identified.After consulting the public health department TB infection-control program, the high-risk protocol is followed in the unit until the PPD test conversion rate is similar to areas of the facility in which occupational exposure to TB patients is unlikely.If the rate remains significantly higher than other areas, further evaluation, including environmental and procedural studies, will be performed to identify possible reasons for the high conversion rate. Hospital C. The overall HCW PPD test conversion rate in the facility is 2.4%.Rates range from 0 to 2.6% for the individual areas and occupational groups.None of these rates is significantly higher than rates for areas in which occupational exposure to M. tuberculosis is unlikely.No particular HCW group has higher conversion rates than the other groups.No clusters of HCW PPD test conversions have occurred.In two of the areas, HCWs cared for more than six TB patients during the preceding year.These two areas will follow the intermediate-risk protocol, and all other areas will follow the low-risk protocol.This hospital is located in the southeastern United States, and these conversion rates may reflect cross-reactivity with nontuberculous mycobacteria. Hospital D. The overall HCW PPD test conversion rate in the facility is 1.2%. In no area did HCWs care for six or more TB patients during the preceding year.Three of the 20 respiratory therapists tested had PPD conversions, for a rate of 15%.The respiratory therapists who had PPD test conversions had spent all or part of their time in the pulmonary function laboratory, where induced sputum specimens were obtained.A low-risk protocol is maintained for all areas and occupational groups in the facility except for respiratory therapists.A problem evaluation is conducted in the pulmonary function laboratory (Section II.K).It is determined that the ventilation in this area is inadequate.Booths are installed for sputum induction.PPD testing and the risk assessment are repeated 3 months later.If the repeat testing at 3 months indicates that no more conversions have occurred, the respiratory therapists will return to the low-risk protocol. Hospital E. Hospital E is located in a community that has a relatively low incidence of TB.To optimize TB services in the community, the four hospitals in the community have developed an agreement that one of them (e.g., Hospital G) will provide all inpatient services to persons who have # C. Identifying, Evaluating, and Initiating Treatment for Patients Who May Have Active TB The most important factors in preventing transmission of M. tuberculosis are the early identification of patients who may have infectious TB, prompt implementation of TB precautions for such patients, and prompt initiation of effective treatment for those who are likely to have TB. # Identifying patients who may have active TB - Health-care personnel who are assigned responsibility for TB infection control in ambulatory-care and inpatient settings should develop, implement, and enforce protocols for the early identification of patients who may have infectious TB. - The criteria used in these protocols should be based on the prevalence and characteristics of TB in the population served by the specific facility.These protocols should be evaluated periodically and revised according to the results of the evaluation.Review of medical records of patients who were examined in the facility and diagnosed as having TB may serve as a guide for developing or revising these protocols. - A diagnosis of TB may be considered for any patient who has a persistent cough (i.e., a cough lasting for ≥3 weeks) or other signs or symptoms compatible with active TB (e.g., bloody sputum, night sweats, weight loss, anorexia, or fever).However, the index of suspicion for TB will vary in different geographic areas and will depend on the prevalence of TB and other characteristics of the population served by the facility.The index of suspicion for TB should be very high in geographic areas or among groups of patients in which the prevalence of TB is high (Section I.B).Appropriate diagnostic measures should be conducted and TB precautions implemented for patients in whom active TB is suspected. # Diagnostic evaluation for active TB - Diagnostic measures for identifying TB should be conducted for patients in whom active TB is being considered.These measures include obtaining a medical history and performing a physical examination, PPD skin test, chest radiograph, and microscopic examination and culture of sputum or other appropriate specimens (6,34,35 ).Other diagnostic procedures (e.g., bronchoscopy or biopsy) may be indicated for some patients (36,37 ). - Prompt laboratory results are crucial to the proper treatment of the TB patient and to early initiation of infection control.To ensure timely results, laboratories performing mycobacteriologic tests should be proficient at both the laboratory and administrative aspects of specimen processing.Laboratories should use the most rapid methods available (e.g., fluorescent microscopy for AFB smears; radiometric culture methods for isolation of mycobacteria; ρ-nitro-α-acetylaminoβ-hydroxy-proprophenone test, nucleic acid probes, or highpressure liquid chromatography for species identification; and radiometric methods for drug-susceptibility testing).As other more rapid or sensitive tests become available, practical, and affordable, such tests should be incorporated promptly into the mycobacteriology laboratory.Laboratories that rarely receive specimens for mycobacteriologic analysis should refer the specimens to a laboratory that more frequently performs these tests. - Results of AFB sputum smears should be available within 24 hours of specimen collection (38 ). - - TB may be more difficult to diagnose among persons who have HIV infection (or other conditions associated with severe suppression of cell-mediated immunity) because of a nonclassical clinical or radiographic presentation and/or the simultaneous occurrence of other pulmonary infections (e.g., P. carinii pneumonia and M. avium complex).The difficulty in diagnosing TB in HIV-infected persons may be further compounded by impaired responses to PPD skin tests (39,40 ), the possibly lower sensitivity of sputum smears for detecting AFB ( 41), or the overgrowth of cultures with M. avium complex in specimens from patients infected with both M. avium complex and M. tuberculosis (42 ). - Immunosuppressed patients who have pulmonary signs or symptoms that are ascribed initially to infections or conditions other than TB should be evaluated initially for coexisting TB.The evaluation for TB should be repeated if the patient does not respond to appropriate therapy for the presumed cause(s) of the pulmonary abnormalities (Suppl.1; Suppl.2). - Patients with suspected or confirmed TB should be reported immediately to the appropriate public health department so that standard procedures for identifying and evaluating TB contacts can be initiated. # Initiation of treatment for suspected or confirmed TB - Patients who have confirmed active TB or who are considered highly likely to have active TB should be started promptly on appropriate treatment in accordance with current guidelines (Suppl.2) (43 ).In geographic areas or facilities that have a high prevalence of MDR-TB, the initial regimen used may need to be enhanced while the results of drugsusceptibility tests are pending.The decision should be based on analysis of surveillance data. - While the patient is in the health-care facility, anti-TB drugs should be administered by directly observed therapy (DOT), the process by which an HCW observes the patient swallowing the medications.Continuing DOT after the patient is discharged should be strongly considered.This decision and the arrangements for providing outpatient DOT should be made in collaboration with the public health department. # D. Management of Patients Who May Have Active TB in Ambulatory-Care Settings and Emergency Departments - Triage of patients in ambulatory-care settings and emergency departments should include vigorous efforts to promptly identify patients who have active TB.HCWs who are the first points of contact in facilities that serve populations at risk for TB should be trained to ask questions that will facilitate identification of patients with signs and symptoms suggestive of TB. - Patients with signs or symptoms suggestive of TB should be evaluated promptly to minimize the amount of time they are in ambulatory-care areas.TB precautions should be followed while the diagnostic evaluation is being conducted for these patients. - TB precautions in the ambulatory-care setting should include a) placing these patients in a separate area apart from other patients, and not in open waiting areas (ideally, in a room or enclosure meeting TB isolation requirements); b) giving these patients surgical masks- to wear and instructing them to keep their masks on; and c) giving these patients tissues and instructing them to cover their mouths and noses with the tissues when coughing or sneezing. - TB precautions should be followed for patients who are known to have active TB and who have not completed therapy until a determination has been made that they are noninfectious (Suppl.1). - Patients with active TB who need to attend a health-care clinic should have appointments scheduled to avoid exposing HIV-infected or otherwise severely immunocompromised persons to M. tuberculosis.This recommendation could be accomplished by designating certain times of the day for appointments for these patients or by treating them in areas where immunocompromised persons are not treated. - Ventilation in ambulatory-care areas where patients at high risk for TB are treated should be designed and maintained to reduce the risk for transmission of M. tuberculosis.General-use areas (e.g., waiting rooms) and special areas (e.g., treatment or TB isolation rooms in ambulatory areas) should be ventilated in the same manner as described for similar inpatient areas (Sections II.E.3, II.F; Suppl.3).Enhanced general ventilation or the use of air-disinfection techniques (e.g., UVGI or recirculation of air within the room through high-efficiency particulate air filters) may be useful in general-use areas of facilities where many infectious TB patients receive care (Section II.F; Suppl.3). - Ideally, ambulatory-care settings in which patients with TB are frequently examined or treated should have a TB isolation room(s) available.Such rooms are not necessary in ambulatory-care settings in which patients who have confirmed or suspected TB are seen infrequently.However, these facilities should have a written protocol for early identification of patients with TB symptoms and referral to an area or a collaborating facility where the patient can be evaluated and managed appropriately.These protocols should be reviewed on a regular basis and revised as necessary. The additional guidelines in Section II.H should be followed in ambulatorycare settings where cough-inducing procedures are performed on patients who may have active TB. *Surgical masks are designed to prevent the respiratory secretions of the person wearing the mask from entering the air.When not in a TB isolation room, patients suspected of having TB should wear surgical masks to reduce the expulsion of droplet nuclei into the air.These patients do not need to wear particulate respirators, which are designed to filter the air before it is inhaled by the person wearing the mask.Patients suspected of having or known to have TB should never wear a respirator that has an exhalation valve, because the device would provide no barrier to the expulsion of droplet nuclei into the air. # E. Management of Hospitalized Patients Who Have Confirmed or Suspected TB 1.Initiation of isolation for TB - In hospitals and other inpatient facilities, any patient suspected of having or known to have infectious TB should be placed in a TB isolation room that has currently recommended ventilation characteristics (Section II.E.3; Suppl.3).Written policies for initiating isolation should specify a) the indications for isolation, b) the person(s) authorized to initiate and discontinue isolation, c) the isolation practices to follow, d) the monitoring of isolation, e) the management of patients who do not adhere to isolation practices, and f) the criteria for discontinuing isolation. - In rare circumstances, placing more than one TB patient together in the same room may be acceptable.This practice is sometimes referred to as "cohorting."Because of the risk for patients becoming superinfected with drug-resistant organisms, patients with TB should be placed in the same room only if all patients involved a) have culture-confirmed TB, b) have drug-susceptibility test results available on a current specimen obtained during the present hospitalization, c) have identical drugsusceptibility patterns on these specimens, and d) are on effective therapy.Having isolates with identical DNA fingerprint patterns is not adequate evidence for placing two TB patients together in the same room, because isolates with the same DNA fingerprint pattern can have different drug-susceptibility patterns. - Pediatric patients with suspected or confirmed TB should be evaluated for potential infectiousness according to the same criteria as are adults (i.e., on the basis of symptoms, sputum AFB smears, radiologic findings, and other criteria) (Suppl.1).Children who may be infectious should be placed in isolation until they are determined to be noninfectious.Pediatric patients who may be infectious include those who have laryngeal or extensive pulmonary involvement, pronounced cough, positive sputum AFB smears, or cavitary TB or those for whom coughinducing procedures are performed (44 ). - The source of infection for a child with TB is often a member of the child's family (45 ).Therefore, parents and other visitors of all pediatric TB patients should be evaluated for TB as soon as possible.Until they have been evaluated, or the source case is identified, they should wear surgical masks when in areas of the facility outside of the child's room, and they should refrain from visiting common areas in the facility (e.g., the cafeteria or lounge areas). - TB patients in intensive-care units should be treated the same as patients in noncritical-care settings.They should be placed in TB isolation and have respiratory secretions submitted for AFB smear and culture if they have undiagnosed pulmonary symptoms suggestive of TB. - If readmitted to a health-care facility, patients who are known to have active TB and who have not completed therapy should have TB precautions applied until a determination has been made that they are noninfectious (Suppl.1). # TB isolation practices - Patients who are placed in TB isolation should be educated about the mechanisms of M. tuberculosis transmission and the reasons for their being placed in isolation.They should be taught to cover their mouths and noses with a tissue when coughing or sneezing, even while in the isolation room, to contain liquid drops and droplets before they are expelled into the air (46 ). - Efforts should be made to facilitate patient adherence to isolation measures (e.g., staying in the TB isolation room).Such efforts might include the use of incentives (e.g., providing them with telephones, televisions, or radios in their rooms or allowing special dietary requests).Efforts should also be made to address other problems that could interfere with adherence to isolation (e.g., management of the patient's withdrawal from addictive substances ). - Patients placed in isolation should remain in their isolation rooms with the door closed.If possible, diagnostic and treatment procedures should be performed in the isolation rooms to avoid transporting patients through other areas of the facility.If patients who may have infectious TB must be transported outside their isolation rooms for medically essential procedures that cannot be performed in the isolation rooms, they should wear surgical masks that cover their mouths and noses during transport.Persons transporting the patients do not need to wear respiratory protection outside the TB isolation rooms.Procedures for these patients should be scheduled at times when they can be performed rapidly and when waiting areas are less crowded. - Treatment and procedure rooms in which patients who have infectious TB or who have an undiagnosed pulmonary disease and are at high risk for active TB receive care should meet the ventilation recommendations for isolation rooms (Section II.E.3; Suppl.3).Ideally, facilities in which TB patients are frequently treated should have an area in the radiology department that is ventilated separately for TB patients.If this is not possible, TB patients should wear surgical masks and should stay in the radiology suite the minimum amount of time possible, then be returned promptly to their isolation rooms. - The number of persons entering an isolation room should be minimal. All persons who enter an isolation room should wear respiratory protection (Section II.G; Suppl.4).The patient's visitors should be given respirators to wear while in the isolation room, and they should be given general instructions on how to use their respirators. - Disposable items contaminated with respiratory secretions are not associated with transmission of M. tuberculosis.However, for general infection-control purposes, these items should be handled and transported in a manner that reduces the risk for transmitting other microorganisms to patients, HCWs, and visitors and that decreases environmental contamination in the health-care facility.Such items should be disposed of in accordance with hospital policy and applicable regulations (Suppl.5). # The TB isolation room - TB isolation rooms should be single-patient rooms with special ventilation characteristics appropriate for the purposes of isolation (Suppl.3).
The primary purposes of TB isolation rooms are to a) separate patients who are likely to have infectious TB from other persons; b) provide an environment that will allow reduction of the concentration of droplet nuclei through various engineering methods; and c) prevent the escape of droplet nuclei from the TB isolation room and treatment room, thus preventing entry of M. tuberculosis into the corridor and other areas of the facility. - To prevent the escape of droplet nuclei, the TB isolation room should be maintained under negative pressure (Suppl.3).Doors to isolation rooms should be kept closed, except when patients or personnel must enter or exit the room, so that negative pressure can be maintained. - Negative pressure in the room should be monitored daily while the room is being used for TB isolation. - The American Society of Heating, Refrigerating and Air-Conditioning Ventilation rates of >6 ACH are likely to produce an incrementally greater reduction in the concentration of bacteria in a room than are lower rates (50)(51)(52).However, accurate quantitation of decreases in risk that would result from specific increases in general ventilation levels has not been performed and may not be possible. For the purposes of reducing the concentration of droplet nuclei, TB isolation and treatment rooms in existing health-care facilities should have an airflow of ≥6 ACH.Where feasible, this airflow rate should be increased to ≥12 ACH by adjusting or modifying the ventilation system or by using auxiliary means (e.g., recirculation of air through fixed HEPA filtration systems or portable air cleaners) (Suppl.3, Section II.B.5.a) (53 ).New construction or renovation of existing health-care facilities should be designed so that TB isolation rooms achieve an airflow of ≥12 ACH. - Air from TB isolation rooms and treatment rooms used to treat patients who have known or suspected infectious TB should be exhausted to the outside in accordance with applicable federal, state, and local regulations.The air should not be recirculated into the general ventilation.In some instances, recirculation of air into the general ventilation system from such rooms is unavoidable (i.e., in existing facilities in which the ventilation system or facility configuration makes venting the exhaust to the outside impossible).In such cases, HEPA filters should be installed in the exhaust duct leading from the room to the general ventilation system to remove infectious organisms and particulates the size of droplet nuclei from the air before it is returned to the general ventilation system (Section II.F; Suppl.3).Air from TB isolation and treatment rooms in new or renovated facilities should not be recirculated into the general ventilation system. - Although not required, an anteroom may increase the effectiveness of the isolation room by minimizing the potential escape of droplet nuclei into the corridor when the door is opened.To work effectively, the anteroom should have positive air pressure in relation to the isolation room. The pressure relationship between the anteroom and the corridor may vary according to ventilation design. - Upper-room air UVGI may be used as an adjunct to general ventilation in the isolation room (Section II.F; Suppl.3).Air in the isolation room may be recirculated within the room through HEPA filters or UVGI devices to increase the effective ACH and to increase thermal efficiency. - Health-care facilities should have enough isolation rooms to appropriately isolate all patients who have suspected or confirmed active TB.This number should be estimated using the results of the risk assessment of the health-care facility.Except for minimal-and very low-risk health-care facilities, all acute-care inpatient facilities should have at least one TB isolation room (Section II.B). - Grouping isolation rooms together in one area of the facility may reduce the possibility of transmitting M. tuberculosis to other patients and may facilitate care of TB patients and the installation and maintenance of optimal engineering (particularly ventilation) controls. # Discontinuation of TB isolation - TB isolation can be discontinued if the diagnosis of TB is ruled out.For some patients, TB can be ruled out when another diagnosis is confirmed.If a diagnosis of TB cannot be ruled out, the patient should remain in isolation until a determination has been made that the patient is noninfectious.However, patients can be discharged from the healthcare facility while still potentially infectious if appropriate postdischarge arrangements can be ensured (Section II.E.5). - The length of time required for a TB patient to become noninfectious after starting anti-TB therapy varies considerably (Suppl.1).Isolation should be discontinued only when the patient is on effective therapy, is improving clinically, and has had three consecutive negative sputum AFB smears collected on different days. - Hospitalized patients who have active TB should be monitored for relapse by having sputum AFB smears examined regularly (e.g., every 2 weeks).Nonadherence to therapy (i.e., failure to take medications as prescribed) and the presence of drug-resistant organisms are the two most common reasons why patients remain infectious despite treat-ment.These reasons should be considered if a patient does not respond clinically to therapy within 2-3 weeks. - Continued isolation throughout the hospitalization should be strongly considered for patients who have MDR-TB because of the tendency for treatment failure or relapse (i.e., difficulty in maintaining noninfectiousness) that has been observed in such cases. # Discharge planning - Before a TB patient is discharged from the health-care facility, the facility's staff and public health authorities should collaborate to ensure continuation of therapy.Discharge planning in the health-care facility should include, at a minimum, a) a confirmed outpatient appointment with the provider who will manage the patient until the patient is cured, b) sufficient medication to take until the outpatient appointment, and c) placement into case management (e.g., DOT) or outreach programs of the public health department.These plans should be initiated and in place before the patient's discharge. - Patients who may be infectious at the time of discharge should only be discharged to facilities that have isolation capability or to their homes.Plans for discharging a patient who will return home must consider whether all the household members were infected previously and whether any uninfected household members are at very high risk for active TB if infected (e.g., children <4 years of age or persons infected with HIV or otherwise severely immunocompromised).If the household does include such persons, arrangements should be made to prevent them from being exposed to the TB patient until a determination has been made that the patient is noninfectious. # F. Engineering Control Recommendations # General ventilation This section deals only with engineering controls for general-use areas of health-care facilities (e.g., waiting-room areas and emergency departments).Recommendations for engineering controls for specific areas of the facility (e.g., TB isolation rooms) are contained in the sections encompassing those areas.Details regarding ventilation design, evaluation, and supplemental approaches are described in Supplement 3. - Health-care facilities should either a) include as part of their staff an engineer or other professional with expertise in ventilation or b) have this expertise available from a consultant who is an expert in ventilation engineering and who also has hospital experience.These persons should work closely with infection-control staff to assist in controlling airborne infections. - Ventilation system designs in health-care facilities should meet any applicable federal, state, and local requirements. - The direction of airflow in health-care facilities should be designed, constructed, and maintained so that air flows from clean areas to less-clean areas. - Health-care facilities serving populations that have a high prevalence of TB may need to supplement the general ventilation or use additional engineering approaches (i.e., HEPA filtration or UVGI) in general-use areas where TB patients are likely to go (e.g., waiting-room areas, emergency departments, and radiology suites).A single-pass, nonrecirculating system that exhausts air to the outside, a recirculation system that passes air through HEPA filters before recirculating it to the general ventilation system, or upper air UVGI may be used in such areas. # Additional engineering control approaches a. HEPA filtration HEPA filters may be used in a number of ways to reduce or eliminate infectious droplet nuclei from room air or exhaust (Suppl.3).These methods include placement of HEPA filters a) in exhaust ducts discharging air from booths or enclosures into the surrounding room; b) in ducts or in ceiling-or wall-mounted units, for recirculation of air within an individual room (fixed recirculation systems); c) in portable air cleaners; d) in exhaust ducts to remove droplet nuclei from air being discharged to the outside, either directly or through ventilation equipment; and e) in ducts discharging air from the TB isolation room into the general ventilation system.In any application, HEPA filters should be installed carefully and maintained meticulously to ensure adequate functioning. The manufacturers of in-room air cleaning equipment should provide documentation of the HEPA filter efficiency and the efficiency of the device in lowering room air contaminant levels. # b. UVGI For general-use areas in which the risk for transmission of M. tuberculosis is relatively high, UVGI lamps may be used as an adjunct to ventilation for reducing the concentration of infectious droplet nuclei (Suppl.3), although the effectiveness of such units has not been evaluated adequately.Ultraviolet (UV) units can be installed in a room or corridor to irradiate the air in the upper portion of the room (i.e., upperroom air irradiation), or they can be installed in ducts to irradiate air passing through the ducts.UV units installed in ducts should not be substituted for HEPA filters in ducts that discharge air from TB isolation rooms into the general ventilation system.However, UV units can be used in ducts that recirculate air back into the same room. To function properly and decrease hazards to HCWs and others in the health-care facility, UV lamps should be installed properly and maintained adequately, which includes the monitoring of irradiance levels. UV tubes should be changed according to the manufacturer's instructions or when meter readings indicate tube failure.An employee trained in the use and handling of UV lamps should be responsible for these measures and for keeping maintenance records.Applicable safety guidelines should be followed.Caution should be exercised to protect HCWs, patients, visitors, and others from excessive exposure to UV radiation. # G. Respiratory Protection - Personal respiratory protection should be used by a) persons entering rooms in which patients with known or suspected infectious TB are being isolated, b) persons present during cough-inducing or aerosol-generating procedures performed on such patients, and c) persons in other settings where administrative and engineering controls are not likely to protect them from inhaling infectious airborne droplet nuclei (Suppl.4).These other settings include transporting patients who may have infectious TB in emergency transport vehicles and providing urgent surgical or dental care to patients who may have infectious TB before a determination has been made that the patient is noninfectious (Suppl.1). - Respiratory protective devices used in health-care settings for protection against M. tuberculosis should meet the following standard performance criteria: 1.The ability to filter particles 1 µm in size in the unloaded- state with a filter efficiency of ≥95% (i.e., filter leakage of ≤5%), given flow rates of up to 50 L per minute. 2.The ability to be qualitatively or quantitatively fit tested in a reliable way to obtain a face-seal leakage of ≤10% (54,55 ). 3.The ability to fit the different facial sizes and characteristics of HCWs, which can usually be met by making the respirators available in at least three sizes. 4.The ability to be checked for facepiece fit, in accordance with standards established by the Occupational Safety and Health Administration (OSHA) and good industrial hygiene practice, by HCWs each time they put on their respirators (54,55 ). - The facility's risk assessment may identify a limited number of selected settings (e.g., bronchoscopy performed on patients suspected of having TB or autopsy performed on deceased persons suspected of having had active TB at the time of death) where the estimated risk for transmission of M. tuberculosis may be such that a level of respiratory protection exceeding the standard performance criteria is appropriate.In such circumstances, a level of respiratory protection exceeding the standard criteria and compatible with patient-care delivery (e.g., more protective negativepressure respirators; powered air-purifying particulate respirators ; or positive-pressure air-line, half-mask respirators) should be *Some filters become more efficient as they become loaded with dust.Health-care settings do not have enough dust in the air to load a filter on a respirator.Therefore, the filter efficiency for respirators used in health-care settings must be determined in the unloaded state. provided by employers to HCWs who are exposed to M. tuberculosis.Information on these and other respirators is in the NIOSH Guide to Industrial Respiratory Protection (55 ) and in Supplement 4 of this document. - In some settings, HCWs may be at risk for two types of exposure: a) inhalation of M. tuberculosis and b) mucous membrane exposure to fluids that may contain bloodborne pathogens.In these settings, protection against both types of exposure should be used. - When operative procedures (or other procedures requiring a sterile field) are performed on patients who may have infectious TB, respiratory protection worn by the HCW should serve two functions: a) it should protect the surgical field from the respiratory secretions of the HCW, and b) it should protect the HCW from infectious droplet nuclei that may be expelled by the patient or generated by the procedure.Respirators with exhalation valves and most positive-pressure respirators do not protect the sterile field. - Health-care facilities in which respiratory protection is used to prevent inhalation of M. tuberculosis are required by OSHA to develop, implement, and maintain a respiratory protection program (Suppl.4).All HCWs who use respiratory protection should be included in this program.Visitors to TB patients should be given respirators to wear while in isolation rooms, and they should be given general instructions on how to use their respirators. - Facilities that do not have isolation rooms and do not perform coughinducing procedures on patients who may have TB may not need to have a respiratory protection program for TB.However, such facilities should have written protocols for the early identification of patients who have signs or symptoms of TB and procedures for referring these patients to a facility where they can be evaluated and managed appropriately.These protocols should be evaluated regularly and revised as needed. - Surgical masks are designed to prevent the respiratory secretions of the person wearing the mask from entering the air.To reduce the expulsion of droplet nuclei into the air, patients suspected of having TB should wear surgical masks when not in TB isolation rooms.These patients do not need to wear particulate respirators, which are designed to filter the air before it is inhaled by the person wearing the respirator.Patients suspected of having or known to have TB should never wear a respirator that has an exhalation valve, because this type of respirator does not prevent expulsion of droplet nuclei into the air. # H. Cough-Inducing and Aerosol-Generating Procedures 1.General guidelines Procedures that involve instrumentation of the lower respiratory tract or induce coughing can increase the likelihood of droplet nuclei being expelled into the air.These cough-inducing procedures include endotracheal intubation and suctioning, diagnostic sputum induction, aerosol treatments (e.g., pentamidine therapy), and bronchoscopy.Other procedures that can generate aerosols (e.g., irrigation of tuberculous abscesses, homogenizing or lyophilizing tissue, or other processing of tissue that may contain tubercle bacilli) are also covered by these recommendations. - Cough-inducing procedures should not be performed on patients who may have infectious TB unless the procedures are absolutely necessary and can be performed with appropriate precautions. - All cough-inducing procedures performed on patients who may have infectious TB should be performed using local exhaust ventilation devices (e.g., booths or special enclosures) or, if this is not feasible, in a room that meets the ventilation requirements for TB isolation. - HCWs should wear respiratory protection when present in rooms or enclosures in which cough-inducing procedures are being performed on patients who may have infectious TB. - After completion of cough-inducing procedures, patients who may have infectious TB should remain in their isolation rooms or enclosures and not return to common waiting areas until coughing subsides.They should be given tissues and instructed to cover their mouths and noses with the tissues when coughing.If TB patients must recover from sedatives or anesthesia after a procedure (e.g, after a bronchoscopy), they should be placed in separate isolation rooms (and not in recovery rooms with other patients) while they are being monitored. - Before the booth, enclosure, or room is used for another patient, enough time should be allowed to pass for at least 99% of airborne contaminants to be removed.This time will vary according to the efficiency of the ventilation or filtration used (Suppl.3, Table S3-1). # Special considerations for bronchoscopy - If performing bronchoscopy in positive-pressure rooms (e.g., operating rooms) is unavoidable, TB should be ruled out as a diagnosis before the procedure is performed.If the bronchoscopy is being performed for the purpose of diagnosing pulmonary disease and that diagnosis could include TB, the procedure should be performed in a room that meets TB isolation ventilation requirements. # Special considerations for the administration of aerosolized pentamidine - Patients should be screened for active TB before prophylactic therapy with aerosolized pentamidine is initiated.Screening should include obtaining a medical history and performing skin testing and chest radiography. - Before each subsequent treatment with aerosolized pentamidine, patients should be screened for symptoms suggestive of TB (e.g., development of a productive cough).If such symptoms are elicited, a diagnostic evaluation for TB should be initiated. - Patients who have suspected or confirmed active TB should take, if clinically practical, oral prophylaxis for P. carinii pneumonia. # I. Education and Training of HCWs All HCWs, including physicians, should receive education regarding TB that is relevant to persons in their particular occupational group.
Ideally, training should be conducted before initial assignment, and the need for additional training should be reevaluated periodically (e.g., once a year).The level and detail of this education will vary according to the HCW's work responsibilities and the level of risk in the facility (or area of the facility) in which the HCW works.However, the program may include the following elements: - The basic concepts of M. tuberculosis transmission, pathogenesis, and diagnosis, including information concerning the difference between latent TB infection and active TB disease, the signs and symptoms of TB, and the possibility of reinfection. - The potential for occupational exposure to persons who have infectious TB in the health-care facility, including information concerning the prevalence of TB in the community and facility, the ability of the facility to properly isolate patients who have active TB, and situations with increased risk for exposure to M. tuberculosis. - The principles and practices of infection control that reduce the risk for transmission of M. tuberculosis, including information concerning the hierarchy of TB infection-control measures and the written policies and procedures of the facility.Site-specific control measures should be provided to HCWs working in areas that require control measures in addition to those of the basic TB infection-control program. - The purpose of PPD skin testing, the significance of a positive PPD test result, and the importance of participating in the skin-test program. - The principles of preventive therapy for latent TB infection.These principles include the indications, use, effectiveness, and the potential adverse effects of the drugs (Suppl.2). - The HCW's responsibility to seek prompt medical evaluation if a PPD test conversion occurs or if symptoms develop that could be caused by TB.Medical evaluation will enable HCWs who have TB to receive appropriate therapy and will help to prevent transmission of M. tuberculosis to patients and other HCWs. - The principles of drug therapy for active TB. - The importance of notifying the facility if the HCW is diagnosed with active TB so that contact investigation procedures can be initiated. - The responsibilities of the facility to maintain the confidentiality of the HCW while ensuring that the HCW who has TB receives appropriate therapy and is noninfectious before returning to duty. - The higher risks associated with TB infection in persons who have HIV infection or other causes of severely impaired cell-mediated immunity, including a) the more frequent and rapid development of clinical TB after infection with M. tuberculosis, b) the differences in the clinical presentation of disease, and c) the high mortality rate associated with MDR-TB in such persons. - The potential development of cutaneous anergy as immune function (as measured by CD4+ T-lymphocyte counts) declines. - Information regarding the efficacy and safety of BCG vaccination and the principles of PPD screening among BCG recipients. - The facility's policy on voluntary work reassignment options for immunocompromised HCWs. # J. HCW Counseling, Screening, and Evaluation A TB counseling, screening, and prevention program for HCWs should be established to protect both HCWs and patients.HCWs who have positive PPD test results, PPD test conversions, or symptoms suggestive of TB should be identified, evaluated to rule out a diagnosis of active TB, and started on therapy or preventive therapy if indicated (5 ).In addition, the results of the HCW PPD screening program will contribute to evaluation of the effectiveness of current infection-control practices. # Counseling HCWs regarding TB - Because of the increased risk for rapid progression from latent TB infection to active TB in HIV-infected or otherwise severely immunocompromised persons, all HCWs should know if they have a medical condition or are receiving a medical treatment that may lead to severely impaired cell-mediated immunity.HCWs who may be at risk for HIV infection should know their HIV status (i.e., they should be encouraged to voluntarily seek counseling and testing for HIV antibody status).Existing guidelines for counseling and testing should be followed routinely (56 ).Knowledge of these conditions allows the HCW to seek the appropriate preventive measures outlined in this document and to consider voluntary work reassignments.Of particular importance is that HCWs need to know their HIV status if they are at risk for HIV infection and they work in settings where patients who have drug-resistant TB may be encountered. - All HCWs should be informed about the need to follow existing recommendations for infection control to minimize the risk for exposure to infectious agents; implementation of these recommendations will greatly reduce the risk for occupational infections among HCWs (57 ).All HCWs should also be informed about the potential risks to severely immunocompromised persons associated with caring for patients who have some infectious diseases, including TB.It should be emphasized that limiting exposure to TB patients is the most protective measure that severely immunosuppressed HCWs can take to avoid becoming infected with M. tuberculosis.HCWs who have severely impaired cell-mediated immunity and who may be exposed to M. tuberculosis may consider a change in job setting to avoid such exposure.HCWs should be advised of the option that severely immunocompromised HCWs can choose to transfer voluntarily to areas and work activities in which there is the lowest possible risk for exposure to M. tuberculosis.This choice should be a personal decision for HCWs after they have been informed of the risks to their health. - Employers should make reasonable accommodations (e.g., alternative job assignments) for employees who have a health condition that compromises cell-mediated immunity and who work in settings where they may be exposed to M. tuberculosis.HCWs who are known to be immunocompromised should be referred to employee health professionals who can individually counsel the employees regarding their risk for TB. Upon the request of the immunocompromised HCW, employers should offer, but not compel, a work setting in which the HCW would have the lowest possible risk for occupational exposure to M. tuberculosis.Evaluation of these situations should also include consideration of the provisions of the Americans With Disabilities Act of 1990- and other applicable federal, state, and local laws. - All HCWs should be informed that immunosuppressed HCWs should have appropriate follow-up and screening for infectious diseases, including TB, provided by their medical practitioner.HCWs who are known to be HIV-infected or otherwise severely immunosuppressed should be tested for cutaneous anergy at the time of PPD testing (Suppl.2).Consideration should be given to retesting, at least every 6 months, those immunocompromised HCWs who are potentially exposed to M. tuberculosis because of the high risk for rapid progression to active TB if they become infected. - Information provided by HCWs regarding their immune status should be treated confidentially.If the HCW requests voluntary job reassignment, the confidentiality of the HCW should be maintained.Facilities should have written procedures on confidential handling of such information. # Screening HCWs for active TB - Any HCW who has a persistent cough (i.e., a cough lasting ≥3 weeks), especially in the presence of other signs or symptoms compatible with active TB (e.g., weight loss, night sweats, bloody sputum, anorexia, or fever), should be evaluated promptly for TB.The HCW should not return to the workplace until a diagnosis of TB has been excluded or until the HCW is on therapy and a determination has been made that the HCW is noninfectious. # Screening HCWs for latent TB infection - The risk assessment should identify which HCWs have potential for exposure to M. tuberculosis and the frequency with which the exposure may occur.This information is used to determine which HCWs to include in the skin-testing program and the frequency with which they should be tested ( - If HCWs are from risks groups with increased prevalence of TB, consideration may be given to including them in the skin-testing program, even if they do not have potential occupational exposure to M. tuberculosis, so that converters can be identified and preventive therapy offered. - Administrators of health-care facilities should ensure that physicians and other personnel not paid by, but working in, the facility receive skin testing at appropriate intervals for their occupational group and work location. - During the pre-employment physical or when applying for hospital privileges, HCWs who have potential for exposure to M. tuberculosis (Table 2), including those with a history of BCG vaccination, should have baseline PPD skin testing performed (Suppl.2).For HCWs who have not had a documented negative PPD test result during the preceding 12 months, the baseline PPD testing should employ the two-step method; this will detect boosting phenomena that might be misinterpreted as a skin-test conversion.Decisions concerning the use of the two-step procedure for baseline testing in a particular facility should be based on the frequency of boosting in that facility. - HCWs who have a documented history of a positive PPD test, adequate treatment for disease, or adequate preventive therapy for infection, should be exempt from further PPD screening unless they develop signs or symptoms suggestive of TB. - PPD-negative HCWs should undergo repeat PPD testing at regular intervals as determined by the risk assessment (Section II.B).In addition, these HCWs should be tested whenever they have been exposed to a TB patient and appropriate precautions were not observed at the time of exposure (Section II.K.3).Performing PPD testing of HCWs who work in the same area or occupational group on different scheduled dates (e.g., test them on their birthdays or on their employment anniversary dates), rather than testing all HCWs in the area or group on the same day, may lead to earlier detection of M. tuberculosis transmission. - All PPD tests should be administered, read, and interpreted in accordance with current guidelines by specified trained personnel (Suppl.2).At the time their test results are read, HCWs should be informed about the interpretation of both positive and negative PPD test results.This information should indicate that the interpretation of an induration that is 5-9 mm in diameter depends on the HCW's immune status and history of exposure to persons who have infectious TB.Specifically, HCWs who have indurations of 5-9 mm in diameter should be advised that such results may be considered positive for HCWs who are contacts of persons with infectious TB or who have HIV infection or other causes of severe immunosuppression (e.g., immunosuppressive therapy for organ transplantation). - When an HCW who is not assigned regularly to a single work area has a PPD test conversion, appropriate personnel should identify the areas where the HCW worked during the time when infection was likely to have occurred.This information can then be considered in analyzing the risk for transmission in those areas. - In any area of the facility where transmission of M. tuberculosis is known to have occurred, a problem evaluation should be conducted (Section II.K), and the frequency of skin testing should be determined according to the applicable risk category (Section II.B). - PPD test results should be recorded confidentially in the individual HCW's employee health record and in an aggregate database of all HCW PPD test results.The database can be analyzed periodically to estimate the risk for acquiring new infection in specific areas or occupational groups in the facility. -If an HCW's PPD test result converts to positive, a history of confirmed or suspected TB exposure should be obtained in an attempt to determine the potential source.When the source of exposure is known, the drug-susceptibility pattern of the M. tuberculosis isolated from the source should be identified so that the correct curative or preventive therapy can be initiated for the HCW with the PPD test conversion.The drug-susceptibility pattern should be recorded in the HCW's medical record, where it will be available if the HCW subsequently develops active TB and needs therapy specific for the drug-susceptibility pattern. # Evaluation and management of - All HCWs, including those with histories of positive PPD test results, should be reminded periodically about the symptoms of TB and the need for prompt evaluation of any pulmonary symptoms suggestive of TB. b. Routine and follow-up chest radiographs - Routine chest radiographs are not required for asymptomatic, PPDnegative HCWs.HCWs with positive PPD test results should have a chest radiograph as part of the initial evaluation of their PPD test; if negative, repeat chest radiographs are not needed unless symptoms develop that could be attributed to TB (58 ).However, more frequent monitoring for symptoms of TB may be considered for recent converters and other PPD-positive HCWs who are at increased risk for developing active TB (e.g., HIV-infected or otherwise severely immunocompromised HCWs). c. Workplace restrictions 1) Active TB - HCWs with pulmonary or laryngeal TB pose a risk to patients and other HCWs while they are infectious, and they should be excluded from the workplace until they are noninfectious.The same work restrictions apply to all HCWs regardless of their immune status. - Before the HCW who has TB can return to the workplace, the health-care facility should have documentation from the HCW's health-care provider that the HCW is receiving adequate therapy, the cough has resolved, and the HCW has had three consecutive negative sputum smears collected on different days.After work duties are resumed and while the HCW remains on anti-TB therapy, facility staff should receive periodic documentation from the HCW's health-care provider that the HCW is being maintained on effective drug therapy for the recommended time period and that the sputum AFB smears continue to be negative. - HCWs with active laryngeal or pulmonary TB who discontinue treatment before they are cured should be evaluated promptly for infectiousness.If the evaluation determines that they are still infectious, they should be excluded from the workplace until treatment has been resumed, an adequate response to therapy has been documented, and three more consecutive sputum AFB smears collected on different days have been negative. - HCWs who have TB at sites other than the lung or larynx usually do not need to be excluded from the workplace if a diagnosis of concurrent pulmonary TB has been ruled out. 2) Latent TB infection - HCWs receiving preventive treatment for latent TB infection should not be restricted from their usual work activities. - HCWs with latent TB infection who cannot take or who do not accept or complete a full course of preventive therapy should not be excluded from the workplace.These HCWs should be counseled about the risk for developing active TB and instructed regularly to seek prompt evaluation if signs or symptoms develop that could be caused by TB.1) to determine the likelihood that transmission of and infection with M. tuberculosis has occurred in the facility; # K. Problem Evaluation 2) to determine the extent to which M. tuberculosis has been transmitted; 3) to identify those persons who have been exposed and infected, enabling them to receive appropriate clinical management; 4) to identify factors that could have contributed to transmission and infection and to implement appropriate interventions; and 5) to evaluate the effectiveness of any interventions that are implemented and to ensure that exposure to and transmission of M. tuberculosis have been terminated. The exact circumstances of these situations are likely to vary considerably, and the associated epidemiologic investigations should be tailored to the individual circumstances.The following sections provide general guidance for conducting these investigations. # Investigating PPD test conversions and active TB in HCWs a. Investigating PPD test conversions in HCWs PPD test conversions may be detected in HCWs as a result of a contact investigation, in which case the probable source of exposure and transmission is already known (Section II.K.3.),or as a result of routine screening, in which case the probable source of exposure and infection is not already known and may not be immediately apparent. If a skin-test conversion in an HCW is identified as part of routine screening, the following steps should be considered (Figure 2): - The HCW should be evaluated promptly for active TB.The initial evaluation should include a thorough history, physical examination, and chest radiograph.On the basis of the initial evaluation, other diagnostic procedures (e.g., sputum examination) may be indicated. - If appropriate, the HCW should be placed on preventive or curative therapy in accordance with current guidelines (Suppl.2) (5 ). - A history of possible exposure to M. tuberculosis should be obtained from the HCW to determine the most likely source of infection.When the source of infection is known, the drug-susceptibility pattern of the M. tuberculosis isolate from the source patient should be identified to determine appropriate preventive or curative therapy regimens. - If the history suggests that the HCW was exposed to and infected with M. tuberculosis outside the facility, no further epidemiologic investigation to identify a source in the facility is necessary. - If the history does not suggest that the HCW was exposed and infected outside the facility but does identify a probable source of exposure in the facility, contacts of the suspected source patient should be identified and evaluated.Possible reasons for the exposure and transmission should be evaluated (Table 4), interventions should be implemented to correct these causes, and PPD testing of PPD-negative HCWs should be performed immediately and repeated after 3 months. If no additional PPD test conversions are detected on follow-up testing, the investigation can be terminated. If additional PPD test conversions are detected on follow-up testing, the possible reasons for exposure and transmission should be reassessed, the appropriateness of and degree of adherence to the interventions implemented should be evaluated, and PPD testing of PPD-negative HCWs should be repeated after another 3 months. If no additional PPD test conversions are detected on the second round of follow-up testing, the investigation can be terminated.However, if additional PPD conversions are detected on the second round of follow-up testing, a high-risk protocol should be implemented in the affected area or occupational group, and the public health department or other persons with expertise in TB infection control should be consulted.
- If the history does not suggest that the HCW was exposed to and infected with M. tuberculosis outside the facility and does not identify a probable source of exposure in the facility, further investigation to identify the probable source patient in the facility is warranted. The interval during which the HCW could have been infected should be estimated.Generally, this would be the interval from 10 weeks before the most recent negative PPD test through 2 weeks before the first positive PPD test (i.e., the conversion). Laboratory and infection-control records should be reviewed to identify all patients or HCWs who have suspected or confirmed infectious TB and who could have transmitted M. tuberculosis to the HCW. If this process does identify a likely source patient, contacts of the suspected source patient should be identified and evaluated, and possible reasons for the exposure and transmission should be evaluated ( If this review and/or screening does not identify additional PPD conversions, nosocomial transmission is less likely, and the contact investigation can probably be terminated.Whether the HCW's PPD test conversion resulted from occupational exposure and infection is uncertain; however, the absence of other data implicating nosocomial transmission suggests that the conversion could have resulted from a) unrecognized exposure to M. tuberculosis outside the facility; b) cross-reactivity with another antigen (e.g., nontuberculous mycobacteria); c) errors in applying, reading, or interpreting the test; d) false positivity caused by the normal variability of the test; or e) false positivity caused by a defective PPD preparation. If this review and/or screening does identify additional PPD test conversions, nosocomial transmission is more likely.In this situation, the patient identification (i.e., triage) process, TB infection-control policies and practices, and engineering controls should be evaluated to identify problems that could have led to exposure and transmission (Table 4). If no such problems are identified, a high-risk protocol should be implemented in the affected area or occupational group, and the public health department or other persons with expertise in TB infection control should be consulted. If such problems are identified, appropriate interventions should be implemented to correct the problem(s), and PPD skin testing of PPDnegative HCWs should be repeated after 3 months. If no additional PPD conversions are detected on follow-up testing, the investigation can be terminated. If additional PPD conversions are detected on follow-up testing, the possible reasons for exposure and transmission should be reassessed, the appropriateness of and adherence to the interventions implemented should be evaluated, and PPD skin testing of PPDnegative HCWs should be repeated after another 3 months. If no additional PPD test conversions are detected on this second round of follow-up testing, the investigation can be terminated.However, if additional PPD test conversions are detected on the second round of follow-up testing, a high-risk protocol should be implemented in the affected area or occupational group, and the public health department or other persons with expertise in TB infection control should be consulted. # b. Investigating cases of active TB in HCWs If an HCW develops active TB, the following steps should be taken: - The case should be evaluated epidemiologically, in a manner similar to PPD test conversions in HCWs, to determine the likelihood that it resulted from occupational transmission and to identify possible causes and implement appropriate interventions if the evaluation suggests such transmission. - Contacts of the HCW (e.g., other HCWs, patients, visitors, and others who have had intense exposure to the HCW) should be identified and evaluated for TB infection and disease (Section II.K.3; Suppl.2).The public health department should be notified immediately for consultation and to allow for investigation of community contacts who were not exposed in the health-care facility. - The public health department should notify facilities when HCWs with TB are reported by physicians so that an investigation of contacts can be conducted in the facility.The information provided by the health department to facilities should be in accordance with state or local laws to protect the confidentiality of the HCW. # Investigating possible patient-to-patient transmission of M. tuberculosis Surveillance of active TB cases in patients should be conducted.If this surveillance suggests the possibility of patient-to-patient transmission of M. tuberculosis (e.g., a high proportion of TB patients had prior admissions during the year preceding onset of their TB, the number of patients with drug-resistant TB increased suddenly, or isolates obtained from multiple patients had identical and characteristic drug-susceptibility or DNA fingerprint patterns), the following steps should be taken: - Review the HCW PPD test results and patient surveillance data for the suspected areas to detect additional patients or HCWs with PPD test conversions or active disease. - Look for possible exposures that patients with newly diagnosed TB could have had to other TB patients during previous admissions.For example, were the patients admitted to the same room or area, or did they receive the same procedure or go to the same treatment area on the same day? If the evaluation thus far suggests transmission has occurred, the following steps should be taken: - Evaluate possible causes of the transmission (e.g., problem with patient detection, institutional barriers to implementing appropriate isolation practices, or inadequate engineering controls) (Table 4). - Ascertain whether other patients or HCWs could have been exposed; if so, evaluate these persons for TB infection and disease (Section II.K.3; Suppl.2). - Notify the public health department so they can begin a community contact investigation if necessary. # Investigating contacts of patients and HCWs who have infectious TB If a patient who has active TB is examined in a health-care facility and the illness is not diagnosed correctly, resulting in failure to apply appropriate precautions, or if an HCW develops active TB and exposes other persons in the facility, the following steps should be taken when the illness is later diagnosed correctly: - To identify other patients and HCWs who were exposed to the source patient before isolation procedures were begun, interview the source patient and all applicable personnel and review that patient's medical record.Determine the areas of the facility in which the source patient was hospitalized, visited, or worked before being placed in isolation (e.g., outpatient clinics, hospital rooms, treatment rooms, radiology and procedure areas, and patient lounges) and the HCWs who may have been exposed during that time (e.g., persons providing direct care, therapists, clerks, transportation personnel, housekeepers, and social workers). - The contact investigation should first determine if M. tuberculosis transmission has occurred from the source patient to those persons with whom the source patient had the most intense contact. - Administer PPD tests to the most intensely exposed HCWs and patients as soon as possible after the exposure has occurred.If transmission did occur to the most intensely exposed persons, then those persons with whom the patient had less contact should be evaluated.If the initial PPD test result is negative, a second test should be administered 12 weeks after the exposure was terminated. - - In addition to PPD testing those HCWs and patients who have been exposed to M. tuberculosis because a patient was not isolated promptly or an HCW with active TB was not identified promptly, the investigation should determine why the diagnosis of TB was delayed.If the correct diagnosis was made but the patient was not isolated promptly, the reasons for the delay need to be defined so that corrective actions can be taken. # L. Coordination with the Public Health Department - As soon as a patient or HCW is known or suspected to have active TB, the patient or HCW should be reported to the public health department so that appropriate follow-up can be arranged and a community contact investigation can be performed.The health department should be notified well before patient discharge to facilitate follow-up and continuation of therapy.A discharge plan coordinated with the patient or HCW, the health department, and the inpatient facility should be implemented. - The public health department should protect the confidentiality of the patient or HCW in accordance with state and local laws. - Health-care facilities and health departments should coordinate their efforts to perform appropriate contact investigations on patients and HCWs who have active TB. - In accordance with state and local laws and regulations, results of all AFBpositive sputum smears, cultures positive for M. tuberculosis, and drugsusceptibility results on M. tuberculosis isolates should be reported to the public health department as soon as these results are available. - The public health department may be able to assist facilities with planning and implementing various aspects of a TB infection-control program (e.g., surveillance, screening activities, and outbreak investigations).In addition, the state health department may be able to provide names of experts to assist with the engineering aspects of TB infection control. # M. Additional Considerations for Selected Areas in Health-Care Facilities and Other Health-Care Settings This section contains additional information for selected areas in health-care facilities and for other health-care settings. # Selected areas in health-care facilities a. Operating rooms - Elective operative procedures on patients who have TB should be delayed until the patient is no longer infectious. - If operative procedures must be performed, they should be done, if possible, in operating rooms that have anterooms.For operating rooms without anterooms, the doors to the operating room should be closed, and traffic into and out of the room should be minimal to reduce the frequency of opening and closing the door.Attempts should be made to perform the procedure at a time when other patients are not present in the operative suite and when a minimum number of personnel are present (e.g., at the end of day). - Placing a bacterial filter on the patient endotracheal tube (or at the expiratory side of the breathing circuit of a ventilator or anesthesia machine if these are used) when operating on a patient who has confirmed or suspected TB may help reduce the risk for contaminating anesthesia equipment or discharging tubercle bacilli into the ambient air. - During postoperative recovery, the patient should be monitored and should be placed in a private room that meets recommended standards for ventilating TB isolation rooms. - When operative procedures (or other procedures requiring a sterile field) are performed on patients who may have infectious TB, respiratory protection worn by the HCW must protect the field from the respiratory secretions of the HCW and protect the HCW from the infectious droplet nuclei generated by the patient.Valved or positivepressure respirators do not protect the sterile field; therefore, a respirator that does not have a valve and that meets the criteria in Section II.G should be used. # b. Autopsy rooms - Because infectious aerosols are likely to be present in autopsy rooms, such areas should be at negative pressure with respect to adjacent areas (Suppl.3), and the room air should be exhausted directly to the outside of the building.ASHRAE recommends that autopsy rooms have ventilation that provides an airflow of 12 ACH (47 ), although the effectiveness of this ventilation level in reducing the risk for M. tuberculosis transmission has not been evaluated. Where possible, this level should be increased by means of ventilation system design or by auxiliary methods (e.g., recirculation of air within the room through HEPA filters) (Suppl.3). - Respiratory protection should be worn by personnel while performing autopsies on deceased persons who may have had TB at the time of death (Section II.G; Suppl.4). - Recirculation of HEPA-filtered air within the room or UVGI may be used as a supplement to the recommended ventilation (Suppl.3). # c. Laboratories - Laboratories in which specimens for mycobacteriologic studies (e.g., AFB smears and cultures) are processed should be designed to conform with criteria specified by CDC and the National Institutes of Health (59 ). # Other health-care settings TB precautions may be appropriate in a number of other types of healthcare settings.The specific precautions that are applied will vary depending on the setting.At a minimum, a risk assessment should be performed yearly for these settings; a written TB infection-control plan should be de- - EMS personnel should be included in a comprehensive PPD screening program and should receive a baseline PPD test and follow-up testing as indicated by the risk assessment.They should also be included in the follow-up of contacts of a patient with infectious TB.- b. Hospices - Hospice patients who have confirmed or suspected TB should be managed in the manner described in this document for management of TB patients in hospitals.General-use and specialized areas (e.g., treatment or TB isolation rooms) should be ventilated in the same manner as described for similar hospital areas. c. Long-term care facilities - Recommendations published previously for preventing and controlling TB in long-term care facilities should be followed (60 ). - Long-term care facilities should also follow the recommendations outlined in this document. # d. Correctional facilities - Recommendations published previously for preventing and controlling TB in correctional facilities should be followed (61 ). - Prison medical facilities should also follow the recommendations outlined in this document. # e. Dental settings In general, the symptoms for which patients seek treatment in a dentalcare setting are not likely to be caused by infectious TB.Unless a patient requiring dental care coincidentally has TB, it is unlikely that infectious TB will be encountered in the dental setting.Furthermore, generation of droplet nuclei containing M. tuberculosis during dental procedures has not been demonstrated (62 ).Therefore, the risk for transmission of M. tuberculosis in most dental settings is probably quite low.Nevertheless, during dental procedures, patients and dental workers share the same air for varying periods of time.Coughing may be stimulated occasionally by oral manipulations, although no specific dental procedures have been classified as "cough-inducing."In some instances, the population served by a dental-care facility, or the HCWs in the facility, may be at relatively high risk for TB.Because the potential exists for transmission of M. tuberculosis in dental settings, the following recommendations should be followed: TB; management of patients with active TB, relative to provision of urgent dental care; and employer-sponsored HCW education, counseling, and screening. - A - While taking patients' initial medical histories and at periodic updates, dental HCWs should routinely ask all patients whether they have a history of TB disease and symptoms suggestive of TB. - Patients with a medical history or symptoms suggestive of undiagnosed active TB should be referred promptly for medical evaluation of possible infectiousness.Such patients should not remain in the dental-care facility any longer than required to arrange a referral.While in the dental-care facility, they should wear surgical masks and should be instructed to cover their mouths and noses when coughing or sneezing. - Elective dental treatment should be deferred until a physician confirms that the patient does not have infectious TB.If the patient is diagnosed as having active TB, elective dental treatment should be deferred until the patient is no longer infectious. - If urgent dental care must be provided for a patient who has, or is strongly suspected of having, infectious TB, such care should be provided in facilities that can provide TB isolation (Sections II.E and G).Dental HCWs should use respiratory protection while performing procedures on such patients. - Any dental HCW who has a persistent cough (i.e., a cough lasting ≥3 weeks), especially in the presence of other signs or symptoms compatible with active TB (e.g., weight loss, night sweats, bloody sputum, anorexia, and fever), should be evaluated promptly for TB.The HCW should not return to the workplace until a diagnosis of TB has been excluded or until the HCW is on therapy and a determination has been made that the HCW is noninfectious. - In dental-care facilities that provide care to populations at high risk for active TB, it may be appropriate to use engineering controls similar to those used in general-use areas (e.g., waiting rooms) of medical facilities that have a similar risk profile. f. Home-health-care settings - HCWs who provide medical services in the homes of patients who have suspected or confirmed infectious TB should instruct such patients to cover their mouths and noses with a tissue when coughing or sneezing.Until such patients are no longer infectious, HCWs should wear respiratory protection when entering these patients' homes (Suppl.4). - Precautions in the home may be discontinued when the patient is no longer infectious (Suppl.1). - HCWs who provide health-care services in their patients' homes can assist in preventing transmission of M. tuberculosis by educating their patients regarding the importance of taking medications as prescribed and by administering DOT. - Cough-inducing procedures performed on patients who have infectious TB should not be done in the patients' homes unless absolutely necessary.When medically necessary cough-inducing procedures (e.g., AFB sputum collection for evaluation of therapy) must be performed on patients who may have infectious TB, the procedures should be performed in a health-care facility in a room or booth that has the recommended ventilation for such procedures.If these procedures must be performed in a patient's home, they should be performed in a well-ventilated area away from other household members.If feasible, the HCW should consider opening a window to improve ventilation or collecting the specimen while outside the dwelling.The HCW collecting these specimens should wear respiratory protection during the procedure (Section II.G). - HCWs who provide medical services in their patients' homes should be included in comprehensive employer-sponsored TB training, education, counseling, and screening programs.These programs should include provisions for identifying HCWs who have active TB, baseline PPD skin testing, and follow-up PPD testing at intervals appropriate to the degree of risk. - Patients who are at risk for developing active TB and the HCWs who provide medical services in the homes of such patients should be reminded periodically of the importance of having pulmonary symptoms evaluated promptly to permit early detection of and treatment for TB.
# g. Medical offices In general, the symptoms of active TB are symptoms for which patients are likely to seek treatment in a medical office.Furthermore, the populations served by some medical offices, or the HCWs in the office, may be at relatively high risk for TB.Thus, it is likely that infectious TB will be encountered in a medical office.Because of the potential for M. tuberculosis transmission, the following recommendations should be observed: - A risk assessment should be conducted periodically, and TB infection-control policies based on results of the risk assessment should be developed for the medical office.The policies should include provisions for identifying and managing patients who may have undiagnosed active TB; managing patients who have active TB; and educating, training, counseling, and screening HCWs. - While taking patients' initial medical histories and at periodic updates, HCWs who work in medical offices should routinely ask all patients whether they have a history of TB disease or have had symptoms suggestive of TB. - Patients with a medical history and symptoms suggestive of active TB should receive an appropriate diagnostic evaluation for TB and be evaluated promptly for possible infectiousness.Ideally, this evaluation should be done in a facility that has TB isolation capability.At a minimum, the patient should be provided with and asked to wear a surgical mask, instructed to cover the mouth and nose with a tissue when coughing or sneezing, and separated as much as possible from other patients. - Medical offices that provide evaluation or treatment services for TB patients should follow the recommendations for managing patients in ambulatory-care settings (Section II.D). - If cough-inducing procedures are to be administered in a medical office to patients who may have active TB, appropriate precautions should be followed (Section II.H). - Any HCW who has a persistent cough (i.e., a cough lasting ≥3 weeks), especially in the presence of other signs or symptoms compatible with active TB (e.g., weight loss, night sweats, bloody sputum, anorexia, or fever) should be evaluated promptly for TB.HCWs with such signs or symptoms should not return to the workplace until a diagnosis of TB has been excluded or until they are on therapy and a determination has been made that they are noninfectious. - HCWs who work in medical offices in which there is a likelihood of exposure to patients who have infectious TB should be included in employer-sponsored education, training, counseling, and PPD testing programs appropriate to the level of risk in the office. - In medical offices that provide care to populations at relatively high risk for active TB, use of engineering controls as described in this document for general-use areas (e.g., waiting rooms) may be appropriate (Section II.F; Suppl.3). # MMWR October 28, 1994 # Supplement 1: Determining the Infectiousness of a TB Patient The infectiousness of patients with TB correlates with the number of organisms expelled into the air, which, in turn, correlates with the following factors: a) disease in the lungs, airways, or larynx; b) presence of cough or other forceful expiratory measures; c) presence of acid-fast bacilli (AFB) in the sputum; d) failure of the patient to cover the mouth and nose when coughing; e) presence of cavitation on chest radiograph; f) inappropriate or short duration of chemotherapy; and g) administration of procedures that can induce coughing or cause aerosolization of M. tuberculosis (e.g., sputum induction). The most infectious persons are most likely those who have not been treated for TB and who have either a) pulmonary or laryngeal TB and a cough or are undergoing cough-inducing procedures, b) a positive AFB sputum smear, or c) cavitation on chest radiograph.Persons with extrapulmonary TB usually are not infectious unless they have a) concomitant pulmonary disease; b) nonpulmonary disease located in the respiratory tract or oral cavity; or c) extrapulmonary disease that includes an open abscess or lesion in which the concentration of organisms is high, especially if drainage from the abscess or lesion is extensive (20,22 ).Coinfection with HIV does not appear to affect the infectiousness of TB patients (63)(64)(65). In general, children who have TB may be less likely than adults to be infectious; however, transmission from children can occur.Therefore, children with TB should be evaluated for infectiousness using the same parameters as for adults (i.e., pulmonary or laryngeal TB, presence of cough or cough-inducing procedures, positive sputum AFB smear, cavitation on chest radiograph, and adequacy and duration of therapy).Pediatric patients who may be infectious include those who a) are not on therapy, b) have just been started on therapy, or c) are on inadequate therapy, and who a) have laryngeal or extensive pulmonary involvement, b) have pronounced cough or are undergoing cough-inducing procedures, c) have positive sputum AFB smears, or d) have cavitary TB.Children who have typical primary tuberculous lesions and do not have any of the indicators of infectiousness listed previously usually do not need to be placed in isolation.Because the source case for pediatric TB patients often occurs in a member of the infected child's family (45 ), parents and other visitors of all pediatric TB patients should be evaluated for TB as soon as possible. Infection is most likely to result from exposure to persons who have unsuspected pulmonary TB and are not receiving anti-TB therapy or from persons who have diagnosed TB and are not receiving adequate therapy.Administration of effective anti-TB therapy has been associated with decreased infectiousness among persons who have active TB (66 ).Effective therapy reduces coughing, the amount of sputum produced, and the number of organisms in the sputum.However, the period of time a patient must take effective therapy before becoming noninfectious varies between patients (67 ).For example, some TB patients are never infectious, whereas those with unrecognized or inadequately treated drug-resistant TB may remain infectious for weeks or months (24 ).Thus, decisions about infectiousness should be made on an individual basis. In general, patients who have suspected or confirmed active TB should be considered infectious if they a) are coughing, b) are undergoing cough-inducing procedures, or c) have positive AFB sputum smears, and if they a) are not on chemotherapy, b) have just started chemotherapy, or c) have a poor clinical or bacteriologic response to chemotherapy.A patient who has drug-susceptible TB and who is on adequate chemotherapy and has had a significant clinical and bacteriologic response to therapy (i.e., reduction in cough, resolution of fever, and progressively decreasing quantity of bacilli on smear) is probably no longer infectious.However, because drugsusceptibility results are not usually known when the decision to discontinue isolation is made, all TB patients should remain in isolation while hospitalized until they have had three consecutive negative sputum smears collected on different days and they demonstrate clinical improvement. # Supplement 2: Diagnosis and Treatment of Latent TB Infection and Active TB I. Diagnostic Procedures for TB Infection and Disease A diagnosis of TB may be considered for any patient who has a persistent cough (i.e., a cough lasting ≥3 weeks) or other signs or symptoms compatible with TB (e.g., bloody sputum, night sweats, weight loss, anorexia, or fever).However, the index of suspicion for TB will vary in different geographic areas and will depend on the prevalence of TB and other characteristics of the population served by the facility.The index of suspicion for TB should be very high in areas or among groups of patients in which the prevalence of TB is high (Section I.B).Persons for whom a diagnosis of TB is being considered should receive appropriate diagnostic tests, which may include PPD skin testing, chest radiography, and bacteriologic studies (e.g., sputum microscopy and culture). # A. PPD Skin Testing and Anergy Testing 1.Application and reading of PPD skin tests The PPD skin test is the only method available for demonstrating infection with M. tuberculosis.Although currently available PPD tests are <100% sensitive and specific for detection of infection with M. tuberculosis, no better diagnostic methods have yet been devised.Interpretation of PPD test results requires knowledge of the antigen used, the immunologic basis for the reaction to this antigen, the technique used to administer and read the test, and the results of epidemiologic and clinical experience with the test (2,5,6 ).The PPD test, like all medical tests, is subject to variability, but many of the variations in administering and reading PPD tests can be avoided by proper training and careful attention to details. The intracutaneous (Mantoux) administration of a measured amount of PPD-tuberculin is currently the preferred method for doing the test.Onetenth milliliter of PPD (5 TU) is injected just beneath the surface of the skin on either the volar or dorsal surface of the forearm.A discrete, pale elevation of the skin (i.e., a wheal) that is 6-10 mm in diameter should be produced. PPD test results should be read by designated, trained personnel between 48 and 72 hours after injection.Patient or HCW self-reading of PPD test results should not be accepted (68 ).The result of the test is based on the presence or absence of an induration at the injection site.Redness or erythema should not be measured.The transverse diameter of induration should be recorded in millimeters. # Interpretation of PPD skin tests a. General The interpretation of a PPD reaction should be influenced by the purpose for which the test was given (e.g., epidemiologic versus diagnostic purposes), by the prevalence of TB infection in the population being tested, and by the consequences of false classification.Errors in classification can be minimized by establishing an appropriate definition of a positive reaction (Table S2-1). The positive-predictive value of PPD tests (i.e, the probability that a person with a positive PPD test is actually infected with M. tuberculosis) is dependent on the prevalence of TB infection in the population being tested and the specificity of the test (69,70 ).In populations with a low prevalence of TB infection, the probability that a positive PPD test represents true infection with M. tuberculosis is very low if the cut-point is set too low (i.e., the test is not adequately specific).In populations with a high prevalence of TB infection, the probability that a positive PPD test using the same cut-point represents true infection with M. tuberculosis is much higher.To ensure that few persons infected with tubercle bacilli will be misclassified as having negative reactions and few persons not infected with tubercle bacilli will be misclassified as having positive reactions, different cut-points are used to separate positive reactions from negative reactions for different populations, depending on the risk for TB infection in that population. A lower cut-point (i.e., 5 mm) is used for persons in the highest risk groups, which include HIV-infected persons, recent close contacts of persons with TB (e.g., in the household or in an unprotected occupational exposure similar in intensity and duration to household contact), and persons who have abnormal chest radiographs with fibrotic changes consistent with inactive TB.A higher cut-point (i.e., 10 mm) is used for persons who are not in the highest risk group but who have other risk factors (e.g., injecting-drug users known to be HIV seronegative; persons with certain medical conditions that increase the risk for progression from latent TB infection to active TB ); medically underserved, low-income populations; persons born in foreign countries that have a high prevalence of TB; and residents of correctional institutions and nursing homes).An even higher cut-point (i.e., 15 mm) is used for all other persons who have none of the above risk factors. Recent PPD converters are considered members of a high-risk group.A ≥10 mm increase in the size of the induration within a 2-year period is classified as a conversion from a negative to a positive test result for persons <35 years of age.An increase of induration of ≥15 mm within a 2-year period is classified as a conversion for persons ≥35 years of age (5 ). # b. HCWs In general, HCWs should have their skin-test results interpreted according to the recommendations in this supplement and in sections 1, 2, 3, and 5 of Table S2 A recent PPD test conversion in an HCW should be defined generally as an increase of ≥10 mm in the size of induration within a 2-year period. For HCWs in facilities where exposure to TB is very unlikely (e.g., minimal-risk facilities), an increase of ≥15 mm within a 2-year period may be more appropriate for defining a recent conversion because of the lower positive-predictive value of the test in such groups. # Anergy testing HIV-infected persons may have suppressed reactions to PPD skin tests because of anergy, particularly if their CD4+ T-lymphocyte counts decline (71 ).Persons with anergy will have a negative PPD test regardless of infection with M. tuberculosis.HIV-infected persons should be evaluated for anergy in conjunction with PPD testing (72 ).Two companion antigens (e.g., Candida antigen and tetanus toxoid) should be administered in addition to PPD.Persons with ≥3 mm of induration to any of the skin tests (including tuberculin) are considered not anergic.Reactions of ≥5 mm to PPD are considered to be evidence of TB infection in HIV-infected persons regardless of the reactions to the companion antigens.If there is no reaction (i.e., <3 mm induration) to any of the antigens, the person being tested is considered anergic.Determination of whether such persons are likely to be infected with M. tuberculosis must be based on other epidemiologic factors (e.g., the proportion of other persons with the same level of exposure who have positive PPD test results and the intensity or duration of exposure to infectious TB patients that the anergic person experienced). # Pregnancy and PPD skin testing Although thousands (perhaps millions) of pregnant women have been PPD skin tested since the test was devised, thus far no documented episodes of fetal harm have resulted from use of the tuberculin test (73 ). Pregnancy should not exclude a female HCW from being skin tested as part of a contact investigation or as part of a regular skin-testing program. 1.An induration of ≥5 mm is classified as positive in: - persons who have human immunodeficiency virus (HIV) infection or risk factors for HIV infection but unknown HIV status; - persons who have had recent close contact- with persons who have active tuberculosis (TB); - persons who have fibrotic chest radiographs (consistent with healed TB). 2.An induration of ≥10 mm is classified as positive in all persons who do not meet any of the criteria above but who have other risk factors for TB, including: High-risk groups - - injecting-drug users known to be HIV seronegative; - persons who have other medical conditions that reportedly increase the risk for progressing from latent TB infection to active TB (e.g., silicosis; gastrectomy or jejuno-ileal bypass; being ≥10% below ideal body weight; chronic renal failure with renal dialysis; diabetes mellitus; high-dose corticosteroid or other immunosuppressive therapy; some hematologic disorders, including malignancies such as leukemias and lymphomas; and other malignancies); - children <4 years of age. High-prevalence groups - - persons born in countries in Asia, Africa, the Caribbean, and Latin America that have high prevalence of TB; - persons from medically underserved, low-income populations; - residents of long-term-care facilities (e.g., correctional institutions and nursing homes); - persons from high-risk populations in their communities, as determined by local public health authorities. 3.An induration of ≥15 mm is classified as positive in persons who do not meet any of the above criteria. 4.Recent converters are defined on the basis of both size of induration and age of the person being tested: - ≥10 mm increase within a 2-year period is classified as a recent conversion for persons <35 years of age; - ≥15 mm increase within a 2-year period is classified as a recent conversion for persons ≥35 years of age. 5.PPD skin-test results in health-care workers (HCWs) - In general, the recommendations in sections 1, 2, and 3 of this table should be followed when interpreting skin-test results in HCWs. However, the prevalence of TB in the facility should be considered when choosing the appropriate cut-point for defining a positive PPD reaction.In facilities where there is essentially no risk for exposure to Mycobacterium tuberculosis (i.e., minimal-or very low-risk facilities ), an induration ≥15 mm may be a *Recent close contact implies either household or social contact or unprotected occupational exposure similar in intensity and duration to household contact. # BCG vaccination and PPD skin testing BCG vaccination may produce a PPD reaction that cannot be distinguished reliably from a reaction caused by infection with M. tuberculosis.For a person who was vaccinated with BCG, the probability that a PPD test reaction results from infection with M. tuberculosis increases a) as the size of the reaction increases, b) when the person is a contact of a person with TB, c) when the person's country of origin has a high prevalence of TB, and d) as the length of time between vaccination and PPD testing increases. For example, a PPD test reaction of ≥10 mm probably can be attributed to M. tuberculosis infection in an adult who was vaccinated with BCG as a child and who is from a country with a high prevalence of TB (74,75 ). # The booster phenomenon The ability of persons who have TB infection to react to PPD may gradually wane.For example, if tested with PPD, adults who were infected during their childhood may have a negative reaction.However, the PPD could boost the hypersensitivity, and the size of the reaction could be larger on a subsequent test.This boosted reaction may be misinterpreted as a PPD test conversion from a newly acquired infection.Misinterpretation of a boosted reaction as a new infection could result in unnecessary investigations of laboratory and patient records in an attempt to identify the source case and in unnecessary prescription of preventive therapy for HCWs.
Although boosting can occur among persons in any age group, the likelihood of the reaction increases with the age of the person being tested (6,76 ). When PPD testing of adults is to be repeated periodically (as in HCW skintesting programs), two-step testing can be used to reduce the likelihood that a boosted reaction is misinterpreted as a new infection.Two-step testing should be performed on all newly employed HCWs who have an initial negative PPD test result at the time of employment and have not had a documented negative PPD test result during the 12 months preceding the initial test.A second test should be performed 1-3 weeks after the first test. If the second test result is positive, this is most likely a boosted reaction, suitable cut-point for HCWs who have no other risk factors.In facilities where TB patients receive care, the cut-point for HCWs with no other risk factors may be ≥10 mm. - A recent conversion in an HCW should be defined generally as a ≥10 mm increase in size of induration within a 2-year period.For HCWs who work in facilities where exposure to TB is very unlikely (e.g., minimal-risk facilities), an increase of ≥15 mm within a 2-year period may be more appropriate for defining a recent conversion because of the lower positive-predictive value of the test in such groups. # B. Chest Radiography Patients who have positive skin-test results or symptoms suggestive of TB should be evaluated with a chest radiograph regardless of PPD test results. Radiographic abnormalities that strongly suggest active TB include upperlobe infiltration, particularly if cavitation is seen (77 ), and patchy or nodular infiltrates in the apical or subapical posterior upper lobes or the superior segment of the lower lobe.If abnormalities are noted, or if the patient has symptoms suggestive of extrapulmonary TB, additional diagnostic tests should be conducted. The radiographic presentation of pulmonary TB in HIV-infected patients may be unusual (78 ).Typical apical cavitary disease is less common among such patients.They may have infiltrates in any lung zone, a finding that is often associated with mediastinal and/or hilar adenopathy, or they may have a normal chest radiograph, although this latter finding occurs rarely. # C. Bacteriology Smear and culture examination of at least three sputum specimens collected on different days is the main diagnostic procedure for pulmonary TB (6 ).Sputum smears that fail to demonstrate AFB do not exclude the diagnosis of TB.In the United States, approximately 60% of patients with positive sputum cultures have positive AFB sputum smears.HIV-infected patients who have pulmonary TB may be less likely than immunocompetent patients to have AFB present on sputum smears, which is consistent with the lower frequency of cavitary pulmonary disease observed among HIV-infected persons (39,41 ). Specimens for smear and culture should contain an adequate amount of expectorated sputum but not much saliva.If a diagnosis of TB cannot be established from sputum, a bronchoscopy may be necessary (36,37 ).In young children who cannot produce an adequate amount of sputum, gastric aspirates may provide an adequate specimen for diagnosis. A culture of sputum or other clinical specimen that contains M. tuberculosis provides a definitive diagnosis of TB.Conventional laboratory methods may require 4-8 weeks for species identification; however, the use of radiometric culture techniques and nucleic acid probes facilitates more rapid detection and identification of mycobacteria (79,80 ).Mixed mycobacterial infection, either simultaneous or sequential, can obscure the identification of M. tuberculosis during the clinical evaluation and the laboratory analysis (42 ).The use of nucleic acid probes for both M. avium complex and M. tuberculosis may be useful for identifying mixed mycobacterial infections in clinical specimens. (33 ). # II.Preventive Therapy for Persons who have latent TB infection should be advised that they can be reinfected with another strain of M. tuberculosis (93 ). # B. Treatment of Patients Who Have Active TB Drug-susceptibility testing should be performed on all initial isolates from patients with TB.However, test results may not be available for several weeks, making selection of an initial regimen difficult, especially in areas where drug-resistant TB has been documented.Current recommendations for therapy and dosage schedules for the treatment of drug-susceptible TB should be followed (Table S2-2; Table S2-3) (43 ).Streptomycin is contraindicated in the treatment of pregnant women because of the risk for ototoxicity to the fetus.In geographic areas or facilities in which drug-resistant TB is highly prevalent, the initial treatment regimen used while results of drug-susceptibility tests are pending may need to be expanded.This decision should be based on analysis of surveillance data. When results from drug-susceptibility tests become available, the regimen should be adjusted appropriately (94)(95)(96)(97).If drug resistance is present, clinicians unfamiliar with the management of patients with drug-resistant TB should seek expert consultation. For any regimen to be effective, adherence to the regimen must be ensured.The most effective method of ensuring adherence is the use of DOT after the patient has been discharged from the hospital (43,91 ).This practice should be coordinated with the public health department. # Supplement 3: Engineering Controls # I. Introduction This supplement provides information regarding the use of ventilation (Section II) and UVGI (Section III) for preventing the transmission of M. tuberculosis in health-care facilities.The information provided is primarily conceptual and is intended to educate staff in the health-care facility concerning engineering controls and how these controls can be used as part of the TB infection-control program.This supplement should not be used in place of consultation with experts, who can assume responsibility for advising on ventilation system design and selection, installation, and maintenance of equipment. # II.Ventilation Ventilation systems for health-care facilities should be designed, and modified when necessary, by ventilation engineers in collaboration with infection-control and occupational health staff.Recommendations for designing and operating ventilation systems have been published by ASHRAE (47 ), AIA (48 ), and the American Conference of Governmental Industrial Hygienists, Inc. (98 ). As part of the TB infection-control plan, health-care facility personnel should determine the number of TB isolation rooms, treatment rooms, and local exhaust devices (i.e., for cough-inducing or aerosol-generating procedures) that the facility needs.The locations of these rooms and devices will depend on where in the facility the ventilation conditions recommended in this document can be achieved.Grouping isolation rooms together in one area of the facility may facilitate the care of TB patients and the installation and maintenance of optimal engineering controls (particularly ventilation). Periodic evaluations of the ventilation system should review the number of TB isolation rooms, treatment rooms, and local exhaust devices needed and the regular maintenance and monitoring of the local and general exhaust systems (including HEPA filtration systems if they are used). The various types and conditions of ventilation systems in health-care facilities and the individual needs of these facilities preclude the ability to provide specific instructions regarding the implementation of these recommendations.Engineering control methods must be tailored to each facility on the basis of need and the feasibility of using the ventilation and air-cleaning concepts discussed in this supplement. # A. Local Exhaust Ventilation Purpose: To capture airborne contaminants at or near their source (i.e., the source control method) and remove these contaminants without exposing persons in the area to infectious agents (98 ). Source control techniques can prevent or reduce the spread of infectious droplet nuclei into the general air circulation by entrapping infectious droplet nuclei as they are being emitted by the patient (i.e., the source).These techniques are especially important when performing procedures likely to generate aerosols containing infectious particles and when infectious TB patients are coughing or sneezing. Local exhaust ventilation is a preferred source control technique, and it is often the most efficient way to contain airborne contaminants because it captures these contaminants near their source before they can disperse.Therefore, the technique should be used, if feasible, wherever aerosolgenerating procedures are performed.Two basic types of local exhaust devices use hoods: a) the enclosing type, in which the hood either partially or fully encloses the infectious source; and b) the exterior type, in which the infectious source is near but outside the hood.Fully enclosed hoods, booths, or tents are always preferable to exterior types because of their superior ability to prevent contaminants from escaping into the HCW's breathing zone.Descriptions of both enclosing and exterior devices have been published previously (98 ). # Enclosing devices The enclosing type of local exhaust ventilation device includes laboratory hoods used for processing specimens that could contain viable infectious organisms, booths used for sputum induction or administration of aerosolized medications (e.g., aerosolized pentamidine) (Figure S3-1), and tents or hoods made of vinyl or other materials used to enclose and isolate a patient.These devices are available in various configurations.The most simple of these latter devices is a tent that is placed over the patient; the tent has an exhaust connection to the room discharge exhaust system.The most complex device is an enclosure that has a sophisticated selfcontained airflow and recirculation system. Both tents and booths should have sufficient airflow to remove at least 99% of airborne particles during the interval between the departure of one patient and the arrival of the next (99 ).The time required for removing a given percentage of airborne particles from an enclosed space depends on several factors.These factors include the number of ACH, which is determined by the number of cubic feet of air in the room or booth and the rate at which air is entering the room or booth at the intake source; the location of the ventilation inlet and outlet; and the physical configuration of the room or booth (Table S3-1). # Exterior devices The exterior type of local exhaust ventilation device is usually a hood very near, but not enclosing, the infectious patient.The airflow produced by these devices should be sufficient to prevent cross-currents of air near the patient's face from causing escape of droplet nuclei.Whenever possible, the patient should face directly into the hood opening so that any coughing or sneezing is directed into the hood, where the droplet nuclei are captured.The device should maintain an air velocity of ≥200 feet per minute at the patient's breathing zone to ensure capture of droplet nuclei. # Discharge exhaust from booths, tents, and hoods Air from booths, tents, and hoods may be discharged into the room in which the device is located or it may be exhausted to the outside.If the air is discharged into the room, a HEPA filter should be incorporated at the discharge duct or vent of the device.The exhaust fan should be located on the discharge side of the HEPA filter to ensure that the air pressure in the filter housing and booth is negative with respect to adjacent areas.Uncontaminated air from the room will flow into the booth through all openings, The times given assume perfect mixing of the air within the space (i.e., mixing factor = 1).However, perfect mixing usually does not occur, and the mixing factor could be as high as 10 if air distribution is very poor (98 ).The required time is derived by multiplying the appropriate time from the table by the mixing factor that has been determined for the booth or room.The factor and required time should be included in the operating instructions provided by the manufacturer of the booth or enclosure, and these instructions should be followed.thus preventing infectious droplet nuclei in the booth from escaping into the room.Most commercially available booths, tents, and hoods are fitted with HEPA filters, in which case additional HEPA filtration is not needed. If the device does not incorporate a HEPA filter, the air from the device should be exhausted to the outside in accordance with recommendations for isolation room exhaust (Suppl.3, Section II.B.5). (See Supplement 3, Section II.C, for information regarding recirculation of exhaust air.) # B. General Ventilation General ventilation can be used for several purposes, including diluting and removing contaminated air, controlling airflow patterns within rooms, and controlling the direction of airflow throughout a facility.Information on these topics is contained in the following sections. # Dilution and removal Purpose: To reduce the concentration of contaminants in the air. General ventilation maintains air quality by two processes: dilution and removal of airborne contaminants.Uncontaminated supply (i.e., incoming) air mixes with the contaminated room air (i.e., dilution), which is subsequently removed from the room by the exhaust system (i.e., removal).These processes reduce the concentration of droplet nuclei in the room air. # a. Types of general ventilation systems Two types of general ventilation systems can be used for dilution and removal of contaminated air: the single-pass system and the recirculating system.In a single-pass system, the supply air is either outside air that has been appropriately heated and cooled or air from a central system that supplies a number of areas.After air passes through the room (or area), 100% of that air is exhausted to the outside.The single-pass system is the preferred choice in areas where infectious airborne droplet nuclei are known to be present (e.g., TB isolation rooms or treatment rooms) because it prevents contaminated air from being recirculated to other areas of the facility.In a recirculating system, a small portion of the exhaust air is discharged to the outside and is replaced with fresh outside air, which mixes with the portion of exhaust air that was not discharged to the outside.The resulting mixture, which can contain a large proportion of contaminated air, is then recirculated to the areas serviced by the system.This air mixture could be recirculated into the general ventilation, in which case contaminants may be carried from contaminated areas to uncontaminated areas.Alternatively, the air mixture could also be recir-culated within a specific room or area, in which case other areas of the facility will not be affected (Suppl.3, Section II.C.3). # b. Ventilation rates Recommended general ventilation rates for health-care facilities are usually expressed in number of ACH.This number is the ratio of the volume of air entering the room per hour to the room volume and is equal to the exhaust airflow (Q ) divided by the room volume (V ) multiplied by 60 (i.e., ACH = Q ÷ V × 60). The feasibility of achieving specific ventilation rates depends on the construction and operational requirements of the ventilation system (e.g., the energy requirements to move and to heat or cool the air).The feasibility of achieving specific ventilation rates may also be different for retrofitted facilities and newly constructed facilities.The expense and effort of achieving specific higher ventilation rates for new construction may be reasonable, whereas retrofitting an existing facility to achieve similar ventilation rates may be more difficult.However, achieving higher ventilation rates by using auxiliary methods (e.g., room-air recirculation) in addition to exhaust ventilation may be feasible in existing facilities (Suppl.3, Section II.C). # Airflow patterns within rooms (air mixing) Purpose: To provide optimum airflow patterns and prevent both stagnation and short-circuiting of air. General ventilation systems should be designed to provide optimal patterns of airflow within rooms and prevent air stagnation or short-circuiting of air from the supply to the exhaust (i.e., passage of air directly from the air supply to the air exhaust).To provide optimal airflow patterns, the air supply and exhaust should be located such that clean air first flows to parts of the room where HCWs are likely to work, and then flows across the infectious source and into the exhaust.In this way, the HCW is not positioned between the infectious source and the exhaust location.Although this configuration may not always be possible, it should be used whenever feasible.One way to achieve this airflow pattern is to supply air at the side of the room opposite the patient and exhaust it from the side where the patient is located.Another method, which is most effective when the supply air is cooler than the room air, is to supply air near the ceiling and exhaust it near the floor (Figure S3-2).Airflow patterns are affected by large air temperature differentials, the precise location of the supply and exhausts, the location of furniture, the movement of HCWs and patients, and the physical configuration of the space.Smoke tubes can be used to visualize airflow patterns in a manner similar to that described for estimating room air mixing. Adequate air mixing, which requires that an adequate number of ACH be provided to a room (Suppl.3, Section II.B.1), must be ensured to prevent air stagnation within the room.However, the air will not usually be changed the calculated number of times per hour because the airflow patterns in the room may not permit complete mixing of the supply and room air in all parts of the room.This results in an "effective" airflow rate in which the supplied airflow may be less than required for proper ventilation.To account for this variation, a mixing factor (which ranges from 1 for perfect mixing to 10 for poor mixing) is applied as a multiplier to determine the actual supply airflow (i.e., the recommended ACH multiplied by the mixing factor equals the actual required ACH) (51,98 ).The room air supply and exhaust system should be designed to achieve the lowest mixing factor possible.The mixing factor is determined most accurately by experimentally testing each space configuration, but this procedure is complex and time-consuming.A reasonably good qualitative measure of mixing can be estimated by an experienced ventilation engineer who releases smoke from smoke tubes at a number of locations in the room and observes the movement of the smoke.Smoke movement in all areas of the room indicates good mixing.Stagnation of air in some areas of the room # FIGURE S3-2.
Room airflow patterns designed to provide mixing of air and prevent passage of air directly from the air supply to the exhaust* indicates poor mixing, and movement of the supply and exhaust openings or redirection of the supply air is necessary. # Airflow direction in the facility Purpose: To contain contaminated air in localized areas in a facility and prevent its spread to uncontaminated areas. # a. Directional airflow The general ventilation system should be designed and balanced so that air flows from less contaminated (i.e., more clean) to more contaminated (less clean) areas (47,48 ).For example, air should flow from corridors (cleaner areas) into TB isolation rooms (less clean areas) to prevent spread of contaminants to other areas.In some special treatment rooms in which operative and invasive procedures are performed, the direction of airflow is from the room to the hallway to provide cleaner air during these procedures.Cough-inducing or aerosolgenerating procedures (e.g., bronchoscopy and irrigation of tuberculous abscesses) should not be performed in rooms with this type of airflow on patients who may have infectious TB. # b. Negative pressure for achieving directional airflow The direction of airflow is controlled by creating a lower (negative) pressure in the area into which the flow of air is desired.For air to flow from one area to another, the air pressure in the two areas must be different.Air will flow from a higher pressure area to a lower pressure area.The lower pressure area is described as being at negative- pressure relative to the higher pressure area.Negative pressure is attained by exhausting air from an area at a higher rate than air is being supplied.The level of negative pressure necessary to achieve the desired airflow will depend on the physical configuration of the ventilation system and area, including the airflow path and flow openings, and should be determined on an individual basis by an experienced ventilation engineer. # Achieving negative pressure in a room Purpose: To control the direction of airflow between the room and adjacent areas, thereby preventing contaminated air from escaping from the room into other areas of the facility. # a. Pressure differential The minimum pressure difference necessary to achieve and maintain negative pressure that will result in airflow into the room is very small (0.001 inch of water).Higher pressures (≥0.001 inch of water) are satisfactory; however, these higher pressures may be difficult to Negative is defined relative to the air pressure in the area from which air is to flow. achieve.The actual level of negative pressure achieved will depend on the difference in the ventilation exhaust and supply flows and the physical configuration of the room, including the airflow path and flow openings.If the room is well sealed, negative pressures greater than the minimum of 0.001 inch of water may be readily achieved.However, if rooms are not well sealed, as may be the case in many facilities (especially older facilities), achieving higher negative pressures may require exhaust/supply flow differentials beyond the capability of the ventilation system. To establish negative pressure in a room that has a normally functioning ventilation system, the room supply and exhaust airflows are first balanced to achieve an exhaust flow of either 10% or 50 cubic feet per minute (cfm) greater than the supply (whichever is the greater).In most situations, this specification should achieve a negative pressure of at least 0.001 inch of water.If the minimum 0.001 inch of water is not achieved and cannot be achieved by increasing the flow differential (within the limits of the ventilation system), the room should be inspected for leakage (e.g., through doors, windows, plumbing, and equipment wall penetrations), and corrective action should be taken to seal the leaks. Negative pressure in a room can be altered by changing the ventilation system operation or by the opening and closing of the room's doors, corridor doors, or windows.When an operating configuration has been established, it is essential that all doors and windows remain properly closed in the isolation room and other areas (e.g., doors in corridors that affect air pressure) except when persons need to enter or leave the room or area. b. Alternate methods for achieving negative pressure Although an anteroom is not a substitute for negative pressure in a room, it may be used to reduce escape of droplet nuclei during opening and closing of the isolation room door.Some anterooms have their own air supply duct, but others do not.The TB isolation room should have negative pressure relative to the anteroom, but the air pressure in the anteroom relative to the corridor may vary depending on the building design.This should be determined, in accordance with applicable regulations, by a qualified ventilation engineer. If the existing ventilation system is incapable of achieving the desired negative pressure because the room lacks a separate ventilation system or the room's system cannot provide the proper airflow, steps should be taken to provide a means to discharge air from the room.The amount of air to be exhausted will be the same as discussed previously (Suppl.3, Section II.B.4.a). Fixed room-air recirculation systems (i.e., systems that recirculate the air in an entire room) may be designed to achieve negative pressure by discharging air outside the room (Suppl.3, Section II.C.3). Some portable room-air recirculation units (Suppl.3, Section II.C.3.b.)are designed to discharge air to the outside to achieve negative pressure.Air cleaners that can accomplish this must be designed specifically for this purpose. A small centrifugal blower (i.e., exhaust fan) can be used to exhaust air to the outside through a window or outside wall.This approach may be used as an interim measure to achieve negative pressure, but it provides no fresh air and suboptimal dilution. Another approach to achieving the required pressure difference is to pressurize the corridor.Using this method, the corridor's general ventilation system is balanced to create a higher air pressure in the corridor than in the isolation room; the type of balancing necessary depends on the configuration of the ventilation system.Ideally, the corridor air supply rate should be increased while the corridor exhaust rate is not increased.If this is not possible, the exhaust rate should be decreased by resetting appropriate exhaust dampers.Caution should be exercised, however, to ensure that the exhaust rate is not reduced below acceptable levels.This approach requires that all settings used to achieve the pressure balance, including doors, be maintained.This method may not be desirable if the corridor being pressurized has rooms in which negative pressure is not desired.In many situations, this system is difficult to achieve, and it should be considered only after careful review by ventilation personnel. # c. Monitoring negative pressure The negative pressure in a room can be monitored by visually observing the direction of airflow (e.g., using smoke tubes) or by measuring the differential pressure between the room and its surrounding area. Smoke from a smoke tube can be used to observe airflow between areas or airflow patterns within an area.To check the negative pressure in a room by using a smoke tube, hold the smoke tube near the bottom of the door and approximately 2 inches in front of the door, or at the face of a grille or other opening if the door has such a feature, and generate a small amount of smoke by gently squeezing the bulb (Figure S3-3). The smoke tube should be held parallel to the door, and the smoke should be issued from the tube slowly to ensure the velocity of the smoke from the tube does not overpower the air velocity.The smoke will travel in the direction of airflow.If the room is at negative pressure, the smoke will travel under the door and into the room (e.g., from higher to lower pressure).If the room is not at negative pressure, the smoke will be blown outward or will stay stationary.This test must be performed while the door is closed.If room air cleaners are being used in the room, they should be running.The smoke is irritating if inhaled, and care should be taken not to inhale it directly from the smoke tube.However, the quantity of smoke issued from the tube is minimal and is not detectable at short distances from the tube. Differential pressure-sensing devices also can be used to monitor negative pressure; they can provide either periodic (noncontinuous) pressure measurements or continuous pressure monitoring.The continuous monitoring component may simply be a visible and/or audible warning signal that air pressure is low.In addition, it may also provide a pressure readout signal, which can be recorded for later verification or used to automatically adjust the facility's ventilation control system. Pressure-measuring devices should sense the room pressure just inside the airflow path into the room (e.g., at the bottom of the door).Unusual airflow patterns within the room can cause pressure variations; for example, the air can be at negative pressure at the middle of a door and at # Smoke Smoke tube # Opening beneath door Anemometer Door Smoke flowing into the room indicates the room is at negative pressure relative to the corridor, and smoke flowing out of the room indicates the room is at positive pressure relative to the corridor.The anemometer, if used, is placed with the sensor in the airflow path at the bottom of the door. # FIGURE S3-3.Smoke-tube testing and anemometer placement to determine the direction of airflow into and out of a room* positive pressure at the bottom of the same door (Figure S3-4).If the pressure-sensing ports of the device cannot be located directly across the airflow path, it will be necessary to validate that the negative pressure at the sensing point is and remains the same as the negative pressure across the flow path. Pressure-sensing devices should incorporate an audible warning with a time delay to indicate that a door is open.When the door to the room is opened, the negative pressure will decrease.The time-delayed signal should allow sufficient time for persons to enter or leave the room without activating the audible warning. A potential problem with using pressure-sensing devices is that the pressure differentials used to achieve the low negative pressure necessitate the use of very sensitive mechanical devices, electronic devices, or pressure gauges to ensure accurate measurements.Use of devices that cannot measure these low pressures (i.e., pressures as low as 0.001 inch of water) will require setting higher negative pressures that may be difficult and, in some instances, impractical to achieve (Suppl.3, Section II.B.4).system should be checked daily.TB isolation rooms should be checked daily for negative pressure while being used for TB isolation.If these rooms are not being used for patients who have suspected or confirmed TB but potentially could be used for such patients, the negative pressure in the rooms should be checked monthly.If pressure-sensing devices are used, negative pressure should be verified at least once a month by using smoke tubes or taking pressure measurements. # C. HEPA filtration Purpose: To remove contaminants from the air. HEPA filtration can be used as a method of air cleaning that supplements other recommended ventilation measures.For the purposes of these guidelines, HEPA filters are defined as air-cleaning devices that have a demonstrated and documented minimum removal efficiency of 99.97% of particles ≥0.3 µm in diameter.HEPA filters have been shown to be effective in reducing the concentration of Aspergillus spores (which range in size from 1.5 µm to 6 µm) to below measurable levels (100)(101)(102).The ability of HEPA filters to remove tubercle bacilli from the air has not been studied, but M. tuberculosis droplet nuclei probably range from 1 µm to 5 µm in diameter (i.e., approximately the same size as Aspergillus spores).Therefore, HEPA filters can be expected to remove infectious droplet nuclei from contaminated air.HEPA filters can be used to clean air before it is exhausted to the outside, recirculated to other areas of a facility, or recirculated within a room.If the device is not completely passive (e.g., it utilizes techniques such as electrostatics) and the failure of the electrostatic components permits loss of filtration efficiency to <99.97%, the device should not be used in systems that recirculate air back into the general facility ventilation system from TB isolation rooms and treatment rooms in which procedures are performed on patients who may have infectious TB (Suppl.3, Section II.C.2). HEPA filters can be used in a number of ways to reduce or eliminate infectious droplet nuclei from room air or exhaust.These methods include placement of HEPA filters a) in exhaust ducts to remove droplet nuclei from air being discharged to the outside, either directly or through ventilation equipment; b) in ducts discharging room air into the general ventilation system; and c) in fixed or portable room-air cleaners.The effectiveness of portable HEPA room-air cleaning units has not been evaluated adequately, and there is probably considerable variation in their effectiveness.HEPA filters can also be used in exhaust ducts or vents that discharge air from booths or enclosures into the surrounding room (Suppl.3, Section II.A.3).In any application, HEPA filters should be installed carefully and maintained meticulously to ensure adequate function. Manufacturers of room-air cleaning equipment should provide documentation of the HEPA filter efficiency and the efficiency of the installed device in lowering room-air contaminant levels. # Use of HEPA filtration when exhausting air to the outside HEPA filters can be used as an added safety measure to clean air from isolation rooms and local exhaust devices (i.e., booths, tents, or hoods used for cough-inducing procedures) before exhausting it directly to the outside, but such use is unnecessary if the exhaust air cannot re-enter the ventilation system supply.The use of HEPA filters should be considered wherever exhaust air could possibly reenter the system. In many instances, exhaust air is not discharged directly to the outside; rather, the air is directed through heat-recovery devices (e.g., heat wheels). Heat wheels are often used to reduce the costs of operating ventilation systems (103 ).If such units are used with the system, a HEPA filter should also be used.As the wheel rotates, energy is transferred into or removed from the supply inlet air stream.The HEPA filter should be placed upstream from the heat wheel because of the potential for leakage across the seals separating the inlet and exhaust chambers and the theoretical possibility that droplet nuclei could be impacted on the wheel by the exhaust air and subsequently stripped off into the supply air. # Recirculation of HEPA-filtered air to other areas of a facility Air from TB isolation rooms and treatment rooms used to treat patients who have confirmed or suspected infectious TB should be exhausted to the outside in accordance with applicable federal, state, and local regulations.The air should not be recirculated into the general ventilation.In some instances, recirculation of air into the general ventilation system from such rooms is unavoidable (i.e., in existing facilities in which the ventilation system or facility configuration makes venting the exhaust to the outside impossible).In such cases, HEPA filters should be installed in the exhaust duct leading from the room to the general ventilation system to remove infectious organisms and particulates the size of droplet nuclei from the air before it is returned to the general ventilation system (Section II.F; Suppl.3).Air from TB isolation rooms and treatment rooms in new or renovated facilities should not be recirculated into the general ventilation system. # Recirculation of HEPA-filtered air within a room Individual room-air recirculation can be used in areas where there is no general ventilation system, where an existing system is incapable of providing adequate airflow, or where an increase in ventilation is desired without affecting the fresh air supply or negative pressure system already in place.Recirculation of HEPA-filtered air within a room can be achieved in several ways: a) by exhausting air from the room into a duct, filtering it through a HEPA filter installed in the duct, and returning it to the room (Figure S3-5); b) by filtering air through HEPA recirculation systems mounted on the wall or ceiling of the room (Figure S3-6); or c) by filtering air through portable HEPA recirculation systems.In this document, the first two of these HEPA filter and blower 10% Exhaust to outside for negative pressure if room has no ventilation *Such a system can be used to increase the room ventilation rate. The preferred method of recirculating HEPA-filtered air within a room is a built-in system, in which air is exhausted from the room into a duct, filtered through a HEPA filter, and returned to the room (Figure S3-5).This technique may be used to add air changes in areas where there is a recommended minimum ACH that is difficult to meet with general ventilation alone.The air does not have to be conditioned, other than by the filtration, and this permits higher airflow rates than the general ventilation system can usually achieve.An alternative is the use of HEPA filtration units that are mounted on the wall or ceiling of the room (Figure S3-7).Fixed recirculation systems are preferred over portable (free-standing) units because they can be installed and maintained with a greater degree of reliability. # b. Portable room-air recirculation units Portable HEPA filtration units may be considered for recirculating air within rooms in which there is no general ventilation system, where the system is incapable of providing adequate airflow, or where increased effectiveness in room airflow is desired.Effectiveness depends on circulating as much of the air in the room as possible through the HEPA filter, which may be difficult to achieve and evaluate.
The effectiveness of a particular unit can vary depending on the room's configuration, the furniture and persons in the room, and placement of the HEPA filtration unit and the supply and exhaust grilles.Therefore, the effectiveness of the portable unit may vary considerably in rooms with different configurations or in the same room if moved from one location to another in the room.If portable units are used, caution should be exercised to ensure they can recirculate all or nearly all of the room air through the HEPA filter.Some commercially available units may not be able to meet this requirement because of design limitations or insufficient airflow capacity.In addition, units should be designed and operated to ensure that persons in the room cannot interfere with or otherwise compromise the functioning of the unit.Portable HEPA filtration units have not been evaluated adequately to determine their role in TB infectioncontrol programs. Portable HEPA filtration units should be designed to achieve the equivalent of ≥12 ACH.They should also be designed to ensure adequate air mixing in all areas of the hospital rooms in which they are used, and they should not interfere with the current ventilation system.Some HEPA filtration units employ UVGI for disinfecting air after HEPA filtration.However, whether exposing the HEPA-filtered air to UV irradiation further decreases the concentration of contaminants is not known. # c. Evaluation of room-air recirculation systems and units Detailed and accurate evaluations of room-air recirculation systems and units require the use of sophisticated test equipment and lengthy test procedures that are not practical.However, an estimate of the unit's ability to circulate the air in the room can be made by visualizing airflow patterns as was described previously for estimating room air mixing (Suppl.3, Section II.B.1).If the air movement is good in all areas of the room, the unit should be effective. # Installing, maintaining, and monitoring HEPA filters Proper installation and testing and meticulous maintenance are critical if a HEPA filtration system is used (104 ), especially if the system used recirculates air to other parts of the facility.Improper design, installation, or maintenance could allow infectious particles to circumvent filtration and escape into the general ventilation system (47 ).HEPA filters should be installed to prevent leakage between filter segments and between the filter bed and its frame.A regularly scheduled maintenance program is required to monitor the HEPA filter for possible leakage and for filter loading.A quantitative leakage and filter performance test (e.g., the dioctal phthalate penetration test ) should be performed at the initial installation and every time the filter is changed or moved.The test should be repeated every 6 months for filters in general-use areas and in areas with systems that exhaust air that is likely to be contaminated with M. tuberculosis (e.g, TB isolation rooms). A manometer or other pressure-sensing device should be installed in the filter system to provide an accurate and objective means of determining the need for filter replacement.Pressure drop characteristics of the filter are supplied by the manufacturer of the filter.Installation of the filter should allow for maintenance that will not contaminate the delivery system or the area served.For general infection-control purposes, special care should be taken to not jar or drop the filter element during or after removal. The scheduled maintenance program should include procedures for installation, removal, and disposal of filter elements.HEPA filter maintenance should be performed only by adequately trained personnel.Appropriate respiratory protection should be worn while performing maintenance and testing procedures.In addition, filter housing and ducts leading to the housing should be labelled clearly with the words "Contaminated Air" (or a similar warning). When a HEPA filter is used, one or more lower efficiency disposable prefilters installed upstream will extend the useful life of the HEPA filter.A disposable filter can increase the life of a HEPA filter by 25%.If the disposable filter is followed by a 90% extended surface filter, the life of the HEPA filter can be extended almost 900% (98 ).These prefilters should be handled and disposed of in the same manner as the HEPA filter. # D. TB Isolation Rooms and Treatment Rooms Purpose: To separate patients who are likely to have infectious TB from other persons, to provide an environment that will allow reduction of the concentration of droplet nuclei through various engineering methods, and to prevent the escape of droplet nuclei from such rooms into the corridor and other areas of the facility using directional airflow. A hierarchy of ventilation methods used to achieve a reduction in the concentration of droplet nuclei and to achieve directional airflow using negative pressure has been developed (Table S3-2).The methods are listed in order from the most desirable to the least desirable.The method selected will depend on the configuration of the isolation room and the ventilation system in the facility; the determination should be made in consultation with a ventilation engineer. *Ventilation methods are used to reduce the concentration of airborne tubercle bacilli.If the facility HVAC system cannot achieve the recommended ventilation rate, auxiliary room-air recirculation methods may be used.These methods are listed in order from the most desirable to the least desirable.Ultraviolet germicidal irradiation may be used as a supplement to any of the ventilation methods for air cleaning. †Directional airflow using negative pressure can be achieved with the facility HVAC system and/or the auxiliary air-recirculation-cleaning systems.These methods are listed in order from the most desirable to the least desirable. §To remove the amount of return air necessary to achieve negative pressure. ¶The effectiveness of portable room-air HEPA recirculation units can vary depending on the room's configuration, the furniture and persons in the room, the placement of the unit, the supply and exhaust grilles, and the achievable ventilation rates and air mixing.Units should be designed and operated to ensure that persons in the room cannot interfere with or otherwise compromise the function of the unit.Fixed recirculating systems are preferred over portable units in TB isolation rooms of facilities in which services are provided regularly to TB patients.This method simply achieves negative pressure and should be used only as a temporary measure. # Preventing the escape of droplet nuclei from the room Rooms used for TB isolation should be single-patient rooms with negative pressure relative to the corridor or other areas connected to the room.Doors between the isolation room and other areas should remain closed except for entry into or exit from the room.The room's openings (e.g., windows and electrical and plumbing entries) should be sealed as much as possible.However, a small gap of 1 ⁄8 to 1 ⁄2 inch should be at the bottom of the door to provide a controlled airflow path.Proper use of negative pressure will prevent contaminated air from escaping the room. # Reducing the concentration of droplet nuclei in the room ASHRAE (47 ), AIA (48 ), and the Health Resources and Services Administration ( 49) recommend a minimum of 6 ACH for TB isolation rooms and treatment rooms.This ventilation rate is based on comfort-and odorcontrol considerations.The effectiveness of this level of airflow in reducing the concentration of droplet nuclei in the room, thus reducing the transmission of airborne pathogens, has not been evaluated directly or adequately. Ventilation rates >6 ACH are likely to produce an incrementally greater reduction in the concentration of bacteria in a room than are lower rates (50)(51)(52).However, accurate quantitation of decreases in risk that would result from specific increases in general ventilation levels has not been performed and may not be possible. To reduce the concentration of droplet nuclei, TB isolation rooms and treatment rooms in existing health-care facilities should have an airflow of ≥6 ACH.Where feasible, this airflow rate should be increased to ≥12 ACH by adjusting or modifying the ventilation system or by using auxiliary means (e.g., recirculation of air through fixed HEPA filtration units or portable air cleaners) (Suppl.3, Section II.C) (53 ).New construction or renovation of existing health-care facilities should be designed so that TB isolation rooms achieve an airflow of ≥12 ACH. # Exhaust from TB isolation rooms and treatment rooms Air from TB isolation rooms and treatment rooms in which patients with infectious TB may be examined should be exhausted directly to the outside of the building and away from air-intake vents, persons, and animals in accordance with federal, state, and local regulations concerning environmental discharges. (See Suppl.3, Section II.C, for information regarding recirculation of exhaust air.)Exhaust ducts should not be located near areas that may be populated (e.g., near sidewalks or windows that could be opened).Ventilation system exhaust discharges and inlets should be designed to prevent reentry of exhausted air.Wind blowing over a building creates a highly turbulent recirculation zone, which can cause exhausted air to reenter the building (Figure S3-7).Exhaust flow should be discharged above this zone (Suppl.3, Section II.C.1).Design guidelines for proper placement of exhaust ducts can be found in the 1989 ASHRAE Fundamentals Handbook (106 ).If recirculation of air from such rooms into the general ventilation system is unavoidable, the air should be passed through a HEPA filter before recirculation (Suppl.3, Section II.C.2). # Alternatives to TB isolation rooms Isolation can also be achieved by use of negative-pressure enclosures (e.g, tents or booths) (Suppl.3, Section II.A.1).These can be used to provide patient isolation in areas such as emergency rooms and medical testing and treatment areas and to supplement isolation in designated isolation rooms. # III.UVGI Purpose: To kill or inactivate airborne tubercle bacilli. Research has demonstrated that UVGI is effective in killing or inactivating tubercle bacilli under experimental conditions (66,(107)(108)(109)(110) and in reducing transmission of other infections in hospitals (111 ), military housing (112 ), and classrooms (113)(114)(115).Because of the results of numerous studies (116)(117)(118)(119)(120) # FIGURE S3-7.Air recirculation zone- created by wind blowing over a building the experiences of TB clinicians and mycobacteriologists during the past several decades, the use of UVGI has been recommended as a supplement to other TB infection-control measures in settings where the need for killing or inactivating tubercle bacilli is important (2,4,(121)(122)(123)(124)(125). UV radiation is defined as that portion of the electromagnetic spectrum described by wavelengths from 100 to 400 nm.For convenience of classification, the UV spectrum has been separated into three different wavelength bands: UV-A (long wavelengths, range: 320-400 nm), UV-B (midrange wavelengths, range: 290-320 nm), and UV-C (short wavelengths, range: 100-290 nm) (126 ).Commercially available UV lamps used for germicidal purposes are low-pressure mercury vapor lamps ( 127) that emit radiant energy in the UV-C range, predominantly at a wavelength of 253.7 nm (128 ). # A. Applications UVGI can be used as a method of air disinfection to supplement other engineering controls.Two systems of UVGI can be used for this purpose: duct irradiation and upper-room air irradiation. # Duct irradiation Purpose: To inactivate tubercle bacilli without exposing persons to UVGI. In duct irradiation systems, UV lamps are placed inside ducts that remove air from rooms to disinfect the air before it is recirculated.When UVGI duct systems are properly designed, installed, and maintained, high levels of UV radiation may be produced in the duct work.The only potential for human exposure to this radiation occurs during maintenance operations. Duct irradiation may be used: - In a TB isolation room or treatment room to recirculate air from the room, through a duct containing UV lamps, and back into the room.This recirculation method can increase the overall room airflow but does not increase the supply of fresh outside air to the room. - In other patients' rooms and in waiting rooms, emergency rooms, and other general-use areas of a facility where patients with undiagnosed TB could potentially contaminate the air, to recirculate air back into the general ventilation. Duct-irradiation systems are dependent on airflow patterns within a room that ensure that all or nearly all of the room air circulates through the duct. # Upper-room air irradiation Purpose: To inactivate tubercle bacilli in the upper part of the room, while minimizing radiation exposure to persons in the lower part of the room. In upper-room air irradiation, UVGI lamps are suspended from the ceiling or mounted on the wall.The bottom of the lamp is shielded to direct the radiation upward but not downward.The system depends on air mixing to take irradiated air from the upper to the lower part of the room, and nonirradiated air from the lower to the upper part.The irradiated air space is much larger than that in a duct system. UVGI has been effective in killing bacteria under conditions where air mixing was accomplished mainly by convection.For example, BCG was atomized in a room that did not have supplemental ventilation (120 ), and in another study a surrogate bacteria, Serratia marcesens, was aerosolized in a room with a ventilation rate of 6 ACH (129 ).These reports estimated the effect of UVGI to be equivalent to 10 and 39 ACH, respectively, for the organisms tested, which are less resistant to UVGI than M. tuberculosis (120 ).The addition of fans or some heating/air conditioning arrangements may double the effectiveness of UVGI lamps (130)(131)(132).Greater rates of ventilation, however, may decrease the length of time the air is irradiated, thus decreasing the killing of bacteria (117,129 ).The optimal relationship between ventilation and UVGI is not known.Air irradiation lamps used in corridors have been effective in killing atomized S. marcesens (133 ).Use of UVGI lamps in an outpatient room has reduced culturable airborne bacteria by 14%-19%.However, the irradiation did not reduce the concentration of gram-positive, rod-shaped bacteria; although fast-growing mycobacteria were cultured, M. tuberculosis could not be recovered from the room's air samples because of fungal overgrowth of media plates (134 ). Upper-room air UVGI irradiation may be used: - In isolation or treatment rooms as a supplemental method of air cleaning. - In other patients' rooms and in waiting rooms, emergency rooms, corri- dors, and other central areas of a facility where patients with undiagnosed TB could potentially contaminate the air. Determinants of UVGI effectiveness include room configuration, UV lamp placement, and the adequacy of airflow patterns in bringing contaminated air into contact with the irradiated upper-room space.Air mixing may be facilitated by supplying cool air near the ceiling in rooms where warmer air (or a heating device) is present below.The ceiling should be high enough for a large volume of upper-room air to be irradiated without HCWs and patients being overexposed to UV radiation. # B. Limitations Because the clinical effectiveness of UV systems varies, and because of the risk for transmission of M. tuberculosis if a system malfunctions or is maintained improperly, UVGI is not recommended for the following specific applications: 1.Duct systems using UVGI are not recommended as a substitute for HEPA filters if air from isolation rooms must be recirculated to other areas of a facility. 2.UVGI alone is not recommended as a substitute for HEPA filtration or local exhaust of air to the outside from booths, tents, or hoods used for cough-inducing procedures. 3.UVGI is not a substitute for negative pressure. The use of UV lamps and HEPA filtration in a single unit would not be expected to have any infection-control benefits not provided by use of the HEPA filter alone. The effectiveness of UVGI in killing airborne tubercle bacilli depends on the intensity of UVGI, the duration of contact the organism has with the irradiation, and the relative humidity (66,108,111 ).Humidity can have an adverse effect on UVGI effectiveness at levels >70% relative humidity for S. marcescens (135 ).The interaction of these factors has not been fully defined, however, making precise recommendations for individual UVGI installations difficult to develop. Old lamps or dust-covered UV lamps are less effective; therefore, regular maintenance of UVGI systems is crucial. # C. Safety Issues Short-term overexposure to UV radiation can cause erythema and keratoconjunctivitis (136,137 ).Broad-spectrum UV radiation has been associated with increased risk for squamous and basal cell carcinomas of the skin (138 ).UV-C was recently classified by the International Agency for Research on Cancer as "probably carcinogenic to humans (Group 2A)" (138 ).This classification is based on studies suggesting that UV-C radiation can induce skin cancers in animals; DNA damage, chromosomal aberrations and sister chromatid exchange and transformation in human cells in vitro; and DNA damage in mammalian skin cells in vivo.In the animal studies, a contribution of UV-B to the tumor effects could not be excluded, but the effects were greater than expected for UV-B alone (138 ).Although some recent studies have demonstrated that UV radiation can activate HIV gene promoters (i.e., the genes in HIV that prompt replication of the virus) in laboratory samples of human cells (139)(140)(141)(142)(143)(144), the implications of these in vitro findings for humans are unknown. In 1972, the National Institute for Occupational Safety and Health (NIOSH) published a recommended exposure limit (REL) for occupational exposure to UV radiation (136 ).The REL is intended to protect workers from the acute effects of UV exposure (e.g., erythema and photokeratoconjunctivitis).However, photosensitive persons and those exposed concomitantly to photoactive chemicals may not be protected by the recommended standard. # D. Exposure Criteria for UV Radiation The NIOSH REL for UV radiation is wavelength dependent because different wavelengths of UV radiation have different adverse effects on the skin and eyes (136 ).Relative spectral effectiveness (Sλ) is used to compare various UV sources with a source producing UV radiation at 270 nm, the wavelength of maximum ocular sensitivity.For example, the S λ at 254 nm is 0.5; therefore, twice as much energy is required at 254 nm to produce an identical biologic effect at 270 nm (136 ).
Thus, at 254 nm, the NIOSH REL is 0.006 joules per square centimeter (J/cm 2 ); and at 270 nm, it is 0.003 J/cm 2 . For germicidal lamps that emit radiant energy predominantly at a wavelength of 254 nm, proper use of the REL requires that the measured irradiance level (E) in microwatts per square centimeter (µW/cm 2 ) be multiplied by the relative spectral effectiveness at 254 nm (0.5) to obtain the effective irradiance (E eff ).The maximum permissible exposure time can then be determined for selected values of Eeff (Table S3-3), or it can be calculated (in seconds) by dividing 0.003 J/cm 2 (the NIOSH REL at 270 nm) by Eeff in µW/cm 2 (136,150 ). To protect HCWs who are exposed to germicidal UV radiation for 8 hours per workday, the measured irradiance (E) should be ≤0.2 µW/cm 2 .This is calculated by obtaining E eff (0.1 µW/cm 2 ) (Table S3-3) and then dividing this value by S λ (0.5). # E. Maintenance and Monitoring # Labelling and posting Warning signs should be posted on UV lamps and wherever high-intensity (i.e., UV exposure greater than the REL) germicidal UV irradiation is present (e.g., upper-room air space and accesses to ducts ) to alert maintenance staff or other HCWs of the hazard.Some examples are shown below: # Maintenance Because the intensity of UV lamps fluctuates as they age, a schedule for replacing the lamps should be developed.The schedule can be determined from either a time/use log or a system based on cumulative time.The tube should be checked periodically for dust build-up, which lessens the output of UVGI.If the tube is dirty, it should be allowed to cool, then cleaned with a damp cloth.Tubes should be replaced if they stop glowing or if they flicker to an objectionable extent.Maintenance personnel must turn off all UV tubes before entering the upper part of the room or before accessing ducts for any purpose.Only a few seconds of direct exposure to the intense UV radiation in the upper-room air space or in ducts can cause burns.Protective equipment (e.g., gloves and goggles ) should be worn if exposure greater than the recommended standard is anticipated. Banks of UVGI tubes can be installed in ventilating ducts.Safety devices should be used on access doors to eliminate hazard to maintenance personnel.For duct irradiation systems, the access door for servicing the lamps should have an inspection window- through which the lamps are checked periodically for dust build-up and malfunctioning.The access door should have a warning sign written in languages appropriate for maintenance personnel to alert them to the health hazard of looking directly at bare tubes.The lock for this door should have an automatic electric switch or other device that turns off the lamps when the door is opened. Two types of fixtures are used in upper-room air irradiation: wall-mounted fixtures that have louvers to block downward radiation and ceilingmounted fixtures that have baffles to block radiation below the horizontal plane of the UV tube.The actual UV tube in either type of fixture must not be visible from any normal position in the room.Light switches that can be locked should be used, if possible, to prevent injury to personnel who might unintentionally turn the lamps on during maintenance procedures. *Ordinary glass (not quartz) is sufficient to filter out UV radiation. # CAUTION # ULTRAVIOLET ENERGY: TURN OFF LAMPS BEFORE ENTERING UPPER ROOM # CAUTION # ULTRAVIOLET ENERGY: PROTECT EYES & SKIN In most applications, properly shielding the UV lamps to provide protection from most, if not all, of the direct UV radiation is not difficult.However, radiation reflected from glass, polished metal, and high-gloss ceramic paints can be harmful to persons in the room, particularly if more than one UV lamp is in use.Surfaces in irradiated rooms that can reflect UVGI into occupied areas of the room should be covered with non-UV reflecting material. # Monitoring A regularly scheduled evaluation of the UV intensity to which HCWs, patients, and others are exposed should be conducted. UV measurements should be made in various locations within a room using a detector designed to be most sensitive at 254 nm.Equipment used to measure germicidal UV radiation should be maintained and calibrated on a regular schedule. A new UV installation must be carefully checked for hot spots (i.e., areas of the room where the REL is exceeded) by an industrial hygienist or other person knowledgeable in making UV measurements.UV radiation levels should not exceed those in the recommended guidelines. # Supplement 4: Respiratory Protection # I. Considerations for Selection of Respirators Personal respiratory protection should be used by a) persons entering rooms where patients with known or suspected infectious TB are being isolated, b) persons present during cough-inducing or aerosol-generating procedures performed on such patients, and c) persons in other settings where administrative and engineering controls are not likely to protect them from inhaling infectious airborne droplet nuclei.These other settings should be identified on the basis of the facility's risk assessment. Although data regarding the effectiveness of respiratory protection from many hazardous airborne materials have been collected, the precise level of effectiveness in protecting HCWs from M. tuberculosis transmission in health-care settings has not been determined.Information concerning the transmission of M. tuberculosis is incomplete.Neither the smallest infectious dose of M. tuberculosis nor the highest level of exposure to M. tuberculosis at which transmission will not occur has been defined conclusively (59,151,152 ).Furthermore, the size distribution of droplet nuclei and the number of particles containing viable M. tuberculosis that are expelled by infectious TB patients have not been defined adequately, and accurate methods of measuring the concentration of infectious droplet nuclei in a room have not been developed. Nevertheless, in certain settings the administrative and engineering controls may not adequately protect HCWs from airborne droplet nuclei (e.g., in TB isolation rooms, treatment rooms in which cough-inducing or aerosol-generating procedures are performed, and ambulances during the transport of infectious TB patients).Respiratory protective devices used in these settings should have characteristics that are suitable for the organism they are protecting against and the settings in which they are used. # A. Performance Criteria for Personal Respirators for Protection Against Transmission of M. tuberculosis Respiratory protective devices used in health-care settings for protection against M. tuberculosis should meet the following standard criteria.These criteria are based on currently available information, including a) data on the effectiveness of respiratory protection against noninfectious hazardous materials in workplaces other than health-care settings and on an interpretation of how these data can be applied to respiratory protection against M. tuberculosis; b) data on the efficiency of respirator filters in filtering biological aerosols; c) data on face-seal leakage; and d) data on the characteristics of respirators that were used in conjunction with administrative and engineering controls in outbreak settings where transmission to HCWs and patients was terminated. 1.The ability to filter particles 1 µm in size in the unloaded state with a filter efficiency of ≥95% (i.e., filter leakage of ≤5%), given flow rates of up to 50 L per minute. Available data suggest that infectious droplet nuclei range in size from 1 µm to 5 µm; therefore, respirators used in health-care settings should be able to efficiently filter the smallest particles in this range.Fifty liters per minute is a reasonable estimate of the highest airflow rate an HCW is likely to achieve during breathing, even while performing strenuous work activities. 2.The ability to be qualitatively or quantitatively fit tested in a reliable way to obtain a face-seal leakage of ≤10% (54,55 ). 3.The ability to fit the different facial sizes and characteristics of HCWs, which can usually be met by making the respirators available in at least three sizes. 4.The ability to be checked for facepiece fit, in accordance with OSHA standards and good industrial hygiene practice, by HCWs each time they put on their respirators (54,55 ). In some settings, HCWs may be at risk for two types of exposure: a) inhalation of M. tuberculosis and b) mucous membrane exposure to fluids that may contain bloodborne pathogens.In these settings, protection against both types of exposure should be used. When operative procedures (or other procedures requiring a sterile field) are performed on patients who may have infectious TB, respiratory protection worn by the HCW should serve two functions: a) it should protect the surgical field from the respiratory secretions of the HCW and b) it should protect the HCW from infectious droplet nuclei that may be expelled by the patient or generated by the procedure.Respirators with expiration valves and positivepressure respirators do not protect the sterile field; therefore, a respirator that does not have a valve and that meets the criteria in Supplement 4, Section I.A, should be used. # B. Specific Respirators The OSHA respiratory protection standard requires that all respiratory protective devices used in the workplace be certified by NIOSH.- NIOSH-approved HEPA respirators are the only currently available air-purifying respirators that meet or exceed the standard performance criteria stated above.However, the NIOSH certification procedures are currently being revised (153 ).Under the proposed revision, filter materials would be tested at a flow rate of 85 L/min for penetration by particles with a median aerodynamic diameter of 0.3 µm and, if certified, would be placed in one of the following categories: type A, which has ≥99.97% efficiency (similar to current HEPA filter media); type B, ≥99% efficiency; or type C, ≥95% efficiency.According to this proposed scheme, type C filter material would meet or exceed the standard performance criteria specified in this document. # C. The Effectiveness of Respiratory Protective Devices The following information, which is based on experience with respiratory protection in the industrial setting, summarizes the available data about the effectiveness of respiratory protection against hazardous airborne materials.Data regarding protection against transmission of M. tuberculosis are not available. The parameters used to determine the effectiveness of a respiratory protective device are face-seal efficacy and filter efficacy. # Face-seal leakage Face-seal leakage compromises the ability of particulate respirators to protect HCWs from airborne materials (154)(155)(156).A proper seal between the respirator's sealing surface and the face of the person wearing the respirator is essential for effective and reliable performance of any negativepressure respirator.This seal is less critical, but still important, for positive-pressure respirators.Face-seal leakage can result from various factors, including incorrect facepiece size or shape, incorrect or defective facepiece sealing-lip, beard growth, perspiration or facial oils that can cause facepiece slippage, failure to use all the head straps, incorrect positioning of the facepiece on the face, incorrect head strap tension or position, improper respirator maintenance, and respirator damage. Every time a person wearing a negative-pressure particulate respirator inhales, a negative pressure (relative to the workplace air) is created inside the facepiece.Because of this negative pressure, air containing contaminants can take a path of least resistance into the respirator-through leaks at the face-seal interface-thus avoiding the higher-resistance filter material.Currently available, cup-shaped, disposable particulate respirators have from 0 to 20% face-seal leakage (55,154 ).This face-seal leakage results from the variability of the human face and from limitations in the respirator's design, construction, and number of sizes available.The face-seal leakage is probably higher if the respirator is not fitted properly to the HCW's face, tested for an adequate fit by a qualified person, and then checked for fit by the HCW every time the respirator is put on.Face-seal leakage may be reduced to <10% with improvements in design, a greater variety in available sizes, and appropriate fit testing and fit checking. In comparison with negative-pressure respirators, positive-pressure respirators produce a positive pressure inside the facepiece under most conditions of use.For example, in a PAPR, a blower forcibly draws ambient air through HEPA filters, then delivers the filtered air to the facepiece.This air is blown into the facepiece at flow rates that generally exceed the expected inhalation flow rates.The positive pressure inside the facepiece reduces face-seal leakage to low levels, particularly during the relatively low inhalation rates expected in health-care settings.PAPRs with a tightfitting facepiece have <2% face-seal leakage under routine conditions (55 ). Powered-air respirators with loose-fitting facepieces, hoods, or helmets have <4% face-seal leakage under routine conditions (55 ).Thus, a PAPR may offer lower levels of face-seal leakage than nonpowered, half-mask respirators.Full facepiece, nonpowered respirators have the same leakage (i.e., <2%) as PAPRs. Another factor contributing to face-seal leakage of cup-shaped, disposable respirators is that some of these respirators are available in only one size.A single size may produce higher leakage for persons who have smaller or difficult-to-fit faces (157 ).The facepieces used for some reusable (including HEPA and replaceable filter, negative-pressure) and all positivepressure particulate air-purifying respirators are available in as many as three different sizes. # Filter leakage Aerosol leakage through respirator filters depends on at least five independent variables: a) the filtration characteristics for each type of filter, b) the size distribution of the droplets in the aerosol, c) the linear velocity through the filtering material, d) the filter loading (i.e., the amount of contaminant deposited on the filter), and e) any electrostatic charges on the filter and on the droplets in the aerosol (158 ). When HEPA filters are used in particulate air-purifying respirators, filter efficiency is so high (i.e., effectively 100%) that filter leakage is not a consideration.Therefore, for all HEPA-filter respirators, virtually all inward leakage of droplet nuclei occurs at the respirator's face seal. # Fit testing Fit testing is part of the respiratory protection program required by OSHA for all respiratory protective devices used in the workplace.A fit test determines whether a respiratory protective device adequately fits a particular HCW.The HCW may need to be fit tested with several devices to determine which device offers the best fit.However, fit tests can detect only the leakage that occurs at the time of the fit testing, and the tests cannot distinguish face-seal leakage from filter leakage. Determination of facepiece fit can involve qualitative or quantitative tests (55 ).A qualitative test relies on the subjective response of the HCW being fit tested.A quantitative test uses detectors to measure inward leakage. Disposable, negative-pressure particulate respirators can be qualitatively fit tested with aerosolized substances that can be tasted, although the results of this testing are limited because the tests depend on the subjective response of the HCW being tested.Quantitative fit testing of disposable negative-pressure particulate respirators can best be performed if the manufacturer provides a test respirator with a probe for this purpose. Replaceable filter, negative-pressure particulate respirators and all positive-pressure particulate respirators can be fit tested reliably, both qualitatively and quantitatively, when fitted with HEPA filters. # Fit checking A fit check is a maneuver that an HCW performs before each use of the respiratory protective device to check the fit.The fit check can be performed according to the manufacturer's facepiece fitting instructions by using the applicable negative-pressure or positive-pressure test. Some currently available cup-shaped, disposable negative-pressure particulate respirators cannot be fit checked reliably by persons wearing the devices because occluding the entire surface of the filter is difficult.Strategies for overcoming these limitations are being developed by respirator manufacturers. # Reuse of respirators Conscientious respirator maintenance should be an integral part of an overall respirator program.This maintenance applies both to respirators with replaceable filters and respirators that are classified as disposable but that are reused.Manufacturers' instructions for inspecting, cleaning, and maintaining respirators should be followed to ensure that the respirator continues to function properly (55 ). When respirators are used for protection against noninfectious aerosols (e.g., wood dust), which may be present in the air in heavy concentrations, the filter material may become occluded with airborne material.This occlusion may result in an uncomfortable breathing resistance.In healthcare settings where respirators are used for protection against biological aerosols, the concentration of infectious particles in the air is probably low; thus, the filter material in a respirator is very unlikely to become occluded with airborne material.In addition, there is no evidence that particles impacting on the filter material in a respirator are re-aerosolized easily.For these reasons, the filter material used in respirators in the health-care setting should remain functional for weeks to months.Respirators with replaceable filters are reusable, and a respirator classified as disposable may be reused by the same HCW as long as it remains functional. Before each use, the outside of the filter material should be inspected.If the filter material is physically damaged or soiled, the filter should be changed (in the case of respirators with replaceable filters) or the respirator discarded (in the case of disposable respirators).Infection-control personnel should develop standard operating procedures for storing, reusing, and disposing of respirators that have been designated as disposable and for disposing of replaceable filter elements. # II.Implementing a Personal Respiratory Protection Program If personal respiratory protection is used in a health-care setting, OSHA requires that an effective personal respiratory protection program be developed, implemented, administered, and periodically reevaluated (54,55 ). All HCWs who need to use respirators for protection against infection with M. tuberculosis should be included in the respiratory protection program.Visitors to TB patients should be given respirators to wear while in isolation rooms, and they should be given general instructions on how to use their respirators. The number of HCWs included in the respiratory protection program in each facility will vary depending on a) the number of potentially infectious TB patients, b) the number of rooms or areas to which patients with suspected or confirmed infectious TB are admitted, and c) the number of HCWs needed in these rooms or areas.
Where respiratory protection programs are required, they should include enough HCWs to provide adequate care for a patient with known or suspected TB should such a patient be admitted to the facility.However, administrative measures should be used to limit the number of HCWs who need to enter these rooms or areas, thus limiting the number of HCWs who need to be included in the respiratory protection program. Information regarding the development and management of a respiratory protection program is available in technical training courses that cover the basics of personal respiratory protection.Such courses are offered by various organizations, such as NIOSH, OSHA, and the American Industrial Hygiene Association.Similar courses are available from private contractors and universities. To be effective and reliable, respiratory protection programs must contain at least the following elements (55,154 ): 1.Assignment of responsibility.Supervisory responsibility for the respiratory protection program should be assigned to designated persons who have expertise in issues relevant to the program, including infectious diseases and occupational health. 2.Standard operating procedures.Written standard operating procedures should contain information concerning all aspects of the respiratory protection program. 3.Medical screening.HCWs should not be assigned a task requiring use of respirators unless they are physically able to perform the task while wearing the respirator.HCWs should be screened for pertinent medical conditions at the time they are hired, then rescreened periodically (55 ).The screening could occur as infrequently as every 5 years.The screening process should begin with a general screening (e.g., a questionnaire) for pertinent medical conditions, and the results of the screening should then be used to identify HCWs who need further evaluation.Routine physical examination or testing with chest radiographs or spirometry is not necessary or required. Few medical conditions preclude the use of most negative-pressure particulate respirators.HCWs who have mild pulmonary or cardiac conditions may report discomfort with breathing when wearing negative-pressure particulate respirators, but these respirators are unlikely to have adverse health effects on the HCWs.Those HCWs who have more severe cardiac or pulmonary conditions may have more difficulty than HCWs with similar but milder conditions if performing duties while wearing negative-pressure respirators.Furthermore, these HCWs may be unable to use some PAPRs because of the added weight of these respirators. Training.HCWs who wear respirators and the persons who supervise them should be informed about the necessity for wearing respirators and the potential risks associated with not doing so.This training should also include at a minimum: - The nature, extent, and specific hazards of M. tuberculosis transmission in their respective health-care facility. - A description of specific risks for TB infection among persons exposed to M. tuberculosis, of any subsequent treatment with INH or other chemoprophylactic agents, and of the possibility of active TB disease. - A description of engineering controls and work practices and the reasons why they do not eliminate the need for personal respiratory protection. - An explanation for selecting a particular type of respirator, how the respirator is properly maintained and stored, and the operation, capabilities, and limitations of the respirator provided. - Instruction in how the HCW wearing the respirator should inspect, put on, fit check, and correctly wear the provided respirator (i.e., achieve and maintain proper face-seal fit on the HCW's face). - An opportunity to handle the provided respirator and learn how to put it on, wear it properly, and check the important parts. - Instruction in how to recognize an inadequately functioning respirator. 5.Face-seal fit testing and fit checking.HCWs should undergo fit testing to identify a respirator that adequately fits each individual HCW.The HCW should receive fitting instructions that include demonstrations and practice in how the respirator should be worn, how it should be adjusted, and how to determine if it fits properly.The HCW should be taught to check the facepiece fit before each use.6.Respirator inspection, cleaning, maintenance, and storage.Conscientious respirator maintenance should be an integral part of an overall respirator program.This maintenance applies both to respirators with replaceable filters and respirators that are classified as disposable but that are reused.Manufacturers' instructions for inspecting, cleaning, and maintaining respirators should be followed to ensure that the respirator continues to function properly (55 ). 7.Periodic evaluation of the personal respiratory protection program.The program should be evaluated completely at least once a year, and both the written operating procedures and program administration should be revised as necessary based on the results of the evaluation.Elements of the program that should be evaluated include work practices and employee acceptance of respirator use (i.e., subjective comments made by employees concerning comfort during use and interference with duties). # Supplement 5: Decontamination-Cleaning, Disinfecting, and Sterilizing of Patient-Care Equipment Equipment used on patients who have TB is usually not involved in the transmission of M. tuberculosis, although transmission by contaminated bronchoscopes has been demonstrated (159,160 ).Guidelines for cleaning, disinfecting, and sterilizing equipment have been published (161,162 ).The rationale for cleaning, disinfecting, or sterilizing patient-care equipment can be understood more readily if medical devices, equipment, and surgical materials are divided into three general categories.These categories-critical, semicritical, and noncritical items-are defined by the potential risk for infection associated with their use (163,164 ). Critical items are instruments that are introduced directly into the bloodstream or into other normally sterile areas of the body (e.g., needles, surgical instruments, cardiac catheters, and implants).These items should be sterile at the time of use. Semicritical items are those that may come in contact with mucous membranes but do not ordinarily penetrate body surfaces (e.g., noninvasive flexible and rigid fiberoptic endoscopes or bronchoscopes, endotracheal tubes, and anesthesia breathing circuits).Although sterilization is preferred for these instruments, high-level disinfection that destroys vegetative microorganisms, most fungal spores, tubercle bacilli, and small nonlipid viruses may be used.Meticulous physical cleaning of such items before sterilization or high-level disinfection is essential. Noncritical items are those that either do not ordinarily touch the patient or touch only the patient's intact skin (e.g., crutches, bedboards, blood pressure cuffs, and various other medical accessories).These items are not associated with direct transmission of M. tuberculosis, and washing them with detergent is usually sufficient. Health-care facility policies should specify whether cleaning, disinfecting, or sterilizing an item is necessary to decrease the risk for infection.Decisions about decontamination processes should be based on the intended use of the item, not on the diagnosis of the patient for whom the item was used.Selection of chemical disinfectants depends on the intended use, the level of disinfection required, and the structure and material of the item to be disinfected. Although microorganisms are ordinarily found on walls, floors, and other environmental surfaces, these surfaces are rarely associated with transmission of infections to patients or HCWs.This is particularly true with organisms such as M. tuberculosis, which generally require inhalation by the host for infection to occur.Therefore, extraordinary attempts to disinfect or sterilize environmental surfaces are not indicated. If a detergent germicide is used for routine cleaning, a hospital-grade, EPA-approved germicide/disinfectant that is not tuberculocidal can be used.The same routine daily cleaning procedures used in other rooms in the facility should be used to clean TB isolation rooms, and personnel should follow isolation practices while cleaning these rooms.For final cleaning of the isolation room after a patient has been discharged, personal protective equipment is not necessary if the room has been ventilated for the appropriate amount of time (Table S3-1). Single-pass ventilation: Ventilation in which 100% of the air supplied to an area is exhausted to the outside. # Smear (AFB smear): A laboratory technique for visualizing mycobacteria.The specimen is smeared onto a slide and stained, then examined using a microscope.Smear results should be available within 24 hours.In TB, a large number of mycobacteria seen on an AFB smear usually indicates infectiousness.However, a positive result is not diagnostic of TB because organisms other than M. tuberculosis may be seen on an AFB smear (e.g., nontuberculous mycobacteria). Source case: A case of TB in an infectious person who has transmitted M. tuberculosis to another person or persons. # Source control: Controlling a contaminant at the source of its generation, which prevents the spread of the contaminant to the general work space. Specimen: Any body fluid, secretion, or tissue sent to a laboratory where smears and cultures for M. tuberculosis will be performed (e.g., sputum, urine, spinal fluid, and material obtained at biopsy). Sputum: Phlegm coughed up from deep within the lungs.If a patient has pulmonary disease, an examination of the sputum by smear and culture can be helpful in evaluating the organism responsible for the infection.Sputum should not be confused with saliva or nasal secretions. # Sputum induction: A method used to obtain sputum from a patient who is unable to cough up a specimen spontaneously.The patient inhales a saline mist, which stimulates a cough from deep within the lungs. Sputum smear, positive: AFB are visible on the sputum smear when viewed under a microscope.Persons with a sputum smear positive for AFB are considered more infectious than those with smear-negative sputum. Streptomycin: A first-line, injectable anti-TB drug. Symptomatic: Having symptoms that may indicate the presence of TB or another disease (see Asymptomatic). # TB case: A particular episode of clinically active TB.This term should be used only to refer to the disease itself, not the patient with the disease.By law, cases of TB must be reported to the local health department. # TB infection: A condition in which living tubercle bacilli are present in the body but the disease is not clinically active.Infected persons usually have positive tuberculin reactions, but they have no symptoms related to the infection and are not infectious.However, infected persons remain at lifelong risk for developing disease unless preventive therapy is given. # Transmission: The spread of an infectious agent from one person to another.The likelihood of transmission is directly related to the duration and intensity of exposure to M. tuberculosis (see Exposure). Treatment failures: TB disease in patients who do not respond to chemotherapy and in patients whose disease worsens after having improved initially. Tubercle bacilli: M. tuberculosis organisms. # Tuberculin skin test: A method used to evaluate the likelihood that a person is infected with M. tuberculosis.A small dose of PPD-tuberculin is injected just beneath the surface of the skin, and the area is examined 48-72 hours after the injection.A reaction is measured according to the size of the induration.The classification of a reaction as positive or negative depends on the patient's medical history and various risk factors (see Mantoux test, PPD test). # Tuberculosis (TB): A clinically active, symptomatic disease caused by an organism in the M. tuberculosis complex (usually M. tuberculosis or, rarely, M. bovis or M. africanum). # Two-step testing: A procedure used for the baseline testing of persons who will periodically receive tuberculin skin tests (e.g., HCWs) to reduce the likelihood of mistaking a boosted reaction for a new infection.If the initial tuberculin-test result is classified as negative, a second test is repeated 1-3 weeks later.If the reaction to the second test is positive, it probably represents a boosted reaction.If the second test result is also negative, the person is classified as not infected.A positive reaction to a subsequent test would indicate new infection (i.e., a skin-test conversion) in such a person. # Ultraviolet germicidal irradiation (UVGI): The use of ultraviolet radiation to kill or inactivate microorganisms. Ultraviolet germicidal irradiation (UVGI) lamps: Lamps that kill or inactivate microorganisms by emitting ultraviolet germicidal radiation, predominantly at a wavelength of 254 nm (intermediate light waves between visible light and X-rays).UVGI lamps can be used in ceiling or wall fixtures or within air ducts of ventilation systems. Ventilation, dilution: An engineering control technique to dilute and remove airborne contaminants by the flow of air into and out of an area.Air that contains droplet nuclei is removed and replaced by contaminant-free air.If the flow is sufficient, droplet nuclei become dispersed, and their concentration in the air is diminished. Ventilation, local exhaust: Ventilation used to capture and remove airborne contaminants by enclosing the contaminant source (i.e., the patient) or by placing an exhaust hood close to the contaminant source. Virulence: The degree of pathogenicity of a microorganism as indicated by the severity of the disease produced and its ability to invade the tissues of a host.M. tuberculosis is a virulent organism. # List of Tables # List of Figures
# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR PHOSGENE recommends that worker exposure to phosgene in 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 10-hour workday, 40-hour workweek over a working lifetime.Compliance with the standard should therefore prevent adverse effects of phosgene 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 revision as necessary. "Phosgene" is defined as gaseous or liquified phosgene.Synonyms for phosgene include carbonyl chloride, carbon oxychloride, chlorofomyl chloride, and CG (designation used by military agencies). "Occupational exposure to phosgene" is defined as exposure above half the recommended time-weighted average (TWA) environmental limit.Exposure at lower concentrations will not require adherence to the following Sections except "Overexposure" is defined as known or suspected exposure above either the TWA or ceiling concentrations, or any exposure which leads to development of pulmonary symptoms.Procedures for sampling, calibration of equipment, and analysis of environmental samples shall be as provided in Appendices I and II, or by any method shown to be equivalent in precision, accuracy, and sensitivity to the methods specified. Section 2 -Medical (a) Comprehensive preplacement and annual medical examinations shall be made available to all workers to be occupationally exposed to phosgene unless a different frequency is indicated by professional medical judgment based on such factors as emergencies, variations in work periods, and preexisting health status of individual workers. (b) These examinations shall include, but shall not be limited to: (1) Comprehensive or interim medical and work histories. (2) A comprehensive medical examination giving particular attention to pulmonary function.Preplacement and follow-up pulmonary function tests shall be performed and shall include the forced vital 2 capacity (FVC), the one-second forced expiratory volume (FEV 1), and the forced midexpiratory flow (FEF ; a preplacement chest X-ray shall be obtained.The possibility of increased risk for workers with preexisting cardiovascular or pulmonary diseases should be considered and, when appropriate, the workers should be given counseling on the possibility of increased risk. Return to work after an absence for sickness due to phosgene overexposure shall require medical approval. (3) A judgment of the worker's ability to use a negative or positive pressure respirator. (c) Proper medical management shall be provided for workers overexposed to phosgene. In case of known or suspected overexposure to phosgene, first aid measures shall be taken immediately, followed by prompt medical evaluation and care.Overexposed persons should not be permitted any unnecessary physical exertion.They should be carried to a vehicle for subsequent transportation to receive medical assistance.Pressurized oxygen and attendants trained in its use shall be available in the event they are needed for persons in respiratory distress.In case of skin or eye contact with liquid phosgene, contaminated clothing shall be removed immediately and the exposed body areas flushed with copious amounts of water.The plant physician or medical consultant shall be informed of any suspected overexposure to phosgene and shall determine the need for X-ray or Open containers with care. Have respiratory protection available for emergency. # FIRST AID CALL A PHYSICIAN IMMEDIATELY In case of inhalation, remove victim to uncontaminated atmosphere. If breathing stops, administer artificial respiration.Do not allow victim to walk or exercise. In case of liquid contact, immediately flush skin or eyes with water. Remove contaminated clothing without delay and dispose of liquid properly. # (b) The following warning sign shall be affixed in a readily visible location at or near entrances to areas in which phosgene is stored, handled, used, or formed: # CONTAINS PHOSGENE EXTREME HEALTH HAZARD Harmful or fatal if inhaled, may cause delayed lung injury. In emergency, enter only if wearing respiratory, eye, and skin protection.Phosgene respiratory protection located at (specific locations to be supplied by employer).Unauthorized persons keep out. This sign shall be printed both in English and in the predominant language of non-English-speaking workers, if any.All employees shall be trained and informed of the hazardous area with special instruction given to illiterate workers. (c) All systems, piping, and associated equipment containing phosgene shall be plainly marked for positive identification in accordance with American National Standard A13. .Shut-off valves shall be conspicuously labeled.Phosgene containers in use shall be plainly marked "In Use" to distinguish them from those not in use. (1) In addition to the respiratory protection specified in Table 1-1, personnel performing emergency operations involving exposure to liquid phosgene shall wear one-piece suits, impervious to phosgene and tight at the ankles, wrists, and around the neck and face.The suits shall be ventilated with supplied air, preferably cooled, or time in the work area shall be limited with due consideration to the heat stress factors involved.Impervious gloves and boots shall also be worn.Such protective clothing shall be available at a convenient location outside the contaminated area. The employer shall insure a sufficient supply and adequate maintenance of protective clothing. # (b) Eye Protection Personnel handling liquid phosgene in situations where eye contact can occur shall have eye protection afforded by full-face respiratory protection as specified in Table 1- as amended, shall be established and enforced by the employer.Only appropriate respirators as described in Table 1-1 shall be used. 2ppm Greater than 2 ppm or emergency situations (1) Any supplied-air respirator; or (2) Any self-contained breathing apparatus. (1) Any supplied-air respirator with a full facepiece, helmet, or hood; or (2) Any self-contained breathing apparatus with a full facepiece. (1) Self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode; or occupational exposure to phosgene shall have at least 2 sets of selfcontained breathing apparatus readily available in nearby locations which do not require entry into, or passage through, a contaminated area for access. (4) Respirators specified for use in higher concentrations of phosgene may be used in atmospheres of lower concentrations. (5) Employees shall be trained and drilled in the use of respirators assigned to them and in testing for leakage. Canisters shall be discarded and replaced with fresh canisters after use.Unused canisters shall be discarded and replaced when the seal is broken or when the shelf life, as recommended by the manufacturer, is exceeded. # Section 5 -Informing Employees of Hazards from Phosgene At the beginning of employment, workers who will work in areas required to be posted in accordance with Section 3(b) shall be informed of the hazards from phosgene, symptoms of overexposure, emergency procedures, and precautions to ensure safe use and to minimize exposure.First aid procedures shall be included.This information shall be posted in the work place and kept on file, readily accessible to the worker. A continuing educational program shall be instituted for workers whose jobs may involve occupational exposure to phosgene.This is to ensure that all such workers have current knowledge of job hazards, maintenance procedures, and clean-up methods, and that they know how to use respiratory protective equipment and protective clothing.Workers should be advised that the detection of the odor of phosgene at any time indicates the need for immediate corrective procedures or withdrawal from the area. First-line supervisors shall be thoroughly informed of these hazards and procedures and should participate in the education of workers.For all work areas in which there is a potential for emergencies, procedures specified below, as well as any other procedures appropriate for a specific operation or process, shall be formulated in advance and employees shall be instructed and drilled in their implementation. Procedures shall Include prearranged plans for: (A) immediate evacuation of overexposed workers; (B) transportation of overexposed workers; (C) any necessary calls for assistance, including alerting medical facilities of the impending arrival of overexposed workers, and calls to suppliers or manufacturers of phosgene for any necessary technical advice; (D) designation of medical receiving facilities and names of physicians trained in phosgene emergency procedures; (E) reentry for maintenance or clean-up purposes of areas where phosgene leaks or spills have occurred. (2) Approved eye, skin, and respiratory protection as specified in Section 4 shall be used by personnel essential to emergency operations. Water shall not be used on phosgene leaks because accelerated corrosion of metal by phosgene in the presence of moisture will quickly make the leak worse. If possible, phosgene emissions shall be directed to an alkali scrubber or to process (ie, routed by means of appropriate valving within a closed system to a secondary holding vessel or neutralization system). Containers leaking liquid phosgene should he positioned so that gaseous phosgene is discharged through the leak until control is effected.enclosed processes is the preferred method of control for phosgene.Local exhaust ventilation may also be effective, used alone or in combination with process enclosure.Ventilation systems shall be designed to prevent the accumulation or recirculation of phosgene in the workroom, to maintain phosgene concentrations within the limits of the recommended standard, and to remove phosgene from the breathing zones of workmen.Exhaust ventilation systems shall discharge to the outside air through a sorption or a decomposition system (eg, scrubbers containing an alkaline scrubbing medium, such as 5% sodium hydroxide solution).Ventilation systems shall be subject to regular preventive maintenance and cleaning to ensure effectiveness, which shall be verified by periodic air-flow measurements. Tempered makeup air shall be provided to workrooms in which exhaust ventilation is operating. # (c) Storage (1) Phosgene shall be stored in unoccupied, adequately ventilated, cool, and dry rooms, or outdoors shielded from the direct rays of the sun and protected from moisture. (2) Phosgene storage rooms shall be provided with an inspection window to permit viewing of the interior without entry. Other materials should not be stored with phosgene. Phosgene containers shall be frequently inspected for leaks and deterioration.If the hydrostatic test date stamped on cylinders is older than 5 years, the cylinder shall be returned to the vendor, or arrangements shall be made to have the necessary test performed. # (d) Handling and General Work Practices (1) Written operating instructions and emergency medical procedures shall be formulated and posted where phosgene is handled or used. (2) Prompt medical attention shall be obtained if there is known or suspected overexposure to phosgene, whether or not symptoms are present. (3) Returnable phosgene containers shall not be washed out with water. (4) Safety valves and vents for phosgene equipment shall discharge through absorbers or neutralizers (decomposition system). The amount of phosgene used from a container shall be determined by a positive method (eg, weighing the preweighed container). (13) New gaskets shall be used each time phosgene system connections are made. Welding or burning on tanks or equipment which have contained phosgene shall take place only after such tanks or equipment have been thoroughly purged with a dry inert gas, vented to a sorption or decomposition system.Steam or water shall not be introduced to the tanks, system, or equipment.Phosgene equipment, containers, or piping shall not be repaired while in service. Before phosgene is admitted to a system, the system shall be thoroughly cleaned, dried, and tested, using previously formulated procedures. (16) Personnel shall not work alone when phosgene is first admitted to a system or while repairing leaks. Containers and systems shall be handled and opened with care.Approved eye, skin, and respiratory protection shall be worn while opening, connecting, and disconnecting phosgene containers and systems. When opening containers or systems, adequate ventilation shall be available to prevent inadvertent exposure to phosgene. Any odor of phosgene shall be reported to a responsible authority or an alarm sounded as soon as possible after the area has been vacated. (e) Work Areas (1) Where phosgene is stored, piped, handled, or used, eyewash fountains and safety showers shall be located immediately outside the area.They shall be readily accessible and shall be inspected frequently and kept in good working order. (2) Enclosed phosgene work areas shall be equipped with at least 2 exits, remote from each other, to allow escape into uncontaminated areas in case of emergency.Doors shall open outward. (3) Unauthorized personnel shall be prohibited from entering areas where phosgene is handled or used. (4) Wherever possible, phosgene installations shall be outdoors.If it is necessary that such installations be indoors, workers should operate from a pressurized control room supplied with fresh air from an area remote from any possible source of phosgene contamination. (5) For reentry purposes, at least 2 sets of self-contained breathing apparatus as specified in (2) Phosgene shall not be allowed to enter drains or sewers. Appreciable discharges of phosgene shall be passed through an adequate decomposition system, such as a scrubbing tower utilizing sodium hydroxide or ammonium hydroxide, or through a sorbent system. (4) Solid sorbents should be chosen so that desorption of phosgene is unlikely.Heating of the solid sorbent should be avoided. (g) Confined Spaces (1) Entry into confined spaces such as tanks, pits, tank cars, barges, process vessels, and tunnels shall be controlled by a permit system.Permits shall be signed by an authorized employer representative certifying 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. ( The development of the recommended standard for occupational exposure to phosgene has revealed deficiencies in the data base in the following areas: (1) epidemiologic studies of workers exposed to phosgene for extended periods; (2) chronic animal exposure studies at low levels of phosgene; (3) improvement of the sensitivity of sampling and analytical methods for personal monitoring; (4) testing of automatic, continuous monitoring systems and associated alarms. These gaps in our knowledge of phosgene should be filled. # III.BIOLOGIC EFFECTS OF EXPOSURE # Extent of Exposure Phosgene is a colorless gas at normal temperatures and pressure. When liquified under pressure or refrigeration, it is a colorless-to-light yellow liquid. In low concentrations, its odor has been variously described as resembling that of musty hay or green corn. Phosgene is easily manufactured by passing chlorine and excess carbon monoxide over activated carbon. Shortages of chlorine and attendant high prices have somewhat restricted the manufacture of phosgene in recent years. Some phosgene can also be produced by the decomposition of chlorinated hydrocarbons by heat or by ultraviolet radiation. Relevant properties of phosgene are presented in Accordingly, much of the literature on phosgene is concerned with its military applications.Phosgene production in the United States in 1957, the first year the US Tariff Commission started reporting phosgene output, was only 5 million pounds. In 1967, production reached 350 million pounds, in 1971, 530 million pounds, while in 1972, it had increased to 657 million pounds. In contrast to these figures, sales in 1971 were only 11,215,000 pounds and 11,678,000 pounds in 1972. The apparent discrepancy between production and sales is due to the fact that the major portion of the phosgene manufactured is for "captive" use (use by the phosgene manufacturer), while the relatively small remainder is sold. In 1974, phosgene was being produced in 18 plants and capacity was on the increase. It has been estimated that demand will be 1,630 million pounds in 1978. The relatively recent revitalization of the phosgene industry and the rapidly increasing demand are due largely to the use of phosgene in the synthesis of isocyanates, which are starting materials for polyurethane resins.Production of isocyanates accounted for about 75% of all phosgene produced in 1967. In 1974, the uses of phosgene were distributed as follows: production of toluene diisocyanate, 62%; other polymeric isocyanates, 23%; polycarbonates, 6%; pesticides, carbonates, and "specialties," 9%. Some occupations with potential exposure to phosgene are listed in Table XIII-2. NIOSH estimates that 10,000 workers have potential occupational exposure to phosgene during its manufacture and use. # Historical Reports Berghoff reported his observations of 2,000 cases of exposure to war gases during World War I. These included chlorine, mustard gas, and phosgene. The main complaint expressed by those exposed to phosgene was a weakness which developed as early as 2 hours or as late as 3 days after exposure.This weakness lasted for weeks or months.The author also noted that emphysematous patients had a more protracted convalescence than those classified as bronchitic. # Effects on Humans Wells et al published a detailed report on effects of barely detectable concentrations of phosgene on humans.Fifty-six military personnel, without upper respiratory problems, were exposed to increasing concentrations of phosgene until all the subjects could detect phosgene by odor. The authors reported that 50% of "technically trained" (without further clarification) observers detected phosgene at a concentration of Five hours after exposure, the patient felt a slight pressure on his chest. Eight hours after exposure, he became dyspneic and expectorated bloody sputum. He was admitted to the hospital one hour later.Chest films showed pulmonary edema.Thirteen days of hospitalization, which included treatment with corticosteroids, digitalis, and oxygen, were required to resolve his pulmonary problems. The fatal accident involved a 55-year-old mason who was presumed to have been exposed to phosgene released by chipping of brick which had possibly adsorbed phosgene.In this case, phosgene was a byproduct in the production of aluminum chloride.An analysis of the apparatus the patient worked on revealed that 2.5 liters of interstitial air volume in the brick at 360-400 C was available for absorbing the phosgene.The amount of dust inhaled by the patient is unknown.He was exposed for 30 minutes and first complained of dyspnea about 2 hours after completing the job.No first aid was given.Five hours after exposure, he was admitted to the hospital in severe respiratory distress.Chest films showed pulmonary edema.Despite phlebotomy and treatment with digitalis and diuretics, the patient died of acute right heart failure about 14 hours after his initial exposure.
Two cases of phosgene exposure were reported by Gerritsen and Buschmann. They were due to accidental formation of phosgene from chlorinated hydrocarbons.Both cases involved the use of chemical paint removers in poorly ventilated areas heated by portable kerosene stoves. The first case involved a 52-year-old man who was exposed for an unknown period.He noted respiratory irritation soon after beginning work but persisted working for several hours.Chest symptoms occurred thereafter and the patient, upon examination, exhibited signs of pulmonary congestion. Approximately 5 hours later, the patient went into frank pulmonary edema and died within a few hours.Autopsy showed extensive degenerative changes in the epithelium of the trachea, bronchi, and bronchioli, together with hemorrhagic edematous focal pneumonia. The second case involved a 38-year-old woman, in her 7th month of pregnancy, who was exposed in a similar manner for 3 hours in the afternoon. That evening hemoptysis occurred.The next morning, symptoms worsened and she was hospitalized.A chest film upon admission showed pulmonary edema.After 8 days' hospitalization, she was released even though her chest film did not yet show a complete return to normal.After 2 months, she gave birth to a healthy child.This is the only case found which reported phosgene exposure during pregnancy. In attempting to reproduce the circumstances of exposure of the above 2 cases, it was found that methylene chloride was rapidly decomposed with phosgene being the main decomposition product when methylene chloride was exposed to heat in a poorly ventilated area.The authors stated that this was in contrast to the results reported by Little when methylene chloride was decomposed by hot surfaces and low amounts of phosgene were produced in comparison with hydrogen chloride and chlorine. Another case of possible phosgene poisoning resulting in death was reported by Spolyar et al. The case involved a chlorinated solvent degreaser which was inadvertently filled with trichloroethylene instead of perchloroethylene.The operator of the degreaser was found dead 3 1/2 hours after exposure began and 1 hour after he reported that fumes were escaping from the apparatus.Autopsy showed pulmonary edema consistent with exposure to phosgene.It was assumed that the trichloroethylene vaporized and passed through the firebox of a nearby space heater, with decomposition of the trichloroethylene and the production of phosgene. Cause of death was consistent with phosgene exposure but it was suggested that trichloroethylene might have contributed to the circulatory collapse.Phosgene was believed to have been generated by the decomposition of trichloroethylene in contact with the hot tip of a burning cigarette.This theory is contradicted by the work of Little who measured phosgene in the effluent gas of cigarettes and did not detect any in atmospheres containing trichloroethylene, chloroform, carbon tetrachloride, perchloroethylene, or even small amounts of phosgene. Everett and Overholt reported a case of phosgene poisoning but gave no details of exposure other than "massive exposure to phosgene." Initial symptoms were burning of the eyes and coughing.These cleared after a few minutes, but dyspnea occurred in 3 hours.X-ray studies showed pulmonary edema which resolved over 7 days of hospitalization and treatment which included antibiotics, corticosteroids, and oxygen.The patient remained well during the ensuing 2 years. The Bureau of Engineering Safety, Department of Labor and Industry, State of New Jersey, reported one fatality among 6 employees exposed to phosgene at unknown concentrations in separate accidents over a 2-year period.The exposures occurred in a plant conducting "phosgenation" where measurements of air concentrations were normally reported to be below 0.1 ppm.Subsequently, all phosgene operations were stopped because of inadequate engineering controls. Delepine described 2 cases of fatal phosgene poisoning.The first man had his clothing saturated with phosgene and was treated almost immediately. He appeared well but experienced symptoms 6 hours after exposure.Treatment (details not given) was temporarily helpful, but the patient died 11 hours later.The second man was exposed as a result of the explosion of a phosgene cylinder.Death occurred 22 hours after exposure. At autopsy, both cases showed evidence of severe irritation of the respiratory tract with almost complete shedding of the laryngeal, tracheal, and bronchial epithelium. English reported a case of poisoning attributed to phosgene in a 67-year-old male with several years- history of chronic bronchitis and a quiescent duodenal ulcer.After an 8-hour exposure in a room heated by a stove burning paraffin in which paint-strippers containing chlorinated hydrocarbons had been used, the worker experienced dyspnea.The next morning, his symptoms increased and he was hospitalized.Chest X-rays showed diffuse bronchiolitis.Despite treatment, dyspnea persisted for 4 days in the hospital.He was discharged after 6 weeks.English stated that phosgene dissolved in saliva irritated the alimentary mucosa and, hence, was responsible for reactivation of a duodenal ulcer in this patient.He cited no authorities for this statement or clinical or experimental evidence to support it.No other references to the effects of phosgene on gastrointestinal mucosa were found other than Cherkes' statement that stasis and venous hyperemia occur in the gastrointestinal tract as a result of pulmonary edema. Seidelin reported a case of probable phosgene inhalation leading to pulmonary edema in a 16-year-old woman.This occurred after she had used a carbon tetrachloride fire extinguisher in an enclosed space.In 1946, Galdston et al reported studies of 6 cases of acute exposure to phosgene with residual effects up to 19 months after the last known acute exposure.Evaluation of each patient included physical examinations, chest X-rays, pulmonary function tests, and a psychiatric summary.These cases shared a common background of brief single exposures to phosgene at unknown concentrations which usually led to delayed pulmonary edema.One of the cases is interesting in that exposure occurred at a hood which contained an ampule of only 40 ml phosgene. All were treated at Johns Hopkins Hospital and released, some returning to a normal work routine. However, follow-up examinations revealed that all had lingering complaints, and although physical examinations and chest X-rays up to 19 months later were generally normal, pulmonary function tests always revealed some abnormalities consistent with beginning pulmonary emphysema. The authors felt that psychological factors contributed to the lingering symptomatology.Their findings are summarized in Table III-l. Cherkes, in an extensive review of the literature concerning the clinical course of acute phosgene exposure, noted that most fatalities occur during the first 24-48 hours.He reported that most patients dying within the first 72 hours died of pulmonary edema or cardiac problems. Those dying later usually succumbed as a result of complications, such as infection (usually pulmonary), thrombosis, or embolism.He gave no source for these statements other than "according to the data of various authors." The clinical course following phosgene exposure reported by Cherkes is generally in agreement with other reports following human and animal exposure. Ardran pointed out that many victims of phosgene poisoning showed radiological evidence of increased lung volumes.His experiments with dogs indicated that animals that failed to develop an increase in lung volume after phosgene exposure also failed to develop pulmonary edema. This test had been used by him clinically. He reported that, if an expiratory lung film shows evidence of an increase in volume after exposure to phosgene, then pulmonary edema may be expected.He stated that he had looked for this sign in humans exposed to lung irritants and that never, in 20 years, had he found pulmonary edema to develop in the absence of antecedent increased lung volume.There has been no independent Arterial blood oxygen, alveolar air oxygen and carbon dioxide tension studies at rest and after exercise were performed 4-8 months after all other studies were completed.Symptoms, physical and roentgenographic findings were unchanged on reexamination of all available patients (all but one) at that time.From reference 35 # Epidemiologic Studies Levina et al described the working environment in the monuron, 3-(p-chlorophenyl)-l,1-dimethylurea, industry.Phosgene is involved in its synthesis and was found to be contaminating 90 workers1 production areas at a concentration of 1.0-2.0 mg/cu m (JO.2 5 -0 .5 ppm) over a 6-month period under investigation. According to Smelyanskiy and Ulanova, the permissible level for the USSR was 0.5 mg/cu m (0.125 ppm).Other contaminants included chlorobenzene, dimethylamine, and parachlorophenylisocyanate.Levina et al reported no pulmonary problems in these workers, but did not describe searching for them. Levina and Kurando reported their studies of a plant manufacturing a weed killer (isopropylphenylcarbamate) using phosgene, isopropyl alcohol, aniline, and caustic soda as raw materials.Although a closed process was used, phosgene was found in 30% of all air samples, most frequently at a concentration of 0.5 mg/cu m (0.125 ppm).A total of 89 workers were studied for evidence of hematological abnormalities. Methemoglobinemia and anemia were detected which were attributed to the weed killer and aniline.No mention was made of pulmonary problems. At a plant where phosgene is manufactured, the medical records of all exposed workers (326) were compared with those of 6,288 nonexposed workers. (AF Myers, written communication, November 1974) Pulmonary function, lung problems, and deaths related to lung problems were tabulated for both groups. The data were taken to indicate that there were no chronic lung problems related to working in these phosgene operations.By using the age distribution of employees and pensioners and comparing their deaths from lung problems with those expected from a similar age group (described as taken from National Statistics) not exposed to phosgene, no increase in lung-related deaths was noted in the phosgene-industry workers.The They attributed this to differences in the major site of action, ie, the respiratory bronchioles in the first case, and the alveoli in the second. The authors noted that above a Ct of 30 ppm-minutes gas exchange capacity decreased directly with the logarithmic increase in Ct.Rinehart and Hatch noted no significant effect of phosgene on the test animals' pulmonary performance when subjected to exposures less than a Ct of 30 ppm-minutes. The animals' exposures were varied to cover a Ct product range of 12-360 ppm-minutes. Gross et al studied the effect of low concentrations (0.5-4 ppm for 5-480 minutes) on rats.They found that they could produce a chronic pneumonitis which was reversible but left detectable lesions for up to 3 months.They felt they could explain this by the fact that low dosages of phosgene merely irritated the pulmonary alveolar epithelium, resulting in proliferation.The more severe exposures of phosgene usually reported in the literature destroyed the surface epithelium and attacked the underlying alveolar capillaries, thus resulting in pulmonary edema.The authors noted that the severity of the chronic pneumonitis correlated well with the Ct value of the phosgene exposure and seemed to be largely independent of the concentration of the gas in the same bracket of Ct values.Animals in the study by Gross et al were subjected to Ct products ranging from 13 to 360 ppm-minutes.In the 18 rats exposed to phosgene with Ct products equal to 30 ppm-minutes or less, 5 (28%) showed no abnormalities on pathologic examination; 11 (61%) showed slight chronic pneumonitis; and 2 (11%) showed moderate chronic pneumonitis. Wirth studied the effect of low concentrations of phosgene upon cats.He reported that, if the concentration was expressed as mg/cu m, the lethal concentration x the survival time in minutes was approximately 1,000.At low concentrations (5-7 mg/cu m, 1-2 ppm), the constant was as high as 3,000.This shows that the lethal Ct product is considerably higher at low concentrations.The author felt that the increase in Ct product at low concentrations was due to detoxification and that the practical usefulness of the Ct formula was not affected by this, provided it was used within certain concentration limits. Cordier and Cordier Other lung changes were found, but, in general, the effect on the pulmonary alveoli was considered to be insignificant.The authors concluded that this concentration, inhaled daily for 10 minutes, seems to be the minimal concentration capable of creating edematous pulmonary zones.This minimum effect level, expressed as a Ct product (25-37.5 ppm-minutes) concurs with the minimum effect level of 30 ppm-minutes later found by Rinehart and Hatch in experiments with rats using pulmonary uptake of carbon monoxide and ether to measure effect. Koontz gassed dogs with phosgene at the minimum lethal dose (undefined by the author) and then studied 95 of those that survived.Onethird died or were killed by other dogs during the course of the experiment.The other two-thirds were killed at intervals from 2 to 60 weeks.About one-half of the dogs showed no or only minor lesions.Those with more significant abnormalities showed transient bronchial plugging and adjacent atelectasis. Most of the lungs took on a more normal appearance as the time from recovery increased. Durlacher and Bunting exposed 31 dogs to phosgene at concen trations averaging 0.29 mg/ liter (72.0 ppm) for 30 minutes.The animals were given a variety of treatments, including oxygen, transfusions, or venesection.The most striking findings were consolidation of one or more lobes of the lungs 4-9 days after exposure.The authors noted that "pulmonary organization occurred...and caused high mortality in spite of oxygen therapy." The oxygen therapy consisted of maintenance in an atmosphere of 60% oxygen when the arterial oxygen saturation was below 80%. No specific time for initiation of therapy other than "after exposure" was given. Gross et al described their findings concerning pulmonary reactions to toxic gases.They noted that the proliferative lesions produced by phosgene, chlorine, sulfur dioxide, nitrogen dioxide, ozone, and crotonaldehyde differed only quantitatively on a histologic basis.It appeared probable to the authors that, with a proper adjustment of the concentration, even the quantitative difference could be eliminated.They concluded that deep lung irritants preferentially attacked the respiratory bronchioles because of delayed clearance in that region. In 1920, Underhill exposed dogs to phosgene and noted the development of pulmonary edema which was maximal at 24-36 hours and resolved in animals surviving 10 days or more.He concluded that the minimum lethal concentration of phosgene for dogs was 310-350 mg/cu m (75-87 ppm).He found that dogs that survived for 3 days usually recovered. He also concluded that recovery from gassing increased the likelihood of death from regassing of dogs, which differs from the findings of Box and Cullumbine in rats.Underhill explained that tolerance is demonstrable only with low concentrations; it does not decrease subsequent reactions to lethal concentrations.Winternitz et al presented detailed information on the pathology found in these animals at autopsy. Long and Hatch reported that a reduction in the rate of respiratory uptake of carbon monoxide was an early and sensitive test of pulmonary impairment following exposure to pulmonary irritants.The test was developed using unanesthetized rats and phosgene as the test irritant. The animals were exposed to phosgene for 30 minutes at the following levels: 0.5-1, 1-2, 2-3, 3-4, and 4-5 ppm. The responses included a decrease in pulmonary uptake in CO which was progressive for 6-8 hours, followed by gradual recovery.They found that their test detected changes even at the lowest level of phosgene exposure (0.5-1 ppm) in the absence of microscopic changes at autopsy. Boyd and Perry exposed rabbits to phosgene for 30 minutes at a concentration of 270 mg/cu m (67 ppm).They reported a latent period of several hours following exposure. After the latent period, pulmonary edema developed. Noweir et al exposed rats to decomposition products of carbon tetrachloride at its TLV (10 ppm) and demonstrated that up to 10 ppm of All species showed some degree of edema. In a subsequent study, Cameron et al exposed a group of animals to phosgene at an average concentration of 3.47 mg/cu m (0.86 ppm) for a single 5-hour exposure.The animal exposure group consisted of 20 mice, 10 rats, 10 guinea pigs, 10 rabbits, 2 cats, 2 monkeys, and 2 goats.On the morning following exposure, 10% of the rats (1/10) and 60% of the mice (12/20) were dead.There were no other casualties, although one cat and one monkey were very ill with considerable labored breathing.All survivors of the experiment were killed on the morning following exposure. All animals were then autopsied and one lung from each animal was fixed in formalin for sectioning.Upon examination, 54 out of 56 animals (96.4%) showed microscopic evidence of pulmonary involvement which was severe in 29 animals (39%), mild in 17 (31%), and slight in 16 (30%).The most frequent lung change noted was edema. In another study, Cameron et al reported the results of exposing a variety of animals to phosgene at an average concentration of 0.9 mg/cu m (0.2 ppm) for 5 hours daily for 5 consecutive days.The experimental group consisted of 20 mice, 10 rats, 10 guinea pigs, 10 rabbits, 2 cats, and 2 goats. No deaths occurred during the exposures.Except for some labored breathing noted in the cats and in one goat, the other animals showed little evidence of distress.At autopsy, pulmonary lesions were seen in 67% of the animals. In the opinion of the investigators, the great majority of such lesions were slight and of little significance. Discounting the more susceptible animals (guinea pigs) and correcting for the normal incidence of disease in laboratory animals, the authors estimated that probably between 5 and 10% of the animals showed moderately severe lesions. Pulmonary edema was noted in 41% of the animals but was considered to be slight in most cases.In 6 animals (1 rabbit, 1 mouse, 1 rat, and 3 guinea pigs), it was extensive.Acute bronchitis was noted in 22% of the animals and bronchial regeneration in 20%. Their results are shown in Table III-3. In their summary statement, the authors advanced the opinion that there is little doubt that repeated exposure at low concentrations (0.9 mg/cu m) induces damage to the lungs but that such damage was rarely severe.Seemingly in contradiction with this, they also stated that, at this concentration, some fairly severe changes are found in the lungs of experimental animals.
The one animal study devoted to long-term, repeated exposure to phosgene at low concentrations produced pulmonary edema in 41% of the animals.After correcting for the normal incidence of disease in laboratory animals, 5-10% of the animals had moderately severe lesions. Human exposures to phosgene reported in the literature (summarized in is the best substantiated in the American literature and gives details of pulmonary function studies in 11 workers with single acute or repeated exposures to phosgene at unknown concentrations. Unfortunately, other pulmonary irritants were sometimes involved. Galdston et al gave evidence that repeated exposures to phosgene can result in residual pulmonary problems.This paper reports on 5 workers who were studied in detail, 2 of whom had abnormal chest films.It is difficult to extrapolate the results found in these workers to what might be expected in the general population of workers exposed to phosgene over long periods of time. Levina et al found no pulmonary abnormalities in Soviet workers exposed to 1-2 mg/cu m of phosgene for over a 6-month period.Other inhalants apparently caused hematologic abnormalities.Unfortunately, no mention is made of any pulmonary function studies done on these workers. In summary, there are no truly pertinent data in the scientific literature concerned with long-term effects on humans exposed to phosgene at low concentrations.Animal data show a 5-10% incidence of severe pulmonary problems in animals exposed at 0.2 ppm.Despite Cherkes' statement that the dog is the animal most resembling man in terms of susceptibility to phosgene, neither Cherkes nor any other investigator has offered any concrete data to support this contention.In fact, Winternitz Delepine English Steel Over a 2-year period prior to this investigation, at least 6 employees had been acutely exposed to unknown concentrations of phosgene. Four of these were not able to return to work the day after exposure.One death had occurred and was attributed to In 1967, Levina and Kurando described exposures to phosgene and other chemicals in the manufacture of isopropyl phenylcarbamate, used as a herbicide.Totally enclosed equipment kept under reduced pressure prevented the escape of toxic chemicals to a large degree.Equipment and connections were made of corrosion-resistant materials, with special attention to flanges and valves.Atmospheric pollution was prevented by trapping gases and returning them to process.However, where manual labor was substituted for mechanization or total enclosure, some gas escape was possible.Hazardous processes were separated, and ventilation was reported to be correctly designed and located.Makeup air was supplied.Phosgene was detected in 30% of all air samples taken; of the samples where phosgene was detected, the usual concentration was 0.5 mg/cu m (0.125 ppm), the maximum permissible concentration.Methods of sampling and analysis were not described. During operations such as quality control sampling, pressure transfer of phosgene, and pump repair, the concentration of phosgene in the workroom air was 1.0 mg/cu m (0.25 ppm).However, these concentrations were described as transient, because the premises were cleared by release of ammonia whenever the odor of phosgene became discernible.Gas masks were worn by personnel engaged in these tasks. Recommendations for further control included improved sealing of equipment, elimination of manual operations by maximum automation, use of protective clothing, and good personal hygiene. # Rispoli reported 1 and 5 ppm phosgene in a plasticsmanufacturing plant.No details of sampling or analysis were given, but ventilation was described as insufficient. Reporting on 109 cases of phosgene inhalation over a 12-year period, Thiess and Goldmann selected the 3 most severe cases for more detailed discussion. None of the exposures reported were long-term inhalation of low concentrations but were acute accidental exposures at relatively high concentrations. No determinations of workroom air concentrations were reported, but in 2 of the severe cases some assumptions and calculations were made which might have defined the exposure level involved. One case described by Thiess and Goldmann involved a worker removing brick lining, presumably saturated with phosgene, from a reaction vessel.The chemical process for which the reactor was constructed was the chlorination of aluminum oxide in the presence of carbon monoxide for the production of aluminum chloride. Phosgene was a byproduct of this reaction.Contrary to instructions, the brick lining was removed with a jackhammer from the inside of the furnace and without respiratory protection.Instructions had been given to remove the brick from the outside of the vessel and to wear respiratory protection.The exposure lasted about 30 minutes, during which the worker was presumed to have inhaled dust particles with adsorbed phosgene.Again, assumptions and calculations based on porosity measurements of the brick indicated that a total volume of 2.5 liters was available for absorption of gas by the lining material.This exposure terminated fatally.There is at least a suggestion that the effect of phosgene was enhanced because of its association with particulate matter, but this was not proved.In summary, the workroom air measurements of phosgene in a manufacturing unit showed that, about 25% of the time, operators were exposed to very low but measurable concentrations of phosgene.Sampling procedures used did not determine individual peaks. Details of controls or of fixed sampling locations were not given.The plant surveyed was reportedly old and built with out-of-date technology. The decomposition of chlorinated hydrocarbons by means of heat or ultraviolet radiation with the formation of phosgene has been blamed for a number of incidents involving respiratory tract damage in humans.that phosgene was not formed in sufficient quantities by smoking to present a hazard.He also found that various chlorinated hydrocarbons in contact with a heated silica tube did not produce significant quantities of phosgene below 400 C. Even in atmospheres containing small amounts of phosgene, finding no detectable phosgene in effluent gas from cigarettes led to the conclusion that, if any phosgene were formed, it was subsequently decomposed when passed through the combustion zone of the cigarette.It was also hypothesized that the phosgene was absorbed by the tar fraction of the tobacco combustion product. # Crummett and Stenger found that, in contact with heated metals, methyl chloroform (1,1,1-trichloroethane) produced relatively small amounts of phosgene, but much more hydrogen chloride than did carbon tetrachloride. Dahlberg, Dahlberg et al, and Dahlberg and Myrin extensively investigated the interaction of ultraviolet radiation with chlorinated hydrocarbons.These studies indicated that relatively lower amounts of phosgene were formed compared to the quantities of dichloroacetyl chloride formed simultaneously.Although there have been no environmental limits recommended for dichloroacetyl chloride, it seems likely that it would be a strong irritant to skin and eyes.Actual Noweir et al found that, at very high temperatures, phosgene itself decomposes, perhaps accounting for concentrations lower than expected.However, phosgene decomposition was greatly reduced in the presence of carbon tetrachloride, indicating that, at least for this chlorinated hydrocarbon, phosgene formed by its decomposition should be relatively stable as long as some carbon tetrachloride remained. A number of occupational exposures to decomposition products of chlorinated hydrocarbons have been reported.In 1947, Hill briefly reported an investigation of complaints of workers exposed to fumes arising from a carbon arc-welding operation. A presumably adequate exhaust ventilation system existed, but the fumes causing the complaints were sometimes strong enough to be detected at some distance from the arc.The workers had not complained prior to the relocation of the operation to a room near a trichloroethylene degreaser.Qualitative tests indicated the presence of phosgene presumably caused by breakdown of trichloroethylene vapor by the ultraviolet radiation of the arc.It was recommended that the degreaser be replaced with alkaline wash equipment and that the use of chlorinated hydrocarbons in the welding room be prohibited. Spolyar et al investigated the circumstances causing the death of an employee who had installed a trichloroethylene degreaser and had operated it without the condensing coils functioning.A strong odor of solvent was present in the room when the employee's body was discovered. An investigation by the authors took place 3 weeks later, disclosing the following: (1) Trichloroethylene had been used in a degreaser designed for higher-boiling perchloroethylene, causing excessive loss of solvent. (2) A fuel-oil-buming space heater was located in the degreaser room, and all windows and doors had been closed on the day of the accident. (3) Under test conditions, 225-450 ppm trichloroethylene were found near the degreasing tank. The trichloroethylene vapor passing through the firebox of the space heater could be decomposed with the possible formation of phosgene.A re creation of the situation at the time of the accident, described in Effects on Humans, was undertaken, during which it was noted that one of the solvent heaters in the degreaser became red-hot.Samples taken at that time in the approximate location of an operator's breathing zone showed much higher levels of trichloroethylene and 15 ppm phosgene.The authors suggested that the decomposition of the trichloroethylene was caused by the degreaser heating element rather than by the space heater, although a back pressure in the smoke pipe of the latter could occur under adverse weather conditions because of the configuration of the stack. Although some effects due to trichloroethylene were apparent, the authors concluded that the cause of death was consistent with phosgene exposure. In All phosgene samples contained less than 0.1 ppm, although the trichloroethylene concentrations ranged from a reported 0.0 to 238 ppm and the ozone concentrations ranged from 0.9 to 1.7 ppm.The authors concluded that ozone rather than phosgene was the source of the complaints. Exhaust ventilation was installed in the degreasing shop and at the welding positions and operating procedures to prevent solvent drag-out were implemented, resulting in improved working conditions.Physical measurements were based on the olfactory or taste response imparted to tobacco smoke immediately after phosgene inhalation and was considered to be a very sensitive indicator of the gas, although it suffered from the obvious disadvantage of depending on the exposed worker to determine his exposure. A method of analysis based upon chloride present after hydrolysis was reported to depend on aqueous decomposition of phosgene in dilute alkali. Residual base was titrated or the chloride present was determined by the Volhard or the bichromate method; the hydrogen chloride gas produced upon hydrolysis could also be absorbed in ammoniacal silver nitrate and the resultant silver chloride determined gravimetrically. However, these procedures were susceptible to physiologically inert, acid-reacting, or chloride-producing components occurring simultaneously with the phosgene. Iodometric procedures in anhydrous acetone with thiosulfate titration suffered from inherent field limitations due to the anhydrous conditions necessary and evaporation of the volatile solvent. Gravimetric procedures included (1) a method based on insoluble diphenylurea derived from phosgene and aniline, but which was sensitive to halogen interferences and limited to a lower detection threshold of about 10 ppm ; and (2) a modified Kjeldahl nitrogen analysis of the diphenylurea which offered little improvement. Review of colorimetric analytical methods that were developed indicated that the most sensitive and specific detector was 4-(4'-nitrobenzyl)pyridine (NBP) plus N-benzylaniline although it did not readily lend itself to a liquid reagent system.Later investigators developed a method using diethylphthalate as an absorber with NBP and Nbenzylaniline and easily determined phosgene at concentrations less than 0.1 ppm in air.Spot tests have been described for phosgene which generally rely on colored complex formation between heavy metals and diphenylcarbazones. Various detector papers and treated crayons have been described for determination of phosgene with the most sensitive prepared A micromanometric method was described which utilized measurement of gaseous reaction products resulting from hydrolysis of phosgene, but details as to sensitivity and specificity were lacking. Gas chromatographic techniques provide the most specific and sensitive detection methods for phosgene.A silica gel column at 56.5 C with a hot wire detector was first used to detect phosgene in pyrolysis products on a semiquantitative basis. The development of the electron capture detector for the gas chromatograph provided a high degree of specificity for phosgene.This detector was first tried in conjunction with a dodecylphthalate column at 50 C with resultant 2% standard deviation and detection down to 1 ppb.The authors suggested that this method can possibly be used as the basis for an automatic, continuous monitoring system.A later refinement used a column of "20% silicon oil DC 200" (probably silicone DC 200) on Chromosorb W at 25 C for detection from below 1 ppb to 0.1 ppm phosgene.Jeltes et al confirmed detection below 0.005 ppm but pointed out inherent difficulties due to hydrolysis by trace amounts of moisture, leakage of transfer syringes, and problems in transporation and storage of the air samples. Basu et al presented operational parameters, retention times, and response factors for gas mixtures including phosgene using a 3-column, 3detector (thermal conductivity) gas chromatographic system with a resultant reproducibility represented by a ±1% standard deviation. Although the gas chromatographic methods display excellent analytical capabilities, field use is hampered by the lack of an adequate personal sampling method.Recent investigations by Barrett et al of a number of solid sorbents indicated that phosgene can be efficiently collected with activated carbon, alumina, and porous glass, but no satisfactory desorption technique was found. Methods have been reported for automatic or continuous monitoring of phosgene in air. The instrumentation requirements make the methods impractical for field use.In-plant applications may be possible but the lower limit of detection may be questionable. One continuous-sensing instrument which has been found to be generally reliable below 0.1 ppm of phosgene is the Army's M8 portable alarm device for toxic chemical agents.It uses an electrochemical cell as the sensing unit and is designed to give a warning signal when the concentration of phosgene exceeds a certain value.The instrument is therefore not ideally suited for measurement of varying concentrations, but may well have some application as a monitoring or safety device.The device has been tested at concentrations of 0.074 ppm, 0.185 ppm, 0.443 ppm, and 0.625 ppm.The response was found to be linear over this range. The method of choice for detection of phosgene in the workroom air should provide for a minimum limit of detection of less than 0.05 ppm, reasonable freedom from interference from commonly expected chemicals (see Appendix II) and should permit relatively easy sample collection.The method which best meets these requirements is described in an Analytical Guide by the American Industrial Hygiene Association and is an improved nitrobenzylpyridine colorimetric method.It involves drawing air through a midget impinger containing 10 ml of a solution of 0.Color stability is good (only 10-15% loss in color density after 8 hours), sampling and analysis equipment needed is simple and readily available, and operator expertise required is minimal. # V. DEVELOPMENT OF STANDARD # Basis for Previous Standards In 1940, Bowditch et al listed a maximum concentration of 1 ppm (4 mg/cu m) phosgene which was in effect in Massachusetts as a guide to manufacturers interested in maintaining satisfactory working conditions. In 1945, Cook compiled a list of maximum allowable concentrations (MAC) of industrial atmospheric contaminants.Cook noted that 1 ppm (4 mg/cu m) was the MAC value for exposure to phosgene in the workroom air adopted by California, Connecticut, New York, Oregon, Utah, and the US Public Health Service.Cook referred to Fieldner et al and Flury and Zernik as a basis for the accepted value of 1 ppm (4 mg/cu m ) . Fieldner et al indicated that 3 ppm of phosgene in air was irritating to the throat.Flury and Zernik indicated that 1 ppm was the highest tolerable amount in man, with 1.25-2.5 ppm termed as dangerous to life if the exposure was prolonged. In 1947, Bloomfield reviewed the efforts of a committee within the American Conference of Governmental Industrial Hygienists to develop an MAC which could be adopted by all the states.Bloomfield cited unanimous agreement on a phosgene MAC value of 1 ppm (4 mg/cu m) among 23 respondents. In 1947, the American Conference of Governmental Industrial Hygienists adopted an MAC value for phosgene of 1 ppm (4 mg/cu m ) . It was not stated if this MAC was intended as a ceiling value or as a TWA concentration.The April 1948 meeting of this same organization adopted 1 ppm as a recommended limit and changed the name to Threshold Limit Values (TLV's). The TLV of 1 ppm was considered "sufficiently low to cause no more than minimal effects" by the ACGIH according to the 1962 Documentation of the Threshold Limit Values. The Documentation cited Fieldner et al and Henderson and Haggard to explain its selection of a TLV of 1 ppm (4 mg/cu m) for phosgene.Fieldner et al reported that the Chemical Warfare Service at the American University Experiment Station, Washington, DC, considered 1 ppm of phosgene (4 mg/cu m) the maximal concentration safe for prolonged exposure.Henderson and Haggard, in their review on phosgene, referred to Fieldner et al and listed 1 ppm (4 mg/cu m) or less as a maximum concentration allowable for prolonged exposure. Both sources listed 3 ppm as the concentration at which throat irritation first occurs.The Documentation did not quote any other experimental or occupational data to support its recommended TLV. A change to 0.1 ppm (0.4 mg/cu m) was proposed by the ACGIH in 1964 and 1965 and adopted in 1966. A TLV of 0.1 ppm (0.4 mg/cu m) was supported in the 1966 Documentation because of the "seriousness of the response at the experienced levels of phosgene and by analogy with edemagenic agents of similar activity."The Documentation cited Gross et al who wrote that phosgene, which could produce fatal pulmonary edema or acute chemical pneumonia at a high concentration, could also produce chronic pneumonitis at a low concentration.Gross et al suggested that the chronic pneumonitis is reversible even though residual pneumonitis could be found three months later. The alveolar epithelium in rats can become irritated after a single 120-minute phosgene exposure at 0.5 ppm. Studies by Box and Cullumbine indicated that preliminary nonlethal doses of phosgene produced a transitory effect of increasing tolerance to the gas.
It was necessary to damage the lungs of rats and mice to produce this effect.Stokinger et al reported chronic lung injury of small animals after repeated exposure to ozone. They stated that this is a separate process from the development of tolerance to subsequent acute exposure.In reviewing Stokinger's article, the Documentation stated that "the development of tolerance, however, is believed to be the triggering mechanism of chronic, irreversible pulmonary changes of emphysema and fibrosis from prolonged daily exposure at concentrations that produce no ostensible acute response."The Documentation assumed that both ozone and phosgene caused pulmonary edema. The 1971 Documentation was the same as the 1966 Documentation with a few minor style changes and one additional sentence listing a recommendation for the USSR (1959) of 0.1 ppm and mentioning Elkins, who recommended 0.5 ppm. There was no discussion of the additional recommendations nor were any new references cited in the bibliography.In 1974, it was recommended that the TLV of 0.1 ppm be changed to a ceiling concentration of 0.05 ppm (0.2 mg/cu m ) .Documentation for this change was published in the 1974 ACGIH Transactions and refers to Stokinger's article on ozone toxicity studies which indicated that there were chronic, irreversible pulmonary changes from prolonged daily exposure even though there was no acute response.None of the references cited specifically supported the ceiling limit of 0.05 ppm (0.2 mg/cu m) which was recommended because of the irritating effect of phosgene on the respiratory tract. In 1971, Pennsylvania adopted an environmental limit of 0.1 ppm (0.4 mg/cu m) for phosgene. It was a maximum average atmospheric concentration for an 8-hour day.A short-term maximum average exposure limit of 1 ppm (4 mg/cu m) for 5 minutes was established. # Henderson and Haggard, Imperial Chemical Industry, and Patty were cited as the basis for the short-term limit in the Pennsylvania documentation.Those epidemiologic studies involving exposures at low levels of phosgene suffer from a number of defects, including exposures to multiple irritants and limited analytical or medical data. In spite of the weaknesses noted, these studies are at least suggestive that the present federal standard is safe for long-term exposures.Therefore, until more conclusive evidence is developed, NIOSH recommends that the present federal standard of 0.1 ppm as a TWA concentration be maintained. In addition, since phosgene is an acute-acting, irritant gas, it is essential to control the short-term excursions above this average.Animal experiments have demonstrated a threshold for the development of pulmonary lesions after short-term exposure to phosgene.Gross et al reported that exposure of rats to phosgene at a concentration of 3 ppm for 5 minutes resulted in slight to moderate chronic pneumonitis, while rats exposed at 1.3-1.5 ppm for 10 minutes showed no evidence of recognizable pulmonary lesions.Similarly, rat experiments conducted by Rinehart and Hatch revealed that exposures to phosgene at a concentration of 1.5 ppm for 20 minutes or less did not result in any evidence of functional respiratory impairment as measured by carbon monoxide or ether uptake.In both studies, deleterious effects were found at the lowest concentration used, 0.5 ppm, when duration of exposure was 120 minutes or greater. Although no data are available to substantiate the pulmonary effects of brief exposures to phosgene at low concentrations in humans, these studies suggest that a single exposure of 10-15 minutes' duration at concentrations of or below 1.5 ppm are likely to be safe.It is felt, however, that imposing further limitations on the degree of excursion permitted during a 10-hour workday will provide an additional margin of safety to ensure protection of the worker from the consequences of brief exposures to concentrations of phosgene above the recommended TWA limit.NIOSH is therefore proposing a ceiling limit of 0.2 ppm for any 15-minute period. In view of the development of pulmonary edema and evidence of chronic lung changes as a result of exposure to phosgene, medical monitoring, including chest X-rays and pulmonary function tests, is required for the protection of the worker. Professional judgment indicates that local contact with liquid phosgene is likely to cause severe tissue damage which could in part be due to the low temperature of liquid phosgene.Thus skin and eye protection, in addition to respiratory protection, is recommended for those likely to be in contact with liquid phosgene. It is recognized that many workers are exposed to phosgene at concentrations considerably below the recommended occupational limits. Under these conditions, it should not be necessary to comply with many of the provisions of this recommended standard.However, concern for worker health requires that protective measures be instituted below the enforceable limits to ensure that exposures do not exceed the standard. For this reason, "occupational exposure to phosgene" has been defined as exposure above half the recommended TWA, thereby delineating those work situations which do not require the installation of unnecessary controls and the expenditure of health resources for provisions such as environmental and medical monitoring and associated recordkeeping.literature and the Manufacturing Chemists' Association Chemical Safety Data Sheet SD-95. In addition, work practices prescribed for other irritating gases have been adapted for phosgene wherever pertinent (eg, those published in the Chlorine Manual ). # Warning Properties The American Industrial Hygiene Association stated that the irritant properties of phosgene were insufficient to give warning of hazardous concentrations, and that olfactory fatigue caused personnel working with phosgene to lose their ability to detect low concentrations by smell.Supporting data for these statements were not reported. The Manufacturing Chemists' Association reported that the odor of phosgene can be recognized by some persons at 0.5 ppm, but that the sense of smell is conditioned by the gas so that the odor can only be detected briefly at the time of initial exposure.No substantiating data for these statements were cited, but many materials do have the ability to cause odor fatigue. Leonardos et al investigated the odor thresholds of 53 chemicals.They defined the odor threshold as the first concentration at which all members of a trained panel could recognize the odor of a chemical.Their tests indicated an odor threshold for phosgene of 1.0 ppm. The odor was described as being "hay-like." In 1938, Wells et al determined threshold odor detection of phosgene in a number of volunteers.Test concentrations were established with a proportioning instrument known as an osmoscope.Three tests run on 56 subjects showed that all subjects detected the odor of phosgene at or below 37.5 mg/cu m (9.4 ppm), 51.8% detected the odor of phosgene at or below 6.1 mg/cu m (1.5 ppm), and that none detected the odor below 1.8 mg/cu m (0.45 ppm). Macy, summarizing the properties and the physiological action of phosgene, stated that the threshold of odor for phosgene was 4.4 mg/cu m (1.1 ppm).Substantiating data were not included in this report.Phosgene presents no fire or explosion hazard, but high temperatures may rupture containers because of increased hydrostatic pressure. In case of fire, phosgene containers should be removed to a safe place or cooled with water if phosgene is not escaping. Spills are best controlled with solutions of caustic soda or with ammonia.It has been reported that some manufacturers store one ton of ammonia for each ton of stored phosgene for the purpose of neutralizing liquid spills. # Control of Airborne Phosgene Phosgene should be used only in completely closed systems.In addition, local exhaust and general ventilation can be effective for control at points of potential escape. Discharges of ventilation systems or of leaking containers may be passed through scrubbers utilizing caustic soda, ammonia, or steam to prevent phosgene from reaching the outdoor atmosphere. The possibility of phosgene formation must be considered when installing and operating vapor degreasers containing chlorinated hydrocarbons, since under poor operating conditions, these are potential sources of phosgene. They should be controlled to prevent exposure of operators to both solvent vapors and phosgene. During maintenance operations on equipment in which phosgene has been present, there is a potential hazard of exposure to phosgene which is entrapped in the equipment or adsorbed on surfaces or in materials. Respiratory protection should be supplied to maintenance personnel working on equipment that has carried phosgene, unless it can be established that no phosgene is present. # Respiratory Protection Neither chemical cartridge respirators nor half-face masks are recommended for protection against phosgene. Canister-type gas masks are recommended only for rapid escape from a contaminated area because of the following limitations: (1) Their useful life is unpredictable because of a number of variables such as breathing rate, ambient humidity, and contaminant concentration. (2) They cannot be used in atmospheres deficient in oxygen or containing phosgene in concentrations over 2.0% by volume. Therefore, they are not suitable for controlling emergency exposures where the concentration of phosgene and the oxygen content of the air are unknown. (3) Users of gas masks have depended on the detection of an odor of the atmospheric contaminant to warn them of loss of protection by the canister or to indicate leaks. However, phosgene has poor warning properties in low concentrations and therefore the odor cannot be Gas-mask canisters should be replaced immediately after each use, when the seal is broken, when any leakage is detected, when high breathing resistance develops, or when the recommended shelf life expires, whichever occurs first. Because of the irritant properties of phosgene, emergency respiratory protection must provide both eye and respiratory protection for the worker. Full-face masks are the only acceptable devices for employees exposed to phosgene leaks or for the protection of personnel who may be exposed to sudden high concentrations of phosgene.Masks connected to air lines or having a self-contained air or oxygen supply can also be used.Pocket-or mouthpiece-type respirators used for escape in some operations are not recommended for that purpose. # Eye Protection Liquid phosgene is probably a severe eye irritant, as discussed in Chapter V. Protection should be provided against accidental splashes of the liquid. Vapor concentrations of phosgene which are said to affect the eyes (1-10 ppm) are likely to affect the respiratory system as well.Accordingly, eye and respiratory protection should be combined by use of full-face respiratory protection. # Skin Protection Liquid phosgene is said to cause severe skin burns, and although this point is inadequately documented, it is a likely effect as discussed in Chapter V. Skin exposure to liquid phosgene should be prevented by the use of impervious clothing and gloves.Clothing impregnated with phosgene should be removed immediately.near a phosgene leak will produce a visible white cloud. However, this should not be done unless the worker is wearing a respirator. # Leak Control When detected, leaks should be repaired immediately by personnel wearing the proper protective clothing and respiratory protection.Leak repair kits may be assembled or are commercially available. Routine inspection should be scheduled to check pumps, lines, and containers for leaks; this practice is especially important during maintenance operations. Leaking containers should be positioned so that gas rather than liquid phosgene is discharged from the leak. This results in less discharge of phosgene and the escaping gas cools the remaining phosgene, thus reducing pressure and leakage.Introducing moisture into phosgene can cause increased pressures sufficient to rupture containers or can cause leaks through corrosion. VII.RESEARCH NEEDS Check the water manometer to ensure that the pressure drop across the sampling train does not exceed 13 inches of water (approximately 1 inch of mercury). (g) Start a soapbubble up the buret and, with a stopwatch, measure the time it takes the bubble to move from one calibration mark to another. For a 1000-ml buret, a convenient calibration volume is 500 ml. (c) The 95% confidence limits for 10 degrees of freedom are ±0.007 mg at the 0.017-mg level, and ±0.003 mg at the 0.10-mg level.The precision was determined by repeated analyses by the same technician. Rather than air sampling in the field, the precision was determined by analyzing known amounts of phosgene using the same technique as the calibration procedure. # Interference Other acid chlorides, alkyl and aryl derivatives which are sub stituted by active halogen atoms and sulfate esters will produce color with this reagent.However, most of these interferents can be removed in a pre scrubber containing 1,l,2-trichloro-l,2,2-trifluoroethane if necessary. The method is not subject to interference from carbon tetrachloride, # Apparatus (a) Sampling (1) Portable, battery-operated, personal sampling pump. (2) Midget impinger. (3) Flexible plastic tubing as appropriate. # (b) Analysis (1) Glassware as required for reagent measurement. (2) Colorimetric spectrophotometer capable of absorbance measurements at 475 nm. (3) Spectrophotometer cells (cuvettes). # (c) Calibration (1) Pressurized cylinder of phosgene gas. (2) Pressure regulator. (3) Flow meter. (4) Appurtenant equipment for gas dilution methods or a midget impinger. (5) Gas drying tubes. # Summary of Specifications (a) The monitoring device must sound an alarm or otherwise warn employees whenever a phosgene concentration of 0.2 ppm is reached or exceeded. # (b) The monitoring device must have a response time of 90 seconds or less when exposed to phosgene at a concentration of 0.2 ppm. (c) Zero drift should be less than 1% of full scale reading in 24 hours.That portion of the signal manifested as background noise should be less than plus or minus 1% of full scale reading. # (d) The monitoring device must be accurate to within plus or minus 10% of the reading for the range of 0.05-0.4 ppm phosgene. (e) Precision and repeatability must be plus or minus 5% of full scale reading. (f) It is desirable that the instrument respond only to phosgene, but devices which respond to other gases not normally present in the atmosphere may be acceptable.Whenever there is a possibility that gases or vapors, such as hydrogen chloride, chlorine, benzoyl chloride, acetyl chloride, and oxalyl chloride, may be present, it would be desirable to determine in advance the response of the instrument to such gases or vapors. (g) An operating range of 0-0.4 ppm phosgene is recommended, but other ranges may be selected to suit individual needs. (h) The device should be capable of 168 hours of continuous, unattended operation. # (i) The device and alarm should be intrinsically safe for use in locations where explosion hazards may occur. # Discussion The principal requirements for such monitors in addition to responding to phosgene gas are that they be sufficiently rugged to withstand pressure, vibration, normal extremes of temperature, etc, and not be susceptible to plugging or interferences due to contaminants likely to be encountered in most workplaces.They should be so constructed that it is possible to routinely and quickly check the zero setting of the instrument and the response to phosgene at 0.In large plants, where there are considerable distances between work stations, additional monitors may be required to ensure worker safety. Alternately, a multipoint sampling system bringing sampled air to a single instrument may be satisfactory.Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature.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) which each hazardous ingredient of the mixture bears to the whole mixture.This may be indicated as a range or maximum amount, (ie, "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, ie, "100 ppm LC50-rat," "25 mg/kg LD50skin-rabbit," "75 ppm LC man," or "permissible exposure from 29 CFR 1910.1000," or, if not available, from other sources of publications such as the American Conference of Governmental Industrial Hygienists or the American National Standards Institute Inc. The "Health Hazard Data" should be a combined estimate of the hazard of the total product.This can be expressed as a TWA, as a permissible exposure, or by some other indication of an acceptable standard.Other data are acceptable, such as lowest LD 50, 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. "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. (f) Section VI.Reactivity Data The comments in this section 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.
# DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE # PUBLIC HEALTH SER VIC E C E N T E R FO R D ISEA SE C O N T R O L N A T IO N A L INSTITUTE FOR O C C U P A T I O N A L S A F E T Y A N D H E A LT H R O B E R T A. T A F T L A B O R A T O R IE S 4 6 7 6 C O L U M B I A P A R K W The date and time of sample collection. (2) Sampling duration. (3) Volumetric flowrate of sampling. (4) A description of the sampling location. (5) Sampling temperature and pressure. (6) Other pertinent information. # Breathing Zone Sampling
In 1976, the American Thoracic Society (ATS) published brief guidelines for the investigation, diagnostic evaluation, and medical treatment of TB contacts.Although investigation of contacts and treatment of infected contacts is an important component of the U.S. strategy for TB elimination, second in priority to treatment of persons with TB disease, national guidelines have not been updated since 1976.This statement, the first issued jointly by the National Tuberculosis Controllers Association and CDC, was drafted by a working group consisting of members from both organizations on the basis of a review of relevant epidemiologic and other scientific studies and established practices in conducting contact investigations.This statement provides expanded guidelines concerning investigation of TB exposure and transmission and prevention of future cases of TB through contact investigations.In addition to the topics discussed previously, these expanded guidelines also discuss multiple related topics (e.g., data management, confidentiality and consent, and human resources).These guidelines are intended for use by public health officials but also are relevant to others who contribute to TB control efforts.Although the recommendations pertain to the United States, they might be adaptable for use in other countries that adhere to guidelines issued by the World Health Organization,# Introduction Background In 1962, isoniazid (INH) was demonstrated to be effective in preventing tuberculosis (TB) among household contacts of persons with TB disease (1).Investigations of contacts and treatment of contacts with latent TB infection (LTBI) became a strategy in the control and elimination of TB (2,3).In 1976, the American Thoracic Society (ATS) published brief guidelines for the investigation, diagnostic evaluation, and medical treatment of TB contacts (4).Although investigation of contacts and treatment of infected contacts is an important component of the U.S. strategy for TB elimination, second in priority to treatment of persons with TB disease, national guidelines have not been updated since 1976. This statement, the first issued jointly by the National Tuberculosis Controllers Association (NTCA) and CDC, was drafted by a working group consisting of members from both organi-zations on the basis of a review of relevant epidemiologic and other scientific studies and established practices in conducting contact investigations.A glossary of terms and abbreviations used in this report is provided (Box 1 and Appendix A). This statement provides expanded guidelines concerning investigation of TB exposure and transmission and prevention of future cases of TB through contact investigations.In addition to the topics discussed previously, these expanded guidelines also discuss multiple related topics (e.g., data management, confidentiality and consent, and human resources).These guidelines are intended for use by public health officials but also are relevant to others who contribute to TB control efforts.Although the recommendations pertain to the United States, they might be adaptable for use in other countries that adhere to guidelines issued by the World Health Organization, the International Union Against Tuberculosis and Lung Disease, and national TB control programs. Contact investigations are complicated undertakings that typically require hundreds of interdependent decisions, the majority of which are made on the basis of incomplete data, and dozens of time-consuming interventions.Making successful decisions during a contact investigation requires use of a complex, multifactor matrix rather than simple decision trees.For each factor, the predictive value, the relative contribution, and the interactions with other factors have been incompletely studied and understood.For example, the dif-ferences between brief, intense exposure to a contagious patient and lengthy, low-intensity exposure are unknown. Studies have confirmed the contribution of certain factors: the extent of disease in the index patient, the duration that the source and the contact are together and their proximity, and local air circulation (5).Multiple observations have demonstrated that the likelihood of TB disease after an exposure is influenced by medical conditions that impair immune competence, and these conditions constitute a critical factor in assigning contact priorities (6). Other factors that have as yet undetermined importance include the infective burden of Mycobacterium tuberculosis, previous exposure and infection, virulence of the particular M. tuberculosis strain, and a contact's intrinsic predisposition for infection or disease.Further, precise measurements (e.g., duration of exposure) rarely are obtainable under ordinary circumstances, and certain factors (e.g., proximity of exposure) can only be approximated, at best.No safe exposure time to airborne M. tuberculosis has been established.If a single bacterium can initiate an infection leading to TB disease, then even the briefest exposure entails a theoretic risk.However, public health officials must focus their resources on finding exposed persons who are more likely to be infected or to become ill with TB disease.These guidelines establish a standard framework for assembling information and using the findings to inform decisions for contact investigations, but they do not diminish the value of experienced judgment that is required.As a practical matter, these guidelines also take into consideration the scope of resources (primarily personnel) that can be allocated for the work. # Methodology A working group consisting of members from the NTCA and CDC reviewed relevant epidemiologic and other scientific studies and established practices in conducting contact investigations to develop this statement.These published studies provided a scientific basis for the recommendations.Although a controlled trial has demonstrated the efficacy of treating infected contacts with INH (1), the effectiveness of contact investigations has not been established by a controlled trial or study.Therefore, the recommendations (Appendix B) have not been rated by quality or quantity of the evidence and reflect expert opinion derived from common practices that have not been tested critically. These guidelines do not fit every circumstance, and additional considerations beyond those discussed in these guidelines must be taken into account for specific situations.For example, unusually close exposure (e.g., prolonged exposure in a small, poorly ventilated space or a congregate setting) or exposure among particularly vulnerable populations at risk for TB disease (e.g., children or immunocompromised persons) could justify starting an investigation that would normally not be conducted.If contacts are likely to become unavailable (e.g., because of departure), then the investigation should receive a higher priority.Finally, affected populations might experience exaggerated concern regarding TB in their community and demand an investigation. # Structure of this Statement The remainder of this statement is structured in 13 sections, as follows: - Decisions to initiate a contact investigation.This section focuses on deciding when a contact investigation should be undertaken.Index patients with positive acidfast bacillus (AFB) sputum-smear results or pulmonary cavities have the highest priority for investigation.The use of nucleic acid amplification (NAA) tests is discussed in this context. -Investigating the index patient and sites of transmission.This section outlines methods for investigating the index patient.Topics discussed include multiple interviews, definition of an infectious period, multiple visits to places that the patient frequented, and the list of contacts (i.e., persons who were exposed). -Assigning priorities to contacts.This section presents algorithms for assigning priorities to individual contacts for evaluation and treatment.Priority ranking is determined by the characteristics of individual contacts and the features of the exposure.When exposure is related to households, congregate living settings, or cough-inducing medical procedures, contacts are designated as high priority.Because knowledge is insufficient for providing exact recommendations, cut-off points for duration of exposure are not included; state and local program offi-cials should determine cut-off points after considering published results, local experience, and these guidelines. # Diagnostic and public health evaluation of contacts. This section discusses diagnostic evaluation, including specific contact recommendations for children aged <5 years and immunocompromised persons, all of whom should be evaluated with chest radiographs.The recommended period between most recent exposure and final tuberculin skin testing has been revised; it is 8-10 weeks, not 10-15 weeks as recommended previously (4). -Medical treatment for contacts with LTBI.This section discusses medical treatment of contacts who have LTBI (6,7).Effective contact investigations require completion of therapy, which is the single greatest challenge for both patients and health-care providers.Attention should be focused on treating contacts who are assigned high or medium priority. -When to expand a contact investigation.This section discusses when contacts initially classified as being a lower priority should be reclassified as having a higher priority and when a contact investigation should be expanded.Data regarding high-and medium-priority contacts inform this decision. -Communicating through the media.This section outlines principles for reaching out to media sources.Media coverage of contact investigations affords the health department an opportunity to increase public knowledge of TB control and the role of the health department. -Data management and evaluation of contact investigations.This section is the first of three to address health department programmatic tasks.It discusses data management, with an emphasis on electronic data storage and the use of data for assessing the effectiveness of contact investigations. # Confidentiality and consent in contact investigations. This section introduces the interrelated responsibilities of the health department in maintaining confidentiality and obtaining patient consent. -Staffing and training for contact investigations.This section summarizes personnel requirements and training for conducting contact investigations. -Contact investigations in special circumstances.This section offers suggestions for conducting contact investigations in special settings and circumstances (e.g., schools, hospitals, worksites, and congregate living quarters).It also reviews distinctions between a contact investigation and an outbreak investigation. -Source-case investigations.This section addresses sourcecase investigations, which should be undertaken only when more urgent investigations (see Decisions to Initiate a Contact Investigation) are being completed successfully.The effectiveness and outcomes of source-case investigations should be monitored critically because of their general inefficiency. -Other topics.This section reviews three specialized topics: cultural competency, social network analysis, and recently approved blood tests.Newly approved blood tests for the diagnosis of M. tuberculosis infection have been introduced.If these tests prove to be an improvement over the tuberculin skin test (TST), the science of contact investigations will advance quickly. # Decisions to Initiate a Contact Investigation Competing demands restrict the resources that can be allocated to contact investigations.Therefore, public health officials must decide which contact investigations should be assigned a higher priority and which contacts to evaluate first (see Assigning Priorities to Contacts).A decision to investigate an index patient depends on the presence of factors used to predict the likelihood of transmission (Table 1).In addition, other information regarding the index patient can influence the investigative strategy. # Factors that Predict Likely Transmission of TB Anatomical Site of Disease With limited exceptions, only patients with pulmonary or laryngeal TB can transmit their infection (8,9).For contact investigations, pleural disease is grouped with pulmonary disease because sputum cultures can yield M. tuberculosis even when no lung abnormalities are apparent on a radiograph (10).Rarely, extrapulmonary TB causes transmission during medical procedures that release aerosols (e.g., autopsy, embalming, and irrigation of a draining abscess) (see Contact Investigations in Special Circumstances) (11)(12)(13)(14)(15) # Sputum Bacteriology Relative infectiousness has been associated with positive sputum culture results and is highest when the smear results are also positive (16)(17)(18)(19).The significance of results from respiratory specimens other than expectorated sputum (e.g., bronchial washings or bronchoalveolar lavage fluid) is undetermined.Experts recommend that these specimens be regarded as equivalent to sputum (20). # Radiographic Findings Patients who have lung cavities observed on a chest radiograph typically are more infectious than patients with noncavitary pulmonary disease (15,16,21).This is an independent predictor after bacteriologic findings are taken into account.The importance of small lung cavities that are detectable with computerized tomography (CT) but not with plain radiography is undetermined.Less commonly, instances of highly contagious endobroncheal TB in severely immunocompromised patients who temporarily had normal chest radiographs have contributed to outbreaks.The frequency and relative importance of such instances is unknown, but in one group of human immunodeficiency virus (HIV)-infected TB patients, 3% of those who had positive sputum smears had normal chest radiographs at the time of diagnosis (22,23). # Behaviors That Increase Aerosolization of Respiratory Secretions Cough frequency and severity are not predictive of contagiousness (24).However, singing is associated with TB transmission (25)(26)(27).Sociability of the index patient might contribute to contagiousness because of the increased number of contacts and the intensity of exposure. # Age Transmission from children aged <10 years is unusual, although it has been reported in association with the presence of pulmonary forms of disease typically reported in adults (28,29).Contact investigations concerning pediatric cases should be undertaken only in such unusual circumstances (see Source-Case Investigations). # HIV Status TB patients who are HIV-infected with low CD4 T-cell counts frequently have chest radiographic findings that are not typical of pulmonary TB.In particular, they are more likely than TB patients who are not HIV-infected to have mediastinal adenopathy and less likely to have upper-lobe infiltrates and cavities (30).Atypical radiographic findings increase the potential for delayed diagnosis, which increases transmission.However, HIV-infected patients who have pul- # TABLE 1.Characteristics of the index patient and behaviors associated with increased risk for tuberculosis (TB) transmission monary or laryngeal TB are, on average, as contagious as TB patients who are not HIV-infected (31,32). # Administration of Effective Treatment That TB patients rapidly become less contagious after starting effective chemotherapy has been corroborated by measuring the number of viable M. tuberculosis organisms in sputa and by observing infection rates in household contacts (33)(34)(35)(36).However, the exact rate of decrease cannot be predicted for individual patients, and an arbitrary determination is required for each.Guinea pigs exposed to exhaust air from a TB ward with patients receiving chemotherapy were much more likely to be infected by drug-resistant organisms (8), which suggests that drug resistance can delay effective bactericidal activity and prolong contagiousness. # Initiating a Contact Investigation A contact investigation should be considered if the index patient has confirmed or suspected pulmonary, laryngeal, or pleural TB (Figure 1).An investigation is recommended if the sputum smear has AFB on microscopy, unless the result from an approved NAA test (Amplified Mycobacterium tuber-culosis Direct Test , GenProbe, ® San Diego, California, and Amplicor ® Mycobacterium tuberculosis Test , Roche ® Diagnostic Systems Inc., Branchburg, New Jersey) for M. tuberculosis is negative (37). If AFB are not detected by microscopy of three sputum smears, an investigation still is recommended if the chest radiograph (i.e., the plain view or a simple tomograph) indicates the presence of cavities in the lung.Parenchymal cavities of limited size that can be detected only by computerized imaging techniques (i.e., CT, computerized axial tomography scan, or magnetic resonance imaging of the chest) are not included in this recommendation. When sputum samples have not been collected, either because of an oversight or as a result of the patient's inability to expectorate, results from other types of respiratory specimens (e.g., gastric aspirates or bronchoalveolar lavage) may be interpreted in the same way as in the above recommendations.However, whenever feasible, sputum samples should be collected (through sputum induction, if necessary) before initiating chemotherapy. Contact investigations of persons with AFB smear or culturepositive sputum and cavitary TB are assigned the highest priority.However, even if these conditions are not present, contact # Investigating the Index Patient and Sites of Transmission Comprehensive information regarding an index patient is the foundation of a contact investigation.This information includes disease characteristics, onset time of illness, names of contacts, exposure locations, and current medical factors (e.g., initiation of effective treatment and drug susceptibility results).Health departments are responsible for conducting TB contact investigations.Having written policies and procedures for investigations improve the efficiency and uniformity of investigations. Establishing trust and consistent rapport between public health workers and patients is critical to gain full information and long-term cooperation during treatment.Good interview skills can be taught and learned skills improved with practice.Workers assigned these tasks should be trained in interview methods and tutored on the job (see Staffing and Training for Contact Investigations and Contact Investigations in Special Situations). The majority of TB patients in the United States were born in other countries, and their fluency in English often is insufficient for productive interviews to be conducted in English.Patients should be interviewed by persons who are fluent in their primary language.If this is not possible, health departments should provide interpretation services. # Preinterview Phase Background information regarding the patient and the circumstances of the illness should be gathered in preparation for the first interview.One source is the current medical record (38).Other sources are the physician who reported the case and (if the patient is in a hospital) the infection control nurse.The information in the medical record can be disclosed to public health authorities under exemptions in the Privacy Rule of the Health Insurance Portability and Accountability Act (HIPAA) of 1996 (.htm) (39).The patient's name should be matched to prior TB registries and to the surveillance database to determine if the patient has been previously listed. Multiple factors are relevant to a contact investigation, including the following: - history of previous exposure to TB, - history of previous TB disease and treatment, - anatomical sites of TB disease, - symptoms of the illness, - date of onset, - chest radiograph results, - other results of diagnostic imaging studies, - diagnostic specimens that were sent for histologic or bacteriologic analysis (with dates, specimen tracking numbers, and destinations), - current bacteriologic results, - anti-TB chemotherapy regimen (with dates, medications, dosages, and treatment plan), - results from HIV testing, - the patient's concurrent medical conditions (e.g., renal failure implies that a renal dialysis center might be part of the patient's recent experience), - other diagnoses (e.g., substance abuse, mental illness, or dementia) that impinge directly on the interview, and - identifying demographic information (e.g., residence, employment, first language, given name and street names, aliases, date of birth, telephone numbers, other electronic links, and next-of-kin or emergency connections). # Determining the Infectious Period Determining the infectious period focuses the investigation on those contacts most likely to be at risk for infection and sets the timeframe for testing contacts.
Because the start of the infectious period cannot be determined with precision by available methods, a practical estimation is necessary.On the basis of expert opinion, an assigned start that is 3 months before a TB diagnosis is recommended (Table 2).In certain circumstances, an even earlier start should be used.For example, a patient (or the patient's associates) might have been aware of protracted illness (in extreme cases, >1 year).Information from the patient interview and from other sources should be assembled to assist in estimating the infectious period.Helpful details are the approximate dates that TB symptoms were noticed, mycobacteriologic results, and extent of disease (especially the presence of large lung cavities, which imply prolonged illness and infectiousness) (40,41). The infectious period is closed when the following criteria are satisfied: 1) effective treatment (as demonstrated by M. tuberculosis susceptibility results) for >2 weeks; 2) diminished symptoms; and 3) mycobacteriologic response (e.g., decrease in grade of sputum smear positivity detected on sputum-smear microscopy).The exposure period for individual contacts is determined by how much time they spent with the index patient during the infectious period.Multidrugresistant TB (MDR TB) can extend infectiousness if the treatment regimen is ineffective.Any index patient with signs of extended infectiousness should be continually reassessed for recent contacts. More stringent criteria should be applied for setting the end of the infectious period if particularly susceptible contacts are involved.A patient returning to a congregate living setting or to any setting in which susceptible persons might be exposed should have at least three consecutive negative sputum AFB smear results from sputum collected >8 hours apart (with one specimen collected during the early morning) before being considered noninfectious (42). # Interviewing the Patient In addition to setting the direction for the contact investigation, the first interview provides opportunities for the patient to acquire information regarding TB and its control and for the public health worker to learn how to provide treatment and specific care for the patient.Because of the urgency of finding other infectious persons associated with the index patient, the first interview should be conducted <1 business day of reporting for infectious persons and <3 business days for others.The interview should be conducted in person (i.e., face to face) in the hospital, the TB clinic, the patient's home, or a convenient location that accommodates the patient's right to privacy. A minimum of two interviews is recommended.At the first interview, the index patient is unlikely to be oriented to the contact investigation because of social stresses related to the illness (e.g., fear of disability, death, or rejection by friends and family).The second interview is conducted 1-2 weeks later, when the patient has had time to adjust to the disruptions caused by the illness and has become accustomed to the interviewer, which facilitates a two-way exchange.The number of additional interviews required depends on the amount of information needed and the time required to develop consistent rapport. Interviewing skills are crucial because the patient might be reluctant to share vital information stemming from concerns regarding disease-associated stigma, embarrassment, or illegal activities.Interviewing skills require training and periodic onthe-job tutoring.Only trained personnel should interview index patients. In addition to standard procedures for interviewing TB patients (43), the following general principles should be considered: - Establishing rapport.Respect should be demonstrated by assuring privacy during the interview.Establishing respect is critical so rapport can be built.The interviewer should display official identification and explain the reasons for the interview.The interviewer should also discuss confidentiality and privacy (see Confidentiality and Consent in Contact Investigations) in frank terms that help the patient decide how to share information.These topics should be discussed several times during the interview to stress their importance.Sufficient time should be allocated, possibly >1 hour, for a two-way exchange of information, although the patient's endurance should be considered.provide an overview of the processes in the contact investigation, and remind the patient regarding confidentiality and its limits.The patient especially should be told how site visits are conducted and confidentiality protected. An appointment for the next interview should be set within the context of the schedule for medical care. -Follow-up interviews.The best setting for the second and subsequent interviews is the patient's residence.If the original interviewer senses incomplete rapport with the index patient, a second interviewer can be assigned.The follow-up interviews are extensions of the initial interview.If the interviewer senses resistance to meeting in certain places or discussing those places, making site visits to those places might facilitate identification of additional contacts whom the index patient had not remembered or wanted to name. # Proxy Interview Proxy interviews can build on the information provided by the index patient and are essential when the patient cannot be interviewed.Key proxy informants are those likely to know the patient's practices, habits, and behaviors; informants are needed from each sphere of the patient's life (e.g., home, work, and leisure).However, because proxy interviews jeopardize patient confidentiality, TB control programs should establish clear guidelines for these interviews that recognize the challenge of maintaining confidentiality. # Field Investigation Site visits are complementary to interviewing.They add contacts to the list and are the most reliable source of information regarding transmission settings (17).Failure to visit all potential sites of transmission has contributed to TB outbreaks (25,44).Visiting the index patient's residence is especially helpful for finding children who are contacts (17,38).The visit should be made <3 days of the initial interview.Each site visit creates opportunities to interview the index patient again, interview and test contacts, collect diagnostic sputum specimens, schedule clinic visits, and provide education.Sometimes environmental clues (e.g., toys suggesting the presence of children) create new directions for an investigation.Certain sites (e.g., congregate settings) require special arrangements to visit (see Contact Investigations in Special Circumstances).Physical conditions at each setting contribute to the likelihood of transmission.Pertinent details include room sizes, ventilation systems, and airflow patterns.These factors should be considered in the context of how often and how long the index patient was in each setting. # Follow-Up Steps A continuing investigation is shaped by frequent reassessments of ongoing results (e.g., secondary TB cases and the estimated infection rate for groups of contacts).Notification and followup communications with public health officials in other jurisdictions should be arranged for out-of-area contacts. The following organizations provide resources to make referrals for contacts and index patients who migrate across the U.S.-Mexican border between the United States and Mexico: # Specific Investigation Plan The investigation plan starts with information gathered in the interviews and site visits; it includes a registry of the contacts and their assigned priorities (see Assigning Priorities to Contacts and Medical Treatment for Contacts with LTBI).A written timeline (Table 3) sets expectations for monitoring the progress of the investigation and informs public health officials whether additional resources are needed for finding, evaluating, and treating the high-and medium-priority contacts.The plan is a pragmatic work in progress and should be revised if additional information indicates a need (see When to Expand a Contact Investigation); it is part of the permanent record of the overall investigation for later review and program evaluation.Data from the investigation should be recorded on standardized forms (see Data Management and Evaluation of Contact Investigations). # Assigning Priorities to Contacts The ideal goal would be to distinguish all recently infected contacts from those who are not infected and prevent TB disease by treating those with infection.In practice, existing technology and methods cannot achieve this goal.For example, although a relatively brief exposure can lead to M. tuberculosis infection and disease (45), certain contacts are not infected even after long periods of intensive exposure.Not all contacts with substantial exposure are identified during the contact investigation.Finally, available tests for M. tuberculosis infection lack sensitivity and specificity and do not differentiate between persons recently or remotely infected. Increasing the intensity and duration of exposure usually increases the likelihood of recent M. tuberculosis infection in contacts.The skin test cannot discriminate between recent and old infections, and including contacts who have had minimal exposure increases the workload while it decreases the public health value of finding positive skin test results.A positive result in contacts with minimal exposure is more likely to be the result of an old infection or nonspecific tuberculin sensitivity (46).Whenever the contact's exposure to the index TB patient has occurred <8-10 weeks necessary for detection of positive skin tests, repeat testing 8-10 weeks after the most recent exposure will help identify recent skin test conversions, which are likely indicative of recent infection. For optimal efficiency, priorities should be assigned to contacts, and resources should be allocated to complete all investigative steps for high-and medium-priority contacts.Priorities are based on the likelihood of infection and the potential hazards to the individual contact if infected.The priority scheme directs resources to selecting contacts who # TABLE 3.Time frames for initial follow-up of contacts of persons exposed to tuberculosis (TB) # Business days from Business days from initial listing of a contact encounter to completion Type of contact to initial encounter- of medical evaluation † High-priority contact: index case AFB § sputum smear positive or cavitary disease 7 5 on chest radiograph (see Figure 2) High-priority contact: index case AFB sputum smear negative (see Figure 3) 7 10 Medium-priority contact: regardless of AFB sputum smear or culture result 14 10 (see Figures 2-4) SOURCE: California Department of Health Services Tuberculosis Control Branch; California Tuberculosis Controllers Association.Contact investigation guidelines.Berkeley, CA: California Department of Health Services; 1998. -A face-to-face meeting that allows the public-health worker to assess the overall health of the contact, administer a tuberculin skin test, and schedule further evaluation. †The medical evaluation is complete when the contact's status with respect to Mycobacterium tuberculosis infection or TB disease has been determined.A normal exception to this schedule is the delay in waiting for final mycobacteriologic results, but this applies to relatively few contacts. §Acid-fast bacilli. - have secondary cases of TB disease, - have recent M. tuberculosis infection and so are most likely to benefit from treatment, and - are most likely to become ill with TB disease if they are infected (i.e., susceptible contacts) or who could suffer severe morbidity if they have TB disease (i.e., vulnerable contacts). # Factors for Assigning Contact Priorities # Characteristics of the Index Patient The decision to initiate a contact investigation is determined on the basis of the characteristics of the index patient (see Decisions to Initiate a Contact Investigation).Contacts of a more infectious index patient (e.g., one with AFB sputum smear positive TB) should be assigned a higher priority than those of a less infectious one because contacts of the more infectious patient are more likely to have recent infection or TB disease (19,40,(47)(48)(49)(50). # Characteristics of Contacts Intrinsic and acquired conditions of the contact affect the likelihood of TB disease progression after infection, although the predictive value of certain conditions (e.g., being underweight for height) is imprecise as the sole basis for assigning priorities (51,52).The most important factors are age <5 years and immune status.Other medical conditions also might affect the probability of TB disease after infection. Age.After infection, TB disease is more likely to occur in younger children; the incubation or latency period is briefer; and lethal, invasive forms of the disease are more common (53)(54)(55)(56)(57)(58).The age-specific incidence of disease for children who have positive skin test results declines through age 4 years (56).Children aged <5 years who are contacts are assigned high priority for investigation. A study of 82,269 tuberculin reactors aged 1-18 years who were control subjects in a Bacille Calmette-Guérin (BCG) trial- in Puerto Rico indicated that peak incidence of TB occurred among children aged 1-4 years (56).Infants and postpubertal adolescents are at increased risk for progression to TB disease if infected, and children aged <4 years are at increased risk for disseminated disease (57).The American Academy of Pediatrics also recommends primary prophylaxis for children aged <4 years (57).Guidelines published by ATS and CDC recommend primary prophylaxis for children aged <5 years (6,59).These guidelines are consistent with previous CDC recommendations in setting the cut-off at age <5 years for assigning priority and recommending primary prophylaxis (6,59). Immune status.HIV infection results in the progression of M. tuberculosis infection to TB disease more frequently and more rapidly than any other known factor, with disease rates estimated at 35-162 per 1,000 person-years of observation and a greater likelihood of disseminated and extrapulmonary disease (60)(61)(62)(63)(64).HIV-infected contacts are assigned high priority, and, starting at the time of the initial encounter, extra vigilance for TB disease is recommended. Contacts receiving >15 mg of prednisone or its equivalent for >4 weeks also should be assigned high priority (6).Other immunosuppressive agents, including multiple cancer chemotherapy agents, antirejection drugs for organ transplantation, and tumor necrosis factor alpha (TNF-α) antagonists, increase the likelihood of TB disease after infection; these contacts also are assigned a high priority (65). Other medical conditions.Being underweight for their height has been reported as a weakly predictive factor promoting progression to TB disease (66); however, assessing weight is not a practical approach for assigning priorities.Other medical conditions that can be considered in assigning priorities include silicosis, diabetes mellitus, and status after gastrectomy or jejunoileal bypass surgery (67)(68)(69)(70)(71)(72)(73)(74)(75)(76). Exposure.Air volume, exhaust rate, and circulation predict the likelihood of transmission in an enclosed space.In large indoor settings, because of diffusion and local circulation patterns, the degree of proximity between contacts and the index patient can influence the likelihood of transmission.Other subtle environmental factors (e.g., humidity and light) are impractical to incorporate into decision making.The terms "close" and "casual," which are frequently used to describe exposures and contacts, have not been defined uniformly and therefore are not useful for these guidelines. The most practical system for grading exposure settings is to categorize them by size (e.g., "1" being the size of a vehicle or car, "2" the size of a bedroom, "3" the size of a house, and "4" a size larger than a house ).This has the added advantage of familiarity for the index patient and contacts, which enables them to provide clearer information. The volume of air shared between an infectious TB patient and contacts dilutes the infectious particles, although this relationship has not been validated entirely by epidemiologic results (15,(77)(78)(79).Local circulation and overall room ventilation also dilute infectious particles, but both factors can redirect exposure into spaces that were not visited by the index patient (80)(81)(82)(83).These factors have to be considered. The likelihood of infection depends on the intensity, frequency, and duration of exposure (16,17,40,84).For example, airline passengers who are seated for >8 hours in the same or adjoining row as a person who is contagious are much more likely to be infected than other passengers (85)(86)(87)(88).One set of criteria for estimating risk after exposure to a person with pulmonary TB without lung cavities includes a cut-off of 120 hours of exposure per month (84).However, for any specific setting, index patient, and contacts, the optimal cut-off duration is undetermined.Administratively determined durations derived from local experience are recommended, with frequent reassessments on the basis of results. # Classification of Contacts Priorities for contact investigation are determined on the basis of the characteristics of the index patient, susceptibility and vulnerability of contacts, and circumstances of the exposures (Figures 2-4).Any contacts who are not classified as high or medium priority are assigned a low priority.Because priority assignments are practical approximations derived from imperfect information, priority classifications should be reconsidered throughout the investigation as findings are analyzed (see When to Expand a Contact Investigation). # Diagnostic and Public Health Evaluation of Contacts On average, 10 contacts are listed for each person with a case of infectious TB in the United States (50,59,89).Approximately 20%-30% of all contacts have LTBI, and 1% have TB disease (50).Of those contacts who ultimately will have TB disease, approximately half acquire disease in the first year after exposure (90,91).For this reason, contact investigations constitute a crucial prevention strategy. Identifying TB disease and LTBI efficiently during an investigation requires identifying, locating, and evaluating high-and medium-priority contacts who are most at risk.Because they have legally mandated responsibilities for disease control, health departments should establish systems for comprehensive TB contact investigations.In certain jurisdictions, legal measures are in place to ensure that evaluation and follow-up of contacts occur.The use of existing communicable disease laws that protect the health of the community (if applicable to contacts) should be considered for contacts who decline examinations, with the least restrictive measures applied first. # Initial Assessment of Contacts During the initial contact encounter, which should be accomplished within 3 working days of the contact having been listed the investigation, the investigator gathers background health information and makes a face-to-face assessment of the person's health.Administering a skin test at this time accelerates the diagnostic evaluation.When initial information has been collected, priority assignments should be reassessed for each contact, and a medical plan for diagnostic tests and possible treatment can be formulated for high-and medium-priority contacts.Lowpriority contacts should not be included unless resources permit and the program is meeting its performance goals. In 2002, for the first time, the percentage of TB patients who were born outside the United States was >50%; this proportion continues to increase (92).Because immigrants are likely to settle in communities in which persons of similar origin reside, multiple contacts of foreign-born index patients also are foreign born.Contacts who come from countries where both BCG vaccination and TB are common are more likely than other immigrants to have positive skin tests results when they arrive in the United States.They also are more likely to demonstrate the booster phenomenon on a postexposure test (17,40).
Although valuable in preventing severe forms of disease in young children in countries where TB is endemic, BCG vaccination provides imperfect protection and causes tuberculin sensitivity in certain recipients for a variable period of time (93,94).TSTs cannot distinguish reactions related to remote infection or BCG vaccination from those caused by recent infection with M. tuberculosis; boosting related to BCG or remote infection compounds the interpretation of positive results (95). A positive TST in a foreign-born or BCG-vaccinated person should be interpreted as evidence of recent M. tuberculosis infection in contacts of persons with infectious cases.These contacts should be evaluated for TB disease and offered a course of treatment for LTBI. # Voluntary HIV Counseling, Testing, and Referral Approximately 9% of TB patients in the United States have HIV infection at the time of TB diagnosis, with 16% of TB patients aged 25-44 years having HIV infection (96).In addition, an estimated 275,000 persons in the United States are unaware they have HIV infection (97).The majority of # Medium priority contact Yes No Low-priority contact TB contacts have not been tested for HIV infection (98).Contacts of HIV-infected index TB patients are more likely to be HIV infected than contacts of HIV-negative patients (99).Voluntary HIV counseling, testing, and referral for contacts are key steps in providing optimal care, especially in relation to TB (100,101).Systems for achieving convenient HIV-related services require collaboration with health department HIV-AIDS programs.This also can improve adherence to national guidance for these activities (100). # Tuberculin Skin Testing All contacts classified as having high or medium priority who do not have a documented previous positive TST result or previous TB disease should receive a skin test at the initial encounter.If that is not possible, then the test should be administered 5 mm is positive for any contact (1) Serial tuberculin testing programs routinely administer a two-step test at entry into the program.This detects boosting of sensitivity and can avoid misclassifying future positive results as new infections.The two-step procedure typically should not be used for testing contacts; a contact whose second test result is positive after an initial negative result should be classified as recently infected. # Postexposure Tuberculin Skin Testing Among persons who have been sensitized by M. tuberculosis infection, the intradermal tuberculin from the skin test can result in a delayed-type (cellular) hypersensitivity reaction.Depending on the source of recommendations, the estimated interval between infection and detectable skin test reactivity (referred to as the window period) is 2-12 weeks (6,95).However, reinterpretation of data collected previously indicates that 8 weeks is the outer limit of this window period (46,(102)(103)(104)(105)(106).Consequently, NTCA and CDC recommend that the window period be decreased to 8-10 weeks after # Medium-priority contact Yes No Low-priority contact exposure ends.A negative test result obtained <8 weeks after exposure is considered unreliable for excluding infection, and a follow-up test at the end of the window period is therefore recommended. Low-priority contacts have had limited exposure to the index patient and a low probability of recent infection; a positive result from a second skin test among these contacts would more likely represent boosting of sensitivity.A single skin test, probably at the end of the window period, is preferred for these contacts.However, diagnostic evaluation of any contact who has TB symptoms should be immediate, regardless of skin test results. Nonspecific or remote delayed-type hypersensitivity (DTH) response to tuberculin (PPD in the skin test) occasionally wanes or disappears over time.Subsequent TSTs can restore responsiveness; this is called boosting or the booster phenomenon (95,107).For contacts who receive two skin tests, the booster phenomenon can be misinterpreted as evidence of recent infection.This misinterpretation is more likely to occur for foreign-born contacts than it is for those born in the United States (17,108). Skin test conversion refers to a change from a negative to a positive result.To increase the relative certainty that the person has been infected with M. tuberculosis in the interval between tests, the standard U.S. definition for conversion includes a maximum time (2 years) between skin tests and a minimum increase (10 mm) in reaction size (6,34).With the 5 mm cut-off size used for interpreting any single skin test result obtained in contact investigations, the standard definition for conversion typically is irrelevant.For these guidelines, contacts who have a positive result after a previous negative result are said to have had a change in tuberculin status from negative to positive. # Medical Evaluation All contacts whose skin test reaction induration diameter is >5 mm or who report any symptoms consistent with TB disease should undergo further examination and diagnostic testing for TB (6), starting typically with a chest radiograph.Collection of specimens for mycobacteriologic testing (e.g., sputa) is decided on a case-by-case basis and is not recommended for healthy contacts with normal chest radiographs.All contacts who are assigned a high priority because of special susceptibility or vulnerability to TB disease should undergo further examination and diagnostic testing regardless of whether they have a positive skin test result or are ill. # Evaluation and Follow-Up of Specific Groups of Contacts Because children aged 8 weeks after the end of exposure yields a negative result, a full course of treatment for latent M. tuberculosis infection is recommended after a medical evaluation to exclude TB disease (16).The decision to administer complete treatment can be modified by other evidence con-cerning the extent of transmission that was estimated from the contact investigation data. The majority of other high-or medium priority contacts who are immunocompetent adults or children aged >5 years can be tested and evaluated as described (Figure 7).Treatment is recommended for contacts who receive a diagnosis of latent M. tuberculosis infection. Evaluation of low-priority contacts who are being tested can be scheduled with more flexibility (Figure 8).The skin test may be delayed until after the window period, thereby negating the need for a second test.Treatment is also recommended for these contacts if they receive a diagnosis of latent M. tuberculosis infection. The risk for TB disease is undetermined for contacts with documentation of a previous positive TST result (whether infection was treated) or TB disease (Figure 9).Documentation is recommended before making decisions from a contact's verbal report.Contacts who report a history of infection or disease but who do not have documentation are recommended for the standard algorithm (Figure 8).Contacts who are immunocompromised or otherwise susceptible are recommended for diagnostic testing to exclude TB disease and for a full course of treatment for latent M. tuberculosis infection after TB disease has been excluded, regardless of their previous TB history and documentation.Healthy contacts who have a documented previous positive skin test result but have not been treated for LTBI can be considered for treatment as part of the contact investigation.Any contact who is to be treated for LTBI should have a chest radiograph to exclude TB disease before starting treatment. Certain guidance regarding collecting historic information from TB patients or contacts stipulates confirmation of previous TST results (e.g., a documented result from a TST) (4).The decision regarding requiring documentation for a specific detail involves a subtle balance.Memory regarding medi- cal history might be weak or distorted, even among medically trained persons.However, the accuracy of details reported by a TB patient or contact might not be relevant for providing medical care or collecting data.For previous TST results, patients can be confused regarding details from their history; routine skin tests sometimes are administered at the same time as vaccinations, and foreign-born patients might confuse a skin test with BCG vaccination or streptomycin injections.For contacts (but not patients with confirmed TB), a skin test result is critical, and documentation of a previous positive result should be obtained before omitting the skin test from the diagnostic evaluation. # Treatment for Contacts with LTBI The direct benefits of contact investigations include 1) finding additional TB disease cases (thus potentially interrupting further transmission) and 2) finding and treating persons with LTBI.One of the national health objectives for 2010 (objective no.14-13) is to complete treatment in 85% of contacts who have LTBI (107).However, reported rates of treatment initiation and completion have fallen short of national objectives (17,50,109,110).To increase these rates, health department TB control programs must invest in systems for increasing the numbers of infected contacts who are completely treated.These include 1) focusing resources on the contacts most in need of treatment; 2) monitoring treatment, including that of contacts who receive care outside the health department; and 3) providing directly observed therapy (DOT), incentives, and enablers. Contacts identified as having a positive TST result are regarded as recently infected with M. tuberculosis, which puts them at heightened risk for TB disease (6,7).Moreover, contacts with greater durations or intensities of exposure are more likely both to be infected and to have TB disease if infected.A focus first on high-priority and next on medium-priority contacts is recommended in allocating resources for starting and completing treatment of contacts. Decisions to treat contacts who have documentation of a previous positive skin test result or TB disease for presumed LTBI must be individualized because their risk for TB disease is unknown.Considerations for the decision include previous treatment for LTBI, medical conditions putting the contact at risk for TB disease, and the duration and intensity of exposure.Treatment of presumed LTBI is recommended for all HIV-infected contacts in this situation (after TB disease has been excluded), whether they received treatment previously. # Window-Period Prophylaxis Treatment during the window period (see Diagnostic and Public Health Evaluation of Contacts) has been recommended for susceptible and vulnerable contacts to prevent rapidly emerging TB disease (4,6,56,61,111).The evidence for this practice is inferential, but all models and theories support it.Groups of contacts who are likely to benefit from a full course of treatment (beyond just window-period treatment) include those with HIV infection, those taking immunosuppressive therapy for organ transplantation, and persons taking TNF-α antagonists (6,61,62,65).The risks for TB are less clear for patients who chronically take the equivalent of >15 mg per day of prednisone (6).TB disease having been ruled out, prophylactic treatment of presumed M. tuberculosis infection is recommended as an option for all these groups.The decision as to whether to treat individual contacts who have negative skin test results should take into consideration two factors: - the frequency, duration, and intensity of exposure (even brief exposure to a highly contagious TB patient in a confined space probably warrants the same concern as extended exposure to less contagious patients); and - corroborative evidence of transmission from the index patient (a substantial fraction of contacts having positive skin test results implies contagiousness). # Treatment after Exposure to Drug-Resistant TB Guidelines for providing care to contacts of drug-resistant TB patients and selecting treatment regimens have been published (6,7,112).Drug susceptibility results for the M. tuberculosis isolate from the index patient (i.e., the presumed source of infection) are necessary for selecting or modifying the treatment regimen for the exposed contact.Resistance only to INH among the first line agents leaves the option of 4 months of daily rifampin.Additional resistance to rifampin constitutes MDR TB.None of the potential regimens for persons likely infected with MDR TB has been tested fully for efficacy, and these regimens are often poorly tolerated.For these reasons, consultation with a physician with expertise in this area is recommended for selecting or modifying a regimen and managing the care of contacts (6).Contacts who have received a diagnosis of infection attributed to MDR TB should be monitored for 2 years after exposure; guidelines for monitoring these contacts have been published previously (6). # Adherence to Treatment One of the national health objectives for 2010 is to achieve a treatment completion rate of 85% for infected contacts who start treatment (objective no.14-13) (107).However, operational studies indicate that this objective is not being achieved (17,110).Although DOT improves completion rates (17), it is a resource-intensive intervention that might not be feasible for all infected contacts.The following order of priorities is recommended when selecting contacts for DOT (including window-period prophylaxis): - contacts aged <5 years, - contacts who are HIV infected or otherwise substantially immunocompromised, - contacts with a change in their tuberculin status from negative to positive, and - contacts who might not complete treatment because of social or behavior impediments (e.g., alcohol addiction, chronic mental illness, injection-drug use, unstable housing, or unemployment).Checking monthly or more often for adherence and adverse effects of treatment by home visits, pill counts, or clinic appointments is recommended for contacts taking selfsupervised treatment.All contacts being treated for infection should be evaluated in person by a health-care provider at least monthly.Incentives (e.g., food coupons or toys for children) and enablers (e.g., transportation vouchers to go to the clinic or pharmacy) are recommended as aids to adherence.Incentives provide simple rewards whereas enablers increase a patient's opportunities for adherence.Education regarding TB, its treatment, and the signs of adverse drug effects should be part of each patient encounter. # When to Expand a Contact Investigation A graduated approach to contact investigations (i.e., a concentric circles model) has been recommended previously (4,5,113).With this model, if data indicate that contacts with the greatest exposure have an infection rate greater than would be expected in their community, contacts with progressively less exposure are sought.The contact investigation would expand until the rate of positive skin test results for the contacts was indistinguishable from the prevalence of positive results in the community (5).In addition to its simplicity and intuitive appeal, an advantage to this approach is that contacts with less exposure are not sought until evidence of transmission exists.Disadvantages are that 1) surrogates for estimating exposure (e.g., living in the same household) often do not predict the chance of infection, 2) the susceptibility and vulnerability of contacts are not accommodated by the model, and 3) the estimated prevalence for tuberculin sensitivity in a specific community generally is unknown.In addition, when the prevalence for a community is known but is substantial (e.g., >10%), the end-point for the investigation is obscured. Recent operational studies indicate that health departments are not meeting their objectives for high-and mediumpriority contacts (17,50,109).In these settings, contact investigations generally should not be expanded beyond high-and medium-priority contacts.However, if data from an investigation indicate more transmission than anticipated, more contacts might need to be included. When determining whether to expand the contact investigation, consideration of the following factors is recommended: - achievement of program objectives with high-and medium-priority contacts; and - extent of recent transmission, as evidenced by -unexpectedly high rate of infection or TB disease in high-priority contacts (e.g., 10% or at least twice the rate of a similar population without recent exposure, whichever is greater), -evidence of secondary transmission (i.e., from TB patients who were infected after exposure to the source patient), -TB disease in any contacts who had been assigned a low priority, -infection of contacts aged <5 years, and -contacts with change in skin test status from negative to positive between their first and second TST.In the absence of evidence of recent transmission, an investigation should not be expanded to lower priority contacts.When program-evaluation objectives are not being achieved, a contact investigation should be expanded only in exceptional circumstances, generally those involving highly infectious persons with high rates of infection among contacts or evidence for secondary cases and secondary transmission.Expanded investigations must be accompanied by efforts to ensure completion of therapy. The strategy for expanding an investigation should be derived from the data obtained from the investigation previously (4,5,43).The threshold for including a specific contact thereby is decreased.As in the initial investigation, results should be reviewed at least weekly so the strategy can be reassessed. At times, results from an investigation indicate a need for expansion that available resources do not permit.In these situations, seeking consultation and assistance from the next higher level in public health administration (e.g., the county health department consults with the state health department) is recommended.Consultation offers an objective review of strategy and results, additional expertise, and a potential opportunity to obtain personnel or funds for meeting unmet needs. # Communicating Through the Media Routine contact investigations, which have perhaps a dozen contacts, are not usually considered newsworthy.However, certain contact investigations have potential for sensational coverage and attract attention from the media.Typical examples include situations involving numerous contacts (especially children), occurring in public settings (e.g., schools, hospitals, prisons), occurring in workplaces, associated with TB fatalities, or associated with drug-resistant TB. # Reasons for Participating in Media Coverage Media coverage can provide both advantages and drawbacks for the health department, and careful planning is recommended before communicating with reporters.Favorable, accurate coverage - educates the public regarding the nature of TB, - reminds the public of the continued presence of TB in the community, - provides a complementary method to alert exposed contacts of the need for seeking a medical evaluation, - relieves unfounded public fears regarding TB, - illustrates the health department's leadership in communicable disease control, - ensures that constructive public inquiries are directed to the health department, and - validates the need for public resources to be directed to disease control.Potential drawbacks of media coverage are that such coverage can - increase public anxiety, especially after alarmist or inaccurate messages, - lead unexposed persons seeking unnecessary health care because of a perceived threat, - contribute to unfavorable views of the health department (e.g., because of perceived delays in responding to the TB problem), - contribute to spread of misinformation regarding the nature of TB, - trigger unconstructive public inquiries, and - lead to disclosure of confidential information (e.g., patient identity). # Strategy for Media Coverage Anticipatory preparation of clear media messages, coordinated among all parties for clarity and consistency, is recommended.
The majority of health departments have formal policies and systems for arranging media communications, and TB control officials are advised to work with their mediacommunications services in securing training and preparing media messages anticipating news coverage.In certain instances, this will require coordination among local, state, and federal public health organizations.Issuing a press release in advance of any other media coverage is recommended so as to provide clear, accurate messages from the start.Waiting until a story reaches the media through other sources leaves the health department reacting to inaccuracies in the story and could lend credence to a perception that information is being withheld from the public. Certain newsworthy contact investigations involve collaborators outside of the health department because of the setting (e.g., a homeless shelter).The administrators of these settings are likely to have concerns, distinct from the public health agenda, regarding media coverage.For example, a hospital administrator might worry that reports of suspected TB exposures in the hospital will create public distrust of the hospital.Collaboration on media messages is a difficult but necessary part of the overall partnership between the hospital (in this example) and the health department.Early discussions regarding media coverage are recommended for reducing later misunderstandings.In addition, development of a list of communication objectives also is recommended in preparing for media inquiries. # Data Management and Evaluation of Contact Investigations Data collection related to contact investigations has three broad purposes: 1) management of care and follow-up for individual index patients and contacts, 2) epidemiologic analysis of an investigation in progress and investigations overall, and 3) program evaluation using performance indicators that reflect performance objectives.A systematic, consistent approach to data collection, organization, analysis, and dissemination is required (114)(115)(116)(117). Data collection and storage entail both substantial work and an investment in systems to obtain full benefits from the efforts.Selecting data for inclusion requires balancing the extra work of collecting data against the lost information if data are not collected.If data are collected but not studied and used when decisions are made, then data collection is a wasted effort.The most efficient strategy for determining which data to collect is to work back from the intended uses of the data. # Reasons Contact Investigation Data Are Needed For each index patient and the patient's associated contacts, a broad amount of demographic, epidemiologic, historic, and medical information is needed for providing comprehensive care (Tables 2, 4, and 5).In certain instances, such care can last >1 year, so information builds by steps and has numerous longitudinal elements (e.g., number of clinic visits attended, number of treatment doses administered, or mycobacteriologic response to treatment).Data on certain process steps are necessary for monitoring whether the contact investigation is keeping to timeline objectives (e.g., how soon after listing the skin test is administered to a contact). Aggregated data collected during an investigation inform public health officials whether the investigation is on time and complete.The ongoing analysis of data also contributes to reassessment of the strategy used in the investigation (e.g., whether the infection rate was greater for contacts believed to have more exposure). Data from a completed investigation and from all investigations in a fixed period (e.g., 6 months) might demonstrate progress in meeting program objectives (Box 2).However, these core measurements for program evaluation cannot directly demonstrate why particular objectives were not achieved.If the data are structured and stored in formats that permit detailed retrospective review, then the reasons for problems can be studied.CDC's Framework for Program Evaluation in Public Health is recommended for assessing the overall activities of contact investigations (118). Data definitions are crucial for consistency and subsequent mutual comprehension of analytic results.However, detailed definitions that accommodate every contingency defeat the simplicity required for an efficient system.Data definitions are best when they satisfy the most important contingencies.This requires a trade-off between completeness and clarity.As with the initial selection of data, working back from the intended uses of the data is helpful in deciding how much detail the data definitions should have. Routine data collection can indicate whether the priority assignments of contacts were a good match to the final results (e.g., infection rates and achievement of timelines).These data cannot determine whether all contacts with substantial exposure were included in the original list (i.e., whether certain contacts who should have been ranked as high priority were missed completely because of gaps in the investigation). # Methods for Data Collection and Storage Direct computer entry of all contact investigation data is recommended.Systems designed to increase data quality (e.g., through use of error checking rules) are preferred.However, technologic and resource limitations are likely to require at least partial use of paper forms and subsequent transfer at a computer console, which requires a greater level of data quality assurance because of potential errors in the transfer.Security precautions for both paper copy and electronically generated data should be commensurate with the confidentiality of the information.Ongoing training concerning systems is recommended for personnel who collect or use the data. A comprehensive U.S. software system for contact investigation data collection and storage has not been implemented.Health department officials are advised to borrow working systems from other jurisdictions that have similar TB control programs.Any system should incorporate these recommendations.Computer storage of data offers improved performance of daily activities because a comprehensive system can provide reminders regarding the care needs of individual contacts (e.g., notification regarding contacts who need second skin tests and recommended dates).A system also can perform interim analysis of aggregate results at prescheduled intervals.This contributes both to reassessment of the investigative strategy (see When to Expand a Contact Investigation) and to program evaluation. # Confidentiality and Consent in Contact Investigations Multiple laws and regulations protect the privacy and confidentiality of patients' health care information (119).Applicable federal laws include Sections 306 and 308(d) of the Public Health Service Act; the Freedom of Information Act of 1966; the Privacy Act of 1974, which restricts the use of Social Security numbers; the Privacy Protection Act of 1998; and the Privacy Rule of HIPAA, which protects individually identifiable health information and requires an authorization of disclosure (39).Section 164.512 of HIPAA lists exemptions to the need to obtain authorization, which include communicable diseases reported by a public health authority as authorized by law (120).Interrelationships between Federal and State codes are complex, and consultation with health department legal counsel is recommended when preparing policies governing contact investigations. Maintaining confidentiality is challenging during contact investigations because of the social connections between an index patient and contacts.Constant attention is required to maintain confidentiality.Ongoing discussions with the index patient and contacts regarding confidentiality are helpful in finding solutions, and individual preferences often can be accommodated.Legal and ethical issues in sharing confidential information sometimes can be resolved by obtaining consent from the patient to disclose information to specified persons and by documenting this consent with a signed form. The index patient might not know the names of contacts, and contacts might not know the index patient by name.With the patient's consent, a photograph of the patient or of contacts might be a legal option to assist in identifying contacts.In certain places, separate consent forms are required for taking the photograph and for sharing it with other persons.In congregate settings, access to occupancy rosters might be necessary to identify exposed contacts in need of evaluation. In their approach to confidentiality and consent issues for contact investigations, TB control programs will need to address the following: (121).In addition, to the extent that onsite administrators already know confidential information regarding an index patient or contacts, they can be asked to respect confidentiality even if they are not legally bound to do so.Employee and occupancy rosters are often shared with health department personnel to facilitate identification of contacts who should be evaluated.Confidentiality of these records also must be safeguarded. -Other medical conditions besides TB.Legal and ethical concerns for privacy and confidentiality extend beyond TB.All personal information regarding an index patient and contacts is afforded the same protections. # Staffing and Training for Contact Investigations The multiple interrelated tasks in a contact investigation require personnel in the health department and other healthcare-delivery systems to fulfill multiple functions and skills (Box 3).Training and continuous on-the-job supervision in all these functions help ensure successful contact investigations. Job titles of personnel who conduct contact investigations vary among jurisdictions (Box 4).State licensing boards and other authorities govern the scope of practice of health department personnel, and this narrows the assignment of functions.Reflection of these licensure-governed functions is recommended for personnel position descriptions, with specific references to contact investigations as duties. # Contact Investigations in Special Circumstances Contact investigations frequently involve multiple special circumstances, but these circumstances typically are not of substantive concern.This section lists special challenges and suggests how the general guidance in other sections of this document can be adapted in response. # Outbreaks A TB outbreak indicates potential extensive transmission.An outbreak implies that 1) a TB patient was contagious, 2) contacts were exposed for a substantial period, and 3) the interval since exposure has been sufficient for infection to progress to disease.An outbreak investigation involves several overlapping contact investigations, with a surge in the need for public health resources.More emphasis on active case finding is recommended, which can result in more contacts than usual having chest radiographs and specimen collection for mycobacteriologic assessment. Definitions for TB outbreaks are relative to the local context.Outbreak cases can be distinguished from other cases only when certain association in time, location, patient characteristics, or M. tuberculosis attributes (e.g., drug resistance or genotype) become apparent.In low-incidence jurisdictions, any temporal cluster is suspicious for an outbreak.In places where cases are more common, clusters can be obscured by the baseline incidence until suspicion is triggered by a noticeable increase, a sentinel event (e.g., pediatric cases), or genotypically related M. tuberculosis isolates. On average in the United States, 1% of contacts (priority status not specified) have TB disease at the time that they are evaluated (50).This disease prevalence is >100 times greater than that predicted for the United States overall.Nonetheless, this 1% average rate is not helpful in defining outbreaks, because substantial numbers of contacts are required for a statistically meaningful comparison to the 1% average. A working definition of "outbreak" is recommended for planning investigations.A recommended definition is a situation that is consistent with either of two sets of criteria: - during (and because of ) a contact investigation, two or more contacts are identified as having active TB, regardless of their assigned priority; or - any two or more cases occurring <1 year of each other are discovered to be linked, and the linkage is established outside of a contact investigation (e.g., two patients who received a diagnosis of TB outside of a contact investigation are found to work in the same office, and only one or neither of the persons was listed as a contact to the other).The linkage between cases should be confirmed by genotyping results if isolates have been obtained (122).Any secondary case that is unexpectedly linked to a known index patient represents a potential failure of certain contact investigation, and therefore the strategy for the original investigation should be reassessed to determine whether the strategy for finding contacts was optimal and whether the priorities were valid or if additional contacts must be sought.If a secondary case occurred because treatment for a known contact with LTBI was not started or completed, then the strategies for treatment and completion should be reviewed. An outbreak increases the urgency of investigations and places greater demands on the health department.Therefore, whenever possible, a suspected linkage between cases should be corroborated by genotyping results before intensifying an investigation.Even if genotypes match, an epidemiologic investigation is required for determining probable transmission linkages (122)(123)(124)(125). In an outbreak, contacts can be exposed to more than one case, and cases and contacts can be interrelated through multiple social connections which complicate efforts to set priorities.Social network analysis offers an alternative framework (see Other Topics) (126).The risk factors contributing to a specific outbreak should be determined, because these findings will affect the investigation and inform the strategy. Contagious TB undiagnosed or untreated for an extended period, or an extremely contagious case.The challenges created by the extended infectious period include the patient's inability to remember persons and places and a greater number of contacts in a greater number of places.Social network techniques (see other topics) and setting-based investigations are proxy methods for finding contacts.A highly contagious case, sometimes with several pulmonary cavities or laryngeal disease, suggests a greater number of high-priority contacts.If an outbreak has been discovered, and if the patient has one of these forms of TB, any contacts who have indeterminate exposure data should be classified as high priority. Sometimes a delay in treating TB is caused by failure to suspect TB or to report it.Opportunities for educating the providers should be pursued immediately, especially if contacts are likely to seek health care from the same providers. Multidrug resistance can cause prolonged contagiousness if a standard treatment regimen for drug susceptible TB is being administered.This problem can be prevented by obtaining initial susceptibility results, by monitoring the patient's condition and response to therapy, and by suspecting MDR TB when the patient has treatment failure, relapse, or slow recovery from illness (127). Source patient visiting multiple sites.A TB patient who has an active, complex social life and who frequents multiple sites where transmission of M. tuberculosis could occur is also less likely to be able to name all contacts.Proxy interviews (see Investigating the Index Patient and Sites of Transmission) and setting-based investigations are methods that supplement the patient's recall. Patient and contacts in close or prolonged company.When an outbreak has been discovered, high priority is recommended for contacts having close or prolonged exposure. Environment promoting transmission.A small interior space with poor ventilation can act as the focus of intense transmission of M. tuberculosis.High priority is recommended for all contacts who spent time with an outbreak source patient in such spaces, even if the periods of exposure were brief or unknown. Certain larger environments (e.g., a warehouse worksite or a school bus ) have been reported as sites of intensive transmission when patients were highly contagious or when patients and contacts were in prolonged company.If the evidence from the investigation indicates a link between the site and transmission in an outbreak, the contacts in such a site should be designated as high priority, regardless of the site's characteristics. Contacts very susceptible to disease after M. tuberculosis infection.Urgency is required when outbreak cases are diagnosed in contacts who are relatively more susceptible to progression from M. tuberculosis infection to TB disease.Other contacts with similar susceptibility should be sought.If such an outbreak includes children aged <5 years, a source-case investigation should be undertaken if the contagious source is unknown initially (see Source-Case Investigations).Intensified methods for active case finding among contacts are recommended. Gaps in contact investigations and follow-up.Omissions, errors, and system failures can resurface later in the form of secondary TB cases (i.e., an outbreak).Tracing back cases in an outbreak indicates whether prevention opportunities were missed in previous contact investigations or other prevention activities (e.g., targeted testing). Extra-virulent strain of M. tuberculosis.The existence of such strains has not been demonstrated.Determining which strains are more infective or pathogenic for humans is not yet possible, and the relevance of greater/faster pathogenicity of certain strains in laboratory animals is not fully understood yet (58,128,130). # Congregate Settings Overall concerns associated with congregate settings include 1) the substantial numbers of contacts, 2) incomplete information regarding contact names and locations, 3) incomplete data for determining priorities, 4) difficulty in maintaining confidentiality, 5) collaboration with officials and administrators who are unfamiliar with TB, 6) legal implications, and 7) media coverage.Certain settings require intensified onsite approaches for ensuring that contacts are completely evaluated and for meeting objectives for treating LTBI.Requests for supplemental resources are recommended when the scope or duration of an investigation is expected to disrupt other essential TB control functions. Maintaining confidentiality for an index patient is difficult if the patient was conspicuously ill or was absent from the setting while ill (see Data Management and Evaluation of Contact Investigations).Permission should be sought from the index patient before sharing information with any officials (e.g., supervisors, managers, or administrators) at the setting.Collaboration with officials at the setting is essential for obtaining access to employee and occupancy rosters, ascertaining contacts, performing onsite diagnostic evaluations or treatment, and offering education to associates (e.g., classmates, friends, or coworkers) of the index patient. For congregate settings, the types of information for designating priorities are site specific, and therefore a customized algorithm is required for each situation.The general concepts of source-case characteristics, duration and proximity of exposure, environmental factors that modify transmission, and susceptibility of contacts to TB should be included in the algorithm (see Decisions to Initiate a Contact Investigation, Index Patient and Sites of Transmission, and Assigning Priorities to Contacts). The optimum approach for a setting-based investigation is to interview and test contacts on site.If this is not possible, then the contacts should be invited for evaluation at the health department, which should consider having additional personnel or extended hours.As a last resort, contacts can be noti-fied in writing to seek diagnostic evaluation with their own health-care providers.In this case, the letter should inform health-care providers regarding the TB exposure (including drug susceptibility results), diagnostic methods (including a 5 mm skin test cut point), treatment recommendations for LTBI, and a reference telephone number at the health department for obtaining consultation.
Health-care providers also should receive a form for each contact that can be used to return diagnostic results and treatment decisions to the health department. Certain congregate settings create opportunities for efficient onsite supervision of treatment for numerous contacts.Treatment can be delivered by having health department personnel visit the setting twice weekly for intermittent therapy, or by collaborating with a health professional hired by the setting.Arrangements are needed to maintain confidentiality with this approach.Officials and administrators at the setting are likely to be concerned regarding liability, which can be addressed in advance with legal counsel. For constructive media coverage, the health department should collaborate with the setting in focusing on clear, consistent information.News reports that are factually accurate and that correctly describe the role of the health department can facilitate the investigation (see Communicating Through the News Media). # Correctional Facilities The Advisory Council for the Elimination of Tuberculosis (ACET) has issued guidance on preventing and controlling TB in correctional facilities (131).Jails and prisons have been implicated in TB outbreaks (132)(133)(134)(135).Multiple factors can hinder contact investigations.The best preparation for conducting contact investigations in jails and prisons is preexisting formal collaboration between correctional and public health officials.If collaboration has not been established before a contact investigation is needed, creating it as part of the investigation is necessary. Certain correctional populations have a high prevalence of HIV infection, and reviewing the HIV testing policies, procedures, and aggregate statistics is recommended.If inmates have not been offered voluntary counseling, testing, and referral for HIV infection, and TB exposure is suspected, offering voluntary HIV counseling, testing, and referral is strongly recommended. Inmates move about within correctional facilities on both daily and weekly schedules that can affect TB exposures.In addition, inmates are transferred within and between jails or prisons.Certain correctional settings have convenient, comprehensive longitudinal records for the locations of inmates that are essential for drawing up contact lists, estimating ex-posure periods, and assigning priorities to contacts.A tour of exposure sites within each setting helps in estimating exposure intensity. Prisons typically have onsite health services, but jails might not.Certain prisons and jails test new inmate admissions and employees for M. tuberculosis infection, and certain prisons have periodic surveillance testing of employees, inmates, or both.Health-care providers in an onsite system can provide invaluable assistance in reviewing health records and evaluating and treating contacts.If medical record data (e.g., previous exposure and skin test results) cannot be retrieved rapidly, health department officials should consider requesting additional resources. Investigations in jails can be especially challenging because of rapid turnover of inmates and crowding.The number of contacts who had close proximity to an index patient/inmate can be great, and yet exposure might be brief.This complicates the process of assigning priorities.Unless tracking records for inmates who were in a confined space with an infectious TB patient allow a determination that aggregate exposure was brief (e.g., <8 hours), these contacts should be assigned high priority.High-priority contacts who are transferred, released, or paroled from a correctional facility before medical evaluation for TB should be traced. Unless they have been released or paroled, prison inmates with LTBI can complete a treatment regimen while incarcerated.In contrast, inmates in jails who are contacts are unlikely to be able to complete treatment while incarcerated.A low completion rate is anticipated when inmates are released or paroled unless follow-through supervision can be arranged. # Workplaces A substantial number of persons spend the majority of their waking hours in their workplaces, which can be crowded.Duration and proximity of exposure can be greater than for other settings.Details regarding employment, hours, working conditions, and workplace contacts should be obtained during the initial interview with the index patient (see Investigating the Index Patient and Sites of Transmission), and the workplace should be toured after accounting for confidentiality and permission from workplace administrators or managers.Employee lists are helpful for selecting contacts, but certain employees might have left the workplace and thus been omitted from current employee lists. Occasional customers of a business workplace (e.g., intermittent visitors to a fast-food restaurant) should be designated as low-priority contacts.Customers who visit a business workplace repeatedly should be assigned priorities as in other investigations (see Assigning Priorities to Contacts), especially susceptible or vulnerable contacts. Workplace administrators or managers are likely to express concern regarding liability, lost productivity, and media coverage.In addition, they might have limited obligations to protect patient confidentiality.All these issues can be addressed during planning.For example, the assistance of the health department's media relations specialist can be offered to the workplace.For questions of liability and requirements under law, discussions between the health department's and the workplace's legal counsels are recommended. # Hospitals and Other Health-Care Settings Nearly every type of health-care setting has been implicated in transmission of M. tuberculosis, and guidance on preventing transmission has been provided by CDC, the Healthcare Infection Control Practices Advisory Committee, and other organizations (42,136).State governments have different degrees of regulatory authority over health-care settings.Personnel collaborating with hospitals and other health-care entities should have knowledge of applicable legal requirements. Infection control practitioners, although vital partners in these settings, might not be familiar with TB contact investigations.Multiple settings have engineers who can describe and test the environmental systems.Such an investigation should be planned jointly as a collaboration between the setting and the health department.Initial discussions should include data sharing and divisions of responsibilities.Liability, regulations, confidentiality, media coverage, and occupational safety are complex for health-care settings.Occupational Safety and Health Administration rules, which are interpreted differently by different jurisdictions, might require hospital administrators to report when employees are reported to be infected from occupational exposure.Public health officials should consider inviting legal counsel to the initial planning sessions with health-care administrators. The majority of health-care settings have policies for testing employees for M. tuberculosis infection at the time of employment and, in settings where exposure is anticipated, periodically thereafter.Test results are helpful as baseline data.The availability of baseline results for contacts who were patients or clients of the setting is variable; long-term care facilities might have these data. # Schools This category includes child care centers, preschools, primary through secondary schools, vocational schools that replace or immediately follow secondary school, and colleges or universities.Contact investigations at juvenile detention centers and adult education systems should be managed along the same lines as investigations conducted in correctional settings and in workplaces, respectively. Early collaboration with school officials and community members is recommended when considering an investigation related to a school, even if preliminary information suggests that an investigation is unnecessary.The typical features of contact investigations in schools are the potentially substantial numbers of contacts and difficulties in assigning priorities to contacts who have undetermined durations and proximities of exposure.The potential is great for controversies among public health officials, school officials, and the guardians of the children. The presence of TB in schools often generates publicity.Ideally, the health department should communicate with the school and parents (and guardians) before any media report a story.TB control officials should anticipate media coverage and plan a collaborative strategy (see Communicating Through the News Media). Consent, assent, and disclosure of information are more complex for nonemancipated minors than for adults.Each interaction with a minor is also a potential interaction with the family.The health department typically has limited alternatives for evaluating a minor if permission is not granted.Anticipatory legal consultation is recommended. Public health officials should visit the school to check indoor spaces, observe general conditions, and interview maintenance personnel regarding ventilation.Class assignment records help in listing contacts, estimating durations of exposure, and setting priorities.However, certain schools purge these files at the end of each school year, in which case interviews with students and personnel are necessary to list contacts. Extramural activities add other exposure sites and contacts.Clubs, sports, and certain classes require additional information gained from interviewing the patient, the patient's guardians, and school personnel.For patients who ride school buses, a bus company might keep a roster of riders with addresses. The strategy for contact investigations in child care centers, preschools, and primary schools depends on whether the index patient is a child (i.e., preadolescent) or an adult (e.g., a teacher or caregiver).The potential infectiousness of an adult in the school should be determined (see Decisions to Initiate a Contact Investigation and Investigating the Index Patient and Sites of Transmission). In a source-case investigation of a child aged <5 years who has TB and who attends preschool or child care, all adults in these settings should be included if the source case has not been located in the family or household (see Source-Case Investigations).Certain home-based child care centers include adults who do not provide child care but who still share airspace with the children.Source-case investigations should not be pursued in primary and higher-level schools unless other evidence points to the school as the focus. In secondary and higher levels of education, students usually have adult-form TB, and infectiousness can be estimated by the standard criteria (see Decisions to Initiate a Contact Investigation and Investigating the Index Patient and Sites of Transmission).With advancing education, academic schedules and extramural social schedules become more complex, and the information reported by the index patient is more important for a thorough investigation than it is for younger children. Multiple jurisdictions have pre-employment requirements for TB clearance screening (e.g., a test for M. tuberculosis infection) at schools or daycare settings, and certain jurisdictions require TB clearance for entering students.Certain colleges and universities also have these requirements.These baseline data are helpful for interpreting results from the investigation. Schools that have onsite health services can administer DOT to students with LTBI, or the health department can send workers twice weekly to provide intermittent therapy.This approach should be coordinated with the annual school cycle. School breaks, vacations, graduations, and transfers disrupt the contact investigation.In collaboration with school officials, the health department can notify, by mail, students and other contacts who will be unavailable at the school.These contacts should be referred for evaluation at the health department.Contacts seeking care from their own health-care providers should receive written instructions to give their providers. # Shelters and Other Settings Providing Services for Homeless Persons ACET and CDC have provided guidance for providing TB control services to homeless persons and for preventing TB transmission at settings providing services to them (137).The challenges that can be anticipated for a contact investigation involving a homeless TB patient include difficulty locating the patient and contacts if they are mobile, episodic incarceration, migration from one jurisdiction to another, psychiatric illnesses (including chemical dependency disorders) that hinder communication or participation, and preexisting medical conditions (in particular, HIV infection).When names or locations of specific contacts are unknown, interviews with the patient and potential contacts should focus on social networks and settings, including correctional facilities. One surrogate for degree of exposure at an overnight shelter is the bed/cot assignment.The proximity and duration of overlap should be estimated as closely as possible for selecting highpriority contacts.Certain daytime-use settings keep sign-in lists, but these might lack information regarding overlap of visits. Homeless persons frequently seek health care from multiple volunteer providers, halfway houses, chemical dependency treatment programs, community clinics, urgent care centers, and hospital emergency departments.Consultation and assistance from health-care providers in these systems can be helpful.This also creates an opportunity for collaboration, contact ascertainment, and mutual education. Site visits and interviews are crucial, because the social communities of homeless persons are likely to vary by situation.A contact investigation presents an opportunity to review the screening and testing services and to offer assistance with these and other means of decreasing transmission of M. tuberculosis (e.g., environmental controls).However, transmission also could occur at sites besides shelters (e.g., jails, taverns, abandoned buildings, and cars). Settings providing services to homeless persons are affected by policies, laws, and regulations according to their service population, location, and funding sources, and certain of these issues are relevant for the contact investigation.Access to visitation and occupancy rosters (or logs) and to other information regarding persons, vital for listing contacts and determining priorities, might be restricted by law (e.g., at settings that provide treatment for substance-abuse disorders), and the terms of access should be negotiated. Low treatment-completion rates have been reported for treatment of LTBI diagnosed at homeless shelters (137)(138)(139)(140).TB control officials should work with setting administrators to offer onsite supervised intermittent treatment.Sites with more stable populations are likely to benefit most from this approach. # Transportation Modes Transmission of M. tuberculosis has been confirmed on military vessels at sea, commercial aircraft, passenger trains, and school buses (85,129,(141)(142)(143)(144).However, transmission is unlikely unless ventilation is restricted or exposure is long or repetitive.Investigations for these settings should be assigned low priority unless ventilation is restricted or single-trip exposure time is >8 hours (cumulative if the trip has multiple segments) as currently recommended for commercial airline travel, or at least two separate trips were taken with the index patient (145). # Drug or Alcohol Usage Sites Shared sites of drug or alcohol usage (e.g., taverns and crack houses), have been implicated as sites of M. tuberculosis transmission (146,147).Potential factors are close person-toperson proximity, repetitive exposure, and poor ventilation.Routine interviews might not generate a complete contact list for these settings, and the patient's social network should be explored for other information sources.Connections to correctional settings should be sought.HIV infection is associated with multiple forms of substance abuse, and HIV counseling, testing, and referral services are recommended. # Special Sites Not Under Jurisdiction Examples of sites that are not under the jurisdiction of the local or state health department are those under the jurisdiction of the U.S. government (e.g., military bases), diplomatic missions, or reservations for American Indian/Alaska Native tribes.If these sites have their own health-care systems, the health department can offer technical consultation and can request data from contact investigations.At sites that do not have health-care systems, agreements can be made between local TB control officials and the onsite authorities to delegate the public health response to the health department. # Index Patient Unable to Participate Approximately 8% of pulmonary TB patients with AFB detected on sputum microscopy have no contacts listed (17,50).TB patients who have few or no contacts listed are more likely to be homeless or to have died (i.e., before an interview could be conducted).This implies that the patients might have had contacts, but learning who the contacts were is difficult.Social-network information, setting-based investigations, and proxy methods are recommended to supplement the contact list.In addition, any person in whom a case of pulmonary TB was diagnosed at death indicates that a possible delay in diagnosis has occurred, which could infer increased and prolonged infectiousness and a need to increase the scope of the investigation. # MDR TB The occurrence of MDR TB does not change recommendations for assigning contact priorities.Special consideration should be given to instances when resistance is acquired during treatment or when drug resistance was detected late during the treatment course, because these patients might have had prolonged periods of infectiousness.Treatment regimens for infected contacts require expert consultation (see Treatment for Contacts with LTBI) (6). # Interjurisdictional Contact Investigations Contact investigations that overlap multiple jurisdictional areas require joint strategies for finding contacts, having them evaluated, treating the infected contacts, and gathering data.A different solution usually is required for each situation. Multiple jurisdictions within the United States.The index patient and associated contacts might have stable residences, but travel among sites in different jurisdictions.The health department that counts the index patient is responsible for leading the investigation and notifying the health departments in other jurisdictions regarding contacts residing in those jurisdictions.Notifications should include requests for followthrough results of contact evaluation and treatment.A team of representatives from the multiple health departments can increase the efficiency of such an investigation by planning the overall strategy together and monitoring the progress. Migratory workers.ACET has issued specific TB prevention and control recommendations for migratory agricultural workers (148).An investigation for any migratory workers requires a strategy that is adjusted to their migration and work schedule.The workers' itinerary should be ascertained during initial planning, and health departments in successive destinations should be notified.A selection from among three general types of contact record management is recommended: 1) the transfer of patient records from one health department to the next on the itinerary; 2) the continual referral of information to a single coordinating health department throughout the investigation; or 3) patient ownership of records, with each patient responsible for keeping information while moving.Because of the duration of treatment, treating LTBI is the most difficult phase.Certain seasonal workers remain in one place as long as several months during off-season, and this period should be used to deliver as much treatment as possible. Contagious TB patient traveling within the United States.Officials from the health department that initially encountered the patient should interview the patient to gather as much identifying and locating information as possible for contacts who were visited during the patient's travels.These data should be referred to the jurisdictions in which the contacts are located.The jurisdiction that counts the index patient is assigned responsibility for managing the contact investigation overall. International contact investigations.The United States and Mexico participate in the Referral System for Binational TB Patients Pilot Project, which coordinates follow-up care when a TB patient moves between these two countries, mainly between participating jurisdictions.Cure TB also contributes to continuity of care in other regions of the two countries.Neither of these systems includes contact investigations at present.TBNet is a health-care system for migratory agricultural workers who are receiving treatment for LTBI and thus includes contacts.
For cases or contacts in Canada, U.S. health departments should notify TB control coordinators in provincial health departments. # Unusual Events Causing Exposure to M. tuberculosis Complex The normal mode of transmission is person to person by the airborne route.Unusual events (e.g., laboratory accidents) also can cause M. tuberculosis transmission.In contrast, M. bovis transmission usually occurs via infected dairy products, which is preventable by pasteurization. Animals with human-type or bovine TB.Multiple mammalian and certain nonmammalian species are susceptible to human-type TB, presumably through exposure to persons with TB who are contagious.Multiple animal hosts also can contract bovine TB (i.e., infection with M. bovis), probably from exposure to other infected animals or from consuming infected dairy products or contaminated feed. Standard methods for diagnosing M. tuberculosis infection and disease have not been described for the majority of species.Evaluation and management of an animal exposed to M. tuberculosis should be referred to a veterinarian, who can consult with the state veterinarian.Animal-to-human transmission of human TB in a household has not been confirmed, and the human contacts should be designated as low priority.However, determining the source of M. tuberculosis infection for an animal with TB is recommended. The degree of risk for aerosol-inducing procedures (e.g., intubation, bronchoscopy, or necroscopy) performed on an animal having TB is unknown.However, these procedures are likely to create infectious aerosols.If infection control precautions for preventing M. tuberculosis transmission were not implemented during the procedures, then in-room contacts are assigned high priority. The evaluation and management of animals exposed to M. bovis should be referred to a veterinarian.Cases of M. bovis in animals should be reported to the state veterinarian.Animalto-human transmission of M. bovis from necropsy procedures has been confirmed (149). Patients who acquire M. bovis infection from ingestion are more likely to have extrapulmonary TB (e.g., scrofula or peritonitis), but pulmonary disease is possible.Contact investigations regarding persons who have pulmonary TB caused by M. bovis should be planned according to the guidelines provided in this report.However, the potential for transmission is less clear.Current and proposed tests for infection (e.g., the TST and QuantiFERON ® -TB Gold ) detect M. bovis infection, but the tests are not approved specifically for this indication.After active M. bovis disease has been excluded by symptom review, examination, and tests as indicated by findings, suspected latent M. bovis infection should be treated as ordinary M. tuberculosis infection. Multiple laboratory mammals, especially nonhuman primates, are highly susceptible to human-type TB.Federal animal welfare regulations administered by the U.S. Department of Agriculture () apply to laboratory animals and certain animals used in exhibi-tions.If such animals are exposed to infectious TB, consultation with the state veterinarian is recommended. Microbiology laboratory accidents.Routine laboratory procedures for manipulating either patient specimens or cultured isolates of M. tuberculosis generate infectious aerosols.Unintentional events (e.g., spills outside containment areas) and system failures can cause exposure.A contact investigation for such scenarios should be based on the location of persons in the room at the time of the event and the airflow in the room.Consultation with a microbiologist is recommended.In general, baseline skin test results are available for workers in laboratories in which M. tuberculosis is cultured or kept. Surgical wounds, abscesses, embalming, and autopsies.Diseased tissues are not typical sources of infection unless procedures create aerosols: water-jet irrigation, dripping fluids, electrical cauterization, and cutting with power tools.If procedures were performed on infected tissues before infection control precautions were instituted, then persons in the room at the time should be designated as high-priority contacts. Percutaneous inoculations.M. tuberculosis can cause infection and local disease in skin or deeper tissue after direct inoculation by a contaminated object.Percutaneous exposure would be highly unusual in anyone except a health-care worker, who should have a previous result from baseline testing for infection.A 9-month INH treatment regimen should be started if the M. tuberculosis is likely to be susceptible to it.Treatment should be stopped if a repeat test for M. tuberculosis is negative >8 weeks after exposure, and treatment should be extended to the full course if the test result is positive.If the baseline test result was positive, the full 9 months of treatment is recommended.During treatment, the person should be examined monthly for signs of local infection or spread to regional lymph nodes. # Source-Case Investigations A source-case investigation seeks the source of recent M. tuberculosis infection, perhaps newly diagnosed TB disease (43).TB disease in children aged <5 years typically indicates that the infection must be recent.For this reason, it is a sentinel public health event.Young children usually do not transmit TB to others, and their contacts are unlikely to be infected because of exposure to them (150).A source-case investigation moves in the opposite direction of contact investigation, but the principles used in contact investigation apply.Sourcecase investigations concerning adults with TB disease are not discussed in this report (42,131,151). Source-case investigations typically have low yield for the effort required.They are not recommended unless a TB con-trol program is achieving its objectives (in particular, treatment of infected contacts) when investigating infectious cases. # Source-Case Investigation for a Child with TB Disease The yield of source-case investigations for children who have TB disease varies, typically <50% on average (152)(153)(154)(155)(156).Sourcecase investigations can be considered for children aged <5 years.A younger age cut-off might be advisable because the focus would be on more recent transmission.An investigation may be started before the diagnosis of TB is confirmed because waiting for confirmation can decrease the chances of finding associates. # Source-Case Investigation for a Child with Latent M. tuberculosis Infection A search for the source of infection for a child who has LTBI is unlikely to be productive (157)(158)(159).These kinds of investigations are recommended only regarding infected children aged <2 years and only if data are monitored to determine the value of the investigation. # Procedures for Source-Case Investigation Seeking a source case follows the same overall procedures as a standard contact investigation.Parents or guardians usually are the best informants.Such persons are termed associates.Attention focuses on ill associates who have symptoms of TB disease.A source-case investigation should begin with the closest associates (e.g., household members). Limited data are needed for assessing the productivity of source-case investigations.These data include the number of index patients investigated for their sources, the number of associates screened for TB disease, and the number of times that a source is found. # Other Topics Cultural Competence Culture refers to the integrated pattern of knowledge, beliefs, and behavior that is passed from one generation to another (160), including how persons act and interact.If contact investigations are to be productive, cultural differences must be respected and understood.Cultural competence is the knowledge and interpersonal skills that allow health-care providers to appreciate and work with persons from cultures other than their own.It involves awareness of cultural differences, self-awareness, and sensitivity to a patient's culture and adaptation skills. Language and culture are important factors in TB contact investigations.The ability to understand cultural norms and to bridge the gaps that exist between cultures requires training and experience.Influencing patients to participate in a contact investigation increasingly depends on the cultural competency of the health-care worker.Training that is derived from the National Standards for Culturally and Linguistically Appropriate Services in Health Care is recommended (161). Language interpreters need basic knowledge regarding TB, transmission, contact investigations, and the medical care of contacts.Patient confidentiality is a critical element of training.The use of family-member interpreters is discouraged.The majority of family members do not have a medical orientation.Patients might feel reluctant to reveal contacts of a family member. # Social Network Analysis Social network analysis might offer an effective way to list TB contacts and assign priorities to them (162)(163)(164)(165)(166).Social network analyses have been tested retrospectively on TB outbreak investigations (126,(167)(168)(169)(170) and contact investigations (171,172).However, the use of social network analysis to improve contact investigations has not been tested prospectively, the methods might require additional labor, and further operational research is needed. # Use of Blood Tests for the Detection of Latent M. tuberculosis Infection The majority of experience with diagnosing M. tuberculosis infection, especially LTBI, in contacts has been with the TST.Newly released blood tests now have potential use for this purpose.The initial QuantiFERON ® -TB test (QFT) is a whole blood assay that measures IFN-γ release in response to purified protein derivative (PPD).Good agreement was reported with the skin test in healthy adults being tested for LTBI, and QFT was approved by the U.S. Food and Drug Administration (FDA) (173,174).Data are insufficient to demonstrate the accuracy of QFT test for testing contacts, and it was not recommended for this situation (175). Recently, QFT-G was approved by FDA for use as an in vitro diagnostic to aid in diagnosing M. tuberculosis infection, including both LTBI and TB disease.This test detects the release of IFN-γ from lymphocytes of sensitized persons when their blood is incubated with peptide mixtures simulating two M. tuberculosis proteins called ESAT-6 and CFP-10.These proteins are secreted by all M. tuberculosis and pathogenic M. bovis strains, but are absent from all BCG vaccine strains and commonly encountered non-tuberculous mycobacteria.Therefore, QFT-G offers the possibility of detecting M. tuberculosis infection with greater specificity than has been possible previously with tests that used tuberculin PPD as the TB antigen (175,176). CDC recommends that QFT-G can be used in all circumstances in which the TST is currently used, including contact investigations (177).QFT-G can be used in place of and not in addition to the TST.A positive QFT-G result should prompt the same evaluation and management as a positive TST.No reason typically exists to follow a positive QFT-G with a TST.For persons with recent contact to infectious TB, negative QFT-G results typically should be confirmed with a repeat test performed 8-10 weeks after the end of exposure.Studies to identify the most appropriate times to re-test contacts with QFT-G have not been reported.Until more specific data are available, the timing of QFT-G testing should be similar to that used for the TST. Concern has been expressed that the QFT-G test might be somewhat less sensitive than the TST in detecting LTBI (177).As with a negative TST, a negative QFT-G result alone should not be used to exclude M. tuberculosis infection in severely immunosuppressed adults, children aged <5 years, or patients about to undergo treatment with TNF-α inhibitors, in whom the consequences of accepting a false-negative result could be especially severe. Another blood test for detection of infection, the ELISPOT test (marketed as T-SPOT-TB), is similar in principle to QFT ELISPOT results correlate with TB exposure risk better than skin test results for contacts of pulmonary TB patients), and like QFT-G, it appears able to differentiate between BCG vaccination and M. tuberculosis infection (178,179).ELISPOT has not yet been approved for use in the United States. Additional resources regarding tuberculosis (TB) contact investigations are available from the following organizations: - specimens.It also creates a high risk for M. tuberculosis transmission to health-care workers if it is used on a patient who has TB (even if the patient is smear negative), because the procedure induces coughing. # Bronchoalveolar lavage (BAL). A procedure for collecting respiratory specimens from the airway, typically during bronchoscopy.Sterile saline is flushed through an airway, and the resultant mixture of cells, secretions, and saline is aspirated for studies (e.g., microscopy and culture). Case.A particular instance of a disease (e.g., TB).A case is detected, documented, and reported. # Cavity (pulmonary). A hole in the lung parenchyma, typically not involving the pleural space.Although multiple causes can account for a lung cavity, and its appearance is similar regardless of its cause, in pulmonary TB, it results from the destruction of pulmonary tissue by direct bacterial invasion and an immune interaction triggered by M. tuberculosis.A tuberculous cavity large enough to see with a normal chest radiograph predicts infectiousness. Contact.Refers to someone who has been exposed to M. tuberculosis infection by sharing air space with a person with infectious TB. Contagious.Refers to TB disease of either the lungs or the throat that has been demonstrated to have caused transmission to other persons or the patient who has TB disease. Conversion.A change in the result of a test for M. tuberculosis infection that is interpreted to indicate a change from being uninfected to infected.With the tuberculin skin test, an increase of >10 mm in induration size during <2 years is defined as a conversion.A conversion is presumptive evidence of new M. tuberculosis infection and poses an increased risk for progression to TB disease.The term is applied to contacts only when previous skin test results are available.A change in tuberculin status during the window period is not necessarily consistent with this definition. Delayed-type hypersensitivity (DTH).Cell-mediated inflammatory reaction to an antigen that is recognized by the immune system, typically because of previous exposure to the same or similar antigens.Cell-mediated reactions are contrasted with an antibody (or humoral) response.DTH typically peaks 48-72 hours after exposure to the antigen. Directly observed therapy (DOT).An adherence-enhancing strategy in which a health-care worker or other trained person watches a patient swallow each dose of medication and is The following terms and abbreviations are used in this report.Acid-fast bacilli (AFB).Microorganisms that are distinguished by their retention of specific stains even after being rinsed with an acid solution.The majority of AFB in patient specimens are mycobacteria, including species other than Mycobacterium tuberculosis complex.A positive nucleic acid amplification (NAA) or culture result is needed for confirmation of M. tuberculosis complex.The relative concentration of AFB per unit area on a slide (the smear grade) is associated with infectiousness. Anergy.A condition wherein a person has diminished ability to exhibit delayed T-cell hypersensitivity reaction to antigens because of a condition or situation resulting in altered immune function.When referring to inability to react to a skin test, the correct term is cutaneous anergy.Skin tests for anergy (i.e., control antigens) have poor predictive value and are not recommended. Associate contact.A person who is somehow affiliated with a patient who has noninfectious tuberculosis (TB) or with another contact.Often used in connection with source-case investigations; does not imply an M. tuberculosis transmission pathway. Bacille Calmette-Guérin (BCG).A vaccine for tuberculosis named after the French scientists Calmette and Guérin.The vaccine is effective in preventing disseminated and meningeal TB disease in infants and young children.It might have approximately 50% efficacy for preventing smeardiagnosed pulmonary TB in adults.It is used in multiple countries where TB disease is endemic. Boosting.When nonspecific or remote sensitivity to tuberculin (purified protein derivative in the skin test) wanes or disappears with time, subsequent tuberculin skin tests can restore the sensitivity.This is called boosting or the booster phenomenon.An initially limited reaction size is followed by a larger reaction size on a later test, which can be confused with a conversion or a recent M. tuberculosis infection.Two-step testing is used to distinguish new infections from boosted reactions in infection-control surveillance programs, but this method is not recommended for testing contacts. Bronchoscopy.A procedure for examining the lower respiratory tract that requires inserting the end of an endoscopic instrument through the mouth or nose (or tracheostomy) and into the respiratory tree.It can be used to obtain diagnostic accountable to the public health system.DOT is the preferred method of care for all patients with TB disease and is a preferred option for patients under treatment for latent infection. Disseminated TB.See Miliary TB.Drug-susceptibility test.A laboratory determination to assess whether an M. tuberculosis complex isolate is susceptible or resistant to anti-TB drugs that are added to mycobacterial growth medium.The results predict whether a specific drug is likely to be effective in treating TB disease caused by that isolate. Enabler.A practical item given to a patient for making adherence (e.g., to treatment or to clinic appointments) easier. Exposure.The condition of being subjected to something (e.g., an infectious agent) that could have an effect.A person exposed to M. tuberculosis does not necessarily become infected.Much of the work in a TB contact investigation is dedicated to learning who was exposed and, of these, who became infected. Exposure period.The coincident period when a contact shared the same air space as a person with TB during the infectious period. Exposure site.A location that the index patient visited during the infectious period (e.g., a school, bar, bus, or residence). Immunocompromised and immunosuppressed.Conditions in which at least part of the immune system is functioning at less than normal capacity.According to some style experts, immunocompromised is the broader term, and immunosuppressed is restricted to conditions with iatrogenic causes, including treatments for another condition.Some immunocompromised conditions increase the likelihood that M. tuberculosis infection will progress to TB disease.Certain conditions also make TB disease or infection from M. tuberculosis more difficult to diagnose because manifestations of TB disease differ, and tests for infection rely on an intact immune system. Incentive.A gift given to patients to encourage or acknowledge their adherence to treatment. Index.The first case or patient that comes to attention as an indicator of a potential public health problem.Contrast with Source. Induration.The firmness in the skin test reaction.Induration is produced by immune-cell infiltration in response to tuberculin antigen that was introduced into the skin.It is measured by palpation transversely, and the result is recorded in millimeters (mm).The measurement is compared to guidelines to determine whether the test result is classified as positive or negative. # Infection. A condition in which microorganisms have entered the body and typically have elicited immune responses.
M. tuberculosis infection might progress to TB disease.The expression M. tuberculosis infection includes both latent infection and TB disease.Latent M. tuberculosis infection or latent tuberculosis infection (LTBI) is an asymptomatic condition that follows the initial infection; the infection is still present but is dormant (and believed not to be currently progressive or invasive).TB disease is determined by finding anatomic changes caused by advancing infection (e.g., shadows from infiltrates on a chest radiograph) or by noting symptoms (e.g., malaise, feverishness, or cough), and typically by both.Positive culture results for M. tuberculosis complex typically are interpreted as both an indication of TB disease and its confirmation, but infecting organisms can be obtained from patients who have no other evidence of disease. Infectious.Refers either to TB disease of the lungs or throat, which has the potential to cause transmission to other persons, or to the patient who has TB disease. # Isoniazid (INH). A highly active anti-TB chemotherapeutic agent that is a basis of treatment for TB disease and latent infection. Laryngeal TB.A highly infectious form of TB disease, with erosive, exudative invasion of the larynx. # Latent M. tuberculosis infection (or latent tuberculosis infection ).See Infection. Mantoux method.A skin test performed by intradermally injecting 0.1 mL of PPD tuberculin solution into the volar or dorsal surface of the forearm.This is the recommended method for tuberculin skin testing. Meningeal TB.A highly dangerous and difficult-todiagnose form of TB disease with infectious invasion of the tissues covering the brain.Often indolent but uniformly fatal if untreated, at times it is diagnosed too late to save the patient's life or prevent permanent disability. Miliary TB.Sometimes referred to as disseminated TB.A dangerous, and difficult to diagnose, form of rapidly progressing TB disease that extends throughout the body.Uniformly fatal if untreated, sometimes it is diagnosed too late to save a life.Derives its names from a pathognomonic chest radiograph, but certain patients with this condition have normal findings or ordinary infiltrates on the chest radiograph. Multidrug-resistant TB (MDR TB).TB disease caused by an M. tuberculosis strain that is resistant to at least INH and rifampin.Treatment regimens for curing MDR TB are long, expensive, and difficult to tolerate.The cure rate depends on the susceptibility of M. tuberculosis to alternative chemotherapy. # Mycobacterium bovis (M. bovis). A member organism of M. tuberculosis complex and the causative infectious agent of TB in cattle.It also causes infection and disease in humans, who become infected by consuming unpasteurized dairy products from tuberculous cows.Human M. bovis TB disease has certain distinctive characteristics but in practical terms is indistinguishable from human-variant TB.Human pulmonary M. bovis TB disease probably is transmissible to other humans by the airborne route, and secondary cases can result, especially among vulnerable contacts. Mycobacterium tuberculosis (M. tuberculosis).The namesake member organism of M. tuberculosis complex, and the most common causative infectious agent of TB disease in humans.At times, the species name refers to the entire M. tuberculosis complex, which includes M. bovis and five other related species. Nucleic acid amplification (NAA).A laboratory method used to target and amplify a single DNA or RNA sequence for detecting and identifying (typically) a microorganism.NAA tests for M. tuberculosis complex are sensitive and specific; they can accelerate confirmation of pulmonary TB disease. Purified protein derivative (PPD) tuberculin.A material used in diagnostic tests for M. tuberculosis infection.In the United States, PPD solution (5 tuberculin units per 0.1 mL) is approved for administration as an intradermal injection as a diagnostic aid for M. tuberculosis infection (latent infection or TB disease).PPD tuberculin also was one of the antigens in the first-generation QuantiFERON-TB test. QuantiFERON ® -TB test.An in vitro cytokine assay that detects cell-mediated immune response (see also DTH) to M. tuberculosis in heparinized whole blood from venipuncture.This test requires only a single patient encounter, and the result can be ready <1 day.In 2005, QuantiFERON ® -TB is being replaced by QuantiFERON ® -TB Gold, which has greater specificity because of its synthetic antigens.QuantiFERON ® -TB Gold appears capable of distinguishing between the sensitization caused by M. tuberculosis infection and that caused by BCG vaccination. Radiography.The diagnostic imaging techniques (including plain-film chest radiographs and computerized tomography) that rely on degrees of X-radiation transmission related to differences in tissue densities. Secondary (TB) case.A new case of TB disease that is attributed to recent (i.e., <2 years) transmission as part of a scenario under investigation.Technically, all cases are secondary, in the sense that they arise from other cases that are contagious. Secondary (or "second-generation") transmission.Transmission of M. tuberculosis from persons with secondary cases (see Secondary (TB) case).This creates a chain of transmission, and if secondary transmission is identified as part of a contact investigation, the scenario can be classified as an outbreak. Smear.A laboratory technique for preparing a specimen so bacteria can be visualized microscopically.Material from the specimen is spread onto a glass slide (and typically dried and stained).Smear, stain, and microscopy methods for mycobacteria are specific to this genus (see AFB).The slide can be scanned by light or fluorescent high-power microscopy.These methods require ongoing quality assurance for prompt and reliable results.The results for sputum AFB smears typically are reported as numbers of AFB per high-powered microscopy field, or else as a graded result, from no AFB to 4+ AFB.The quantity of stained organisms is associated with degree of infectiousness. Source case or patient.The case or person that was the original source of infection for secondary cases or contacts.The source case can be, but is not necessarily, the index case. Specimen.Any bodily fluid, secretion, or tissue sent to a laboratory for testing. Sputum.Mucus containing secretions coughed up from within the lungs.Tests of sputum (e.g., smear and culture) can confirm pulmonary TB disease.Sputum is different from saliva or nasal secretions, which are unsatisfactory specimens for detecting TB disease.However, specimens suspected to be inadequate should still be processed because positive cultures can still be obtained and may be the only bacteriologic indication of disease. Suspected TB.A tentative diagnosis of TB that will be confirmed or excluded by subsequent testing.Cases should not remain in this category for >3 months. Symptomatic.A term applied to a patient with healthrelated complaints (i.e., symptoms) that might indicate the presence of disease.At times, the term is applied to a medical condition (e.g., symptomatic pulmonary TB). TB disease.See discussion under Infection.Treatment for LTBI.Treatment that prevents the progression of infection into TB disease. Tuberculin.A precipitate made from a sterile filtrate of M. tuberculosis culture medium. Tuberculin skin test (TST).A diagnostic aid for finding M. tuberculosis infection.A small dose of tuberculin (see also Mantoux method and PPD) is injected just beneath the surface of the skin by the Mantoux method, and the area is examined for induration by palpation 48-72 hours after the injection.Indurated margins should be read transverse (perpendicular) to the long axis of the forearm. Tuberculin skin test conversion.See Conversion. # Tuberculosis (TB). A clinically active, symptomatic disease caused by infection with a member of the M. tuberculosis complex. Two-step (tuberculin) skin test.A procedure used for baseline skin testing of persons who will periodically receive TSTs (e.g., health-care workers or residents of long-term-care facilities) to reduce the likelihood of mistaking a boosted reaction for a new infection.If an initial TST result is classified as negative, a second test is repeated 1-3 weeks later.If the reaction to the second TST is positive, it probably represents a boosted reaction, indicating that the infection was most likely in the past and not recent.If the second TST is also negative, the person is classified as not being infected.Twostep skin testing has no place in contact investigations or in other circumstances in which ongoing transmission of M. tuberculosis is suspected. - The place of residence for the index patient should be visited <3 business days of initiating the contact investigation. -All potential settings for transmission should be visited <5 working days of initiating the contact investigation. -The contact list and priority assignments (see Assigning Priorities to Contacts) should be written into an investigative plan. -Information regarding the index patient should be reassessed at least weekly until drug-susceptibility results are available for the Mycobacterium tuberculosis isolate, for 2 months after notification, or until infectiousness has diminished, whichever is longer. -At 1-2 weeks after the first interview, the index patient should be interviewed again as necessary for clarification and additional information. # Assigning Priorities to Contacts - Priorities for ranking contacts for investigation are set on the basis of the characteristics of the index patient, the duration and circumstances of exposure, and the vulnerability or susceptibility of the contact to disease progression from M. tuberculosis infection. -The optimal exposure cut-off durations for assigning priorities to contacts have not been determined because available data lack this level of precision.The National Tuberculosis Controllers Association work group did not reach consensus on cut-off durations.On the basis of local experience and adjusting for resource limitations, public health officials should set local standards for the durations of exposure that define high, medium, and low priority. # Diagnostic and Public Health Evaluation of Contacts General - Health departments are responsible for ensuring that TB contacts are medically evaluated and treated. -Communicable disease regulations or laws in certain jurisdictions apply to contacts who are not responsive to requests to be examined.The least restrictive means should be applied first. # Decision to Initiate a Contact Investigation - The features of the TB case under investigation inform decisions about whether to perform a contact investigation (see Figure 1).An investigation (i.e., seeking and evaluating contacts) is recommended for the following forms of suspected or confirmed TB because they are likely to be infectious: pulmonary, laryngeal, or pleural TB disease with 1) pulmonary cavities, 2) respiratory specimens that have acid-fast bacilli (AFB) on microscopy, or 3) both. -As time and resources permit and as recommended investigations are completed successfully, other pulmonary TB cases may be investigated if they are confirmed by culture of respiratory secretions. -Pulmonary TB cases without positive mycobacteriology results should not be investigated unless circumstances indicate otherwise (e.g., if mycobacteriologic results are absent because of an error or if a priori information raises suspicion that contacts have been infected). -The only forms of purely extrapulmonary TB (i.e., cases without pulmonary disease) that should be investigated are laryngeal or pleural disease.For other forms, sourcecase investigations can be considered under special circumstances (see Source-Case Investigations). # Investigating the Index Patient and Sites of Transmission - Written policies and procedures for these tasks improve uniformity and efficiency. -Tasks should be assigned to trained and experienced public health workers. -Interviews should be in the index patient's primary language and be conducted by persons fluent in that language or in conjunction with fluent interpreters. -The index patient should be interviewed in person (i.e., not by telephone) <1 business day after notification for cases indicating infectiousness and <3 business days for others.For patients who have died or who are inaccessible, alternative sources of information regarding contacts should be sought. - Each high-and medium-priority contact should be assessed initially <3 working days after being listed. -Each high-and medium-priority contact should be evaluated medically to determine whether TB disease and latent infection with M. tuberculosis are present or absent. -The same diagnostic methods are recommended for all contacts except when they have medical or constitutional conditions making TB more likely or more difficult to diagnose.A contact's country of origin and Bacille Calmette-Guérin (BCG) vaccination status are not included in algorithms for diagnosis or treatment. # Voluntary HIV Counseling, Testing, and Referral - Inform all contacts that HIV infection is the greatest known risk factor for TB disease progressing from M. tuberculosis infection, and ask whether they have been tested for HIV infection. -Offer voluntary HIV counseling, testing, and referral to TB contacts who do not know their HIV infection status.Collaboration with HIV-AIDS programs is recommended for establishing systems that are convenient and flexible for patients. -Voluntary HIV counseling, testing, and referral are recommended for contacts of HIV-infected infectious TB patients. # Tuberculin Skin Testing - A tuberculin skin test (TST) is recommended for all contacts who do not have a documented prior positive test result or documented prior TB disease.The skin test can be administered at the time of the initial assessment.Highpriority contacts should receive a test <7 days after they are listed, and medium-priority contacts <14 days. -A two-step TST as defined for infection control surveillance is not recommended for contact investigations. # Evaluation of Children Aged <5 Years - Contacts aged <5 years exposed to an infectious index patient are assigned a high priority. -Contacts aged <5 years should be medically examined and have a chest radiograph regardless of the result of the current or prior skin tests or history of prior TB disease. # Evaluation of HIV-infected or Other Immunocompromised Contacts - HIV-infected or other immunocompromised contacts are high-priority contacts. -In addition to a medical history, examination, and a TST, a chest radiograph is recommended for all these contacts.Sputum collection for AFB microscopy and culture is recommended if the contact has symptoms consistent with TB disease or if the chest radiograph has abnormalities that could be caused by TB. # Any Contacts Being Evaluated - Contacts who have a positive TST result (>5 mm) should be medically examined, including a chest radiograph, to rule out TB disease.Contacts who have symptoms consistent with TB also should be medically evaluated, including a chest radiograph, to rule out TB, regardless of the results of the skin test, history of a prior positive result, or history of prior TB disease. -During the infectious period, those high-and mediumpriority contacts who have a negative skin test result <8 weeks after their most recent exposure should have a second skin test 8-10 weeks after that exposure. -For low-priority contacts, the initial skin test may be delayed until 8-10 weeks after the most recent exposure if the contact does not have symptoms suggestive of TB disease.If the test is administered <8 weeks after the most recent exposure, the decision to give a second, postexposure skin test can be made on a case-by-case basis. -Use of enablers and incentives and establishment of a positive rapport with contacts who are taking treatment are recommended for enhancing adherence. # Treatment for Contacts with M. tuberculosis Infection # When to Expand a Contact Investigation - Inclusion of lower-priority contacts generally is not recommended unless objectives for high-and medium-priority contacts are being met. -Consider expanding the scope (i.e., number of contacts) of an investigation if any one or more of the following criteria exist: -unexpectedly large rate of infection or TB disease in high-priority contacts, -evidence of second-generation transmission, -TB disease in any contacts who had been assigned low priority, -infection in any contacts aged <5 years, and -contacts with change in skin test status from negative to positive. -After reviewing the results from the investigation to date (i.e., for high-and medium-priority contacts), select the additional contacts by extrapolating the risks for infection as shown by the data. -When results from an investigation indicate that it should be expanded, but resources are insufficient, seeking assistance from the next higher public-health administrative level is recommended. # Communicating Through the Media - Anticipatory media communication (e.g., with a press release) for large or highly visible TB contact investigations is recommended to capitalize on the opportunity for constructive public communications. -Coordination of media communications, both within the health department and with collaborating partners outside the health department, improves the clarity and consistency of media messages. -For efficiency, use of media message templates for contact investigations is recommended. # Data Management and Evaluation of Contact Investigations # Confidentiality and Consent in Contact Investigations - Specific policies for release of confidential information related to contact investigations are recommended.These policies should be consistent with the Privacy Rule of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and Sections 306 and 308(d) of the Public Health Service Act and be developed in consultation from health department legal counsel.These policies typically include instructions for obtaining consents and for breaking confidentiality when required for public health as authorized by laws. -Patient confidentiality is a core element integrated with all activities in contact investigations, and training in its laws and practice is recommended for all personnel who participate. - Discussion with the index patient and contacts regarding their confidentiality beliefs and concerns is recommended.TB control program staff should explain to the index patient the measures that will be taken to maintain confidentiality. -Preparations for protecting confidentiality are recommended for each site visit during an investigation.Anticipatory discussions with any patients who might be affected contribute to the preparations. -Confidentiality applies to all private information and medical conditions in addition to TB. # Staffing and Training for Contact Investigations - Certain functions in contact investigations require state licensure.Delineation of these functions is recommended for preparing personnel position descriptions. -Specialized functions and related skills are needed during contact investigations; they might be provided by sources outside of the health department (Box 3). -Preparatory training and detailed on-the-job supervision as each function is encountered by new health department personnel establish the basis for expertise. -Direct observation by experienced personnel and opportunities for practicing skills are essential when any personnel assume new functions for contact investigations. -Clerical personnel, receptionists, and managers who help with contact investigations need to understand the overall purpose and methods of contact investigations. -
When sources outside the health department serve essential functions in a contact investigation, the health department is responsible for assessing whether the skills are sufficient and offering training so that the functions are met correctly.Before QFT was approved in 2001, the tuberculin skin test (TST) was the only test available for detecting LTBI (3).QFT-G is intended to replace QFT.QFT-G results can be available <24 hours after testing without the need for a second visit, whereas a TST requires a second encounter to read the result 48-72 hours after administration of the test.As a laboratory-based assay, QFT-G is not subject to biases and errors of TST placement and reading.However, errors in collecting or transporting blood specimens or in running and interpreting the assay can decrease the accuracy of QFT-G. Related to the uncertainty in interpreting a test result, including that of the TST, when the test's measurement approaches a fixed cut-off point, the reproducibility of QFT-G is less when the measured amount of IFN-γ is near the test's cut-off point.Detection of substantial amounts of released IFN-γ in the nil sample disallows arriving at a negative test result. # Contact Investigations in Special Circumstances Each of the three tests (TST, QFT, and QFT-G) relies on a different immune response and differs in its relative measures of sensitivity and specificity.The TST assesses in vivo delayedtype hypersensitivity (Type IV), whereas QFT and QFT-G measure in vitro release of IFN-γ.The TST and QFT measure response to PPD, a polyvalent antigenic mixture, whereas QFT-G measures response to a mixture of synthetic peptides simulating two specific antigenic proteins that are present in PPD.The agreement between TST and QFT results in persons at increased risk for LTBI facilitated approval and acceptance of QFT (3,4).Results of similar studies using QFT-G testing for persons at increased risk have not been published, but less agreement between TST and QFT-G results is predictable because fewer and more specific antigens are used in QFT-G. QFT-G is not affected by prior BCG vaccination (1) and is expected to be less influenced by previous infection with nontuberculous mycobacteria (5).TSTs are variably affected by these factors.QFT-G does not trigger an anamnestic response (i.e., boosting) because it does not expose persons to antigen.Injection of PPD for the TST can boost subsequent TST responses, primarily in persons who have been infected with NTM or vaccinated with BCG.Compared with the TST, QFT-G might be less affected by boosting from a previous TST. Assessment of the accuracy of QFT-G and other indirect tests for M. tuberculosis infection (including TSTs) is hampered by the lack of confirmatory tests to diagnose LTBI and culturenegative TB disease (6).This lack is partially addressed by observing the proportion of negative tests among persons who are unlikely to have M. tuberculosis infection because they lack risks (this approach approximates specificity); by observing the proportion positive among persons with culture-confirmed TB disease (this approach approximates sensitivity); and by determining factors associated with discordance between a new test and the TST.One limitation of the first approach is that certain persons who have no recognized risks might be infected with M. tuberculosis, which causes specificity to be underestimated.A broad limitation is that the TST and any newer tests might not perform the same for detecting LTBI as they do for detecting M. tuberculosis infection during TB disease.For example, reduction of in vitro IFN-γ release has been attributed to suppressive cytokines associated with TB disease (7).When comparing an IGRA with a TST, variations in methods also must be considered (e.g., use of different antigens or riskstratified cut-off points for interpreting results). Studies assessing QFT-G with these approximation methods have been published (5,8,9).A specificity of 98.1% was reported in 216 BCG-vaccinated Japanese nursing students who were entering their training and who were at low risk for M. tuberculosis infection, and a sensitivity of 89.0% was reported in 118 patients with culture-confirmed TB (5).However, QFT-G results were derived slightly differently than the methods approved by FDA.In another study (8), QFT-G was compared with TST by using two tuberculin units of RT-23 (8,10).In a group of 99 healthy, BCG-vaccinated medical students in Korea, the specificity of QFT-G was 96%, compared with 49% for the TST.Among 54 patients with pulmonary TB disease, the sensitivity of the QFT-G was 81%, compared with 78% for the TST (8).QFT-G and the TST were compared in an unselected population of 318 hospitalized patients (9).QFT-G had greater sensitivity for TB disease (67%) than did TST (33%), but indeterminate QFT-G responses were common (21%) among patients with negative TST results, the majority of whom were thought to be immunocompromised or immunosuppressed. The antigens or laboratory methods in other studies have varied (2).Although the findings are informative, how QFT-G will perform in the same circumstances is unknown.In an investigation of contacts in a high school in Denmark in which a student had infectious TB, the same ELISA used with QFT-G was employed, but with recombinant ESAT-6 and CFP-10 antigens used rather than the mixtures of synthetic peptides used with QFT-G (11).The IGRA used in that study agreed well with the TST in non-BCG-vaccinated contacts.BCGvaccinated contacts were not skin tested, but their IGRA results closely paralleled those for the nonvaccinated contacts, which suggested that BCG vaccination was not affecting the results of this IGRA. # Methodology During July 2005, CDC convened a meeting in Atlanta, Georgia, of consultants and researchers with expertise in the field to review studies and assess experience with QFT-G. Unpublished data from studies of QFT-G were considered in preparing these guidelines.Expert consultants (see Membership List), researchers, TB control public health practitioners, and representatives of FDA, other federal agencies, and the manufacturer reviewed the evolving data on QFT-G. Data from ongoing studies evaluating QFT-G in U.S. Navy recruits, correctional facility inmates, persons with suspected TB disease, contacts of persons suspected to have TB disease, and health care workers were reviewed.For developing these guidelines, CDC considered the scientific evidence and the opinions of the consultants.Their opinions did not represent endorsement from their organizations. This report provides interim guidance for use and interpretation of QFT-G. Confirming or excluding TB disease and assessing the probability of LTBI require a combination of epidemiologic, historic, physical, and diagnostic findings that should be considered when interpreting QFT-G results.This report is intended to assist public health officials, clinicians, and laboratorians in their efforts to understand the use of QFT-G for TB control. # Indications for QFT-G FDA approved QFT-G as an in vitro diagnostic aid using peptide mixtures simulating ESAT-6 and CFP-10 proteins to stimulate cells in heparinized whole blood.Detection of IFN-γ by ELISA is used to identify in vitro responses to ESAT-6 and CFP-10 that are associated with M. tuberculosis infection (12).From a medical and public health perspective, QFT-G testing is indicated for diagnosing infection with M. tuberculosis, including both TB disease and LTBI.Whenever M. tuberculosis infection or disease is being diagnosed by any method, the optimal approach includes coordination with the local or regional public health TB control program. # How QFT-G Testing is Performed and Interpreted Instructions for the QFT-G assay are in the package insert (13).Aliquots of heparinized whole blood are incubated with the test antigens for 16-24 hours.The blood must be incubated with the test antigens <12 hours after collection.Test kits include two mixtures of synthetic peptides representing ESAT-6 and CFP-10 as test antigens, phytohemaglutinin (a mitogen used as a positive assay control), and saline (used as a nil sample to measure the background level of IFN-γ).After incubation, the concentration of IFN-γ in the plasma is determined by ELISA by using the reagents included in the test kit.The amount of IFN-γ released is determined by subtracting the amount in the nil from the amount in the ESAT-6, CFP-10, or mitogen-stimulated plasma.QFT-G test results can be calculated by using software provided by the manufacturer.This report provides guidelines for interpreting test results (Table ).Laboratory reports should include interpretation of QFT-G test results and indicate the concentration of IFN-γ in each plasma sample. # Cautions and Limitations Certain limitations of QFT-G are similar to those of the TST, but these limitations have not been studied extensively for QFT-G. Whereas the sensitivity of QFT-G for detecting M. tuberculosis infection in persons with untreated culture- The IFN-γ concentration in blood incubated with a mixture of synthetic peptides simulating early secretory antigenic target-6 (ESAT-6) minus the IFN-γ concentration in blood incubated with saline. ¶The IFN-γ concentration in blood incubated with a mixture of synthetic peptides simulating culture filtrate protein-10 (CFP-10) minus the IFN-γ concentration in blood incubated with saline. IFN-γ concentration in blood incubated with mitogen minus the IFN-γ concentration in blood incubated with saline. † †International units per mL. § § Tuberculosis. confirmed TB is approximately 80% in published studies (5,8), its sensitivity for particular groups of TB patients (e.g., young children and immunocompromised patients) has not been determined. QFT-G sensitivity for LTBI might be less than that of the TST, although the lack a confirmatory test makes this difficult to assess.Estimating the sensitivity of any indirect test for LTBI by testing patients who have TB disease might be inaccurate because of differences between these conditions.The ability of QFT-G to predict risk for LTBI progressing subsequently to TB disease has not been determined. QFT-G, as with the TST, cannot differentiate infection associated with TB disease from LTBI.A diagnosis of LTBI requires that TB disease be excluded by medical evaluation, which should include checking for suggestive symptoms and signs, a chest radiograph, and, when indicated, examination of sputum or other clinical samples for the presence of M. tuberculosis. Similar to any other diagnostic test, the predictive value of QFT-G results depends on the prevalence of M. tuberculosis infection in the population being tested.Each QFT-G result and its interpretation should be considered in conjunction with other epidemiologic, historic, physical, and diagnostic findings. As with a negative TST result, negative QFT-G results should not be used alone to exclude M. tuberculosis infection in persons with symptoms or signs suggestive of TB disease.The presence of symptoms or signs suggestive of TB disease increases the likelihood that M. tuberculosis infection is present, and these circumstances decrease the predictive value of a negative QFT-G or TST result.Medical evaluation of such persons should include a history and physical examination, chest radiograph, bacteriologic studies, serology for human immunodeficiency virus (HIV), and, when indicated, other tests or studies. The performance of QFT-G, in particular its sensitivity and its rate of indeterminate results, has not been determined in persons who, because of impaired immune function, are at increased risk for M. tuberculosis infection progressing to TB disease.Impaired immune function can be caused by HIV infection or acquired immunodeficiency syndrome (AIDS); current treatment with immunosuppressive drugs including highdose corticosteroids, tumor necrosis factor-alpha (TNF-α) antagonists, and drugs used for managing organ transplantation; selected hematologic disorders (e.g., myeloproliferative disorders, leukemias, and lymphomas); specific malignancies (e.g., carcinoma of the head, neck, or lung); diabetes; silicosis; and chronic renal failure (6).Each of these conditions or treatments is known or suspected to decrease responsiveness to the TST, and they also might decrease production of IFN-γ in the QFT-G assay.Consequently, as with a negative TST result, negative QFT-G results alone might not be sufficient to exclude M. tuberculosis infection in these persons. Published data are relatively limited concerning the use of QFT-G among persons recently exposed to TB (e.g., contacts) and other populations at high risk for LTBI.No published data document the performance of QFT-G in children aged <17 years. With any of the testing methods, persons who have a negative test result can still have LTBI.Those who have a negative result but who are likely to have LTBI and who are at greater risk for severe illness or poor outcomes if TB disease occurs might need treatment or closer monitoring for disease (6).Potential examples include close contacts who are aged <5 years, those who are immunocompromised because of HIV infection, or those who will undergo treatment with TNF-α antagonists (which increase the risk for progression from LTBI to TB disease) (14)(15)(16). QFT-G has practical limitations that include the need to draw blood and to ensure its receipt in a qualified laboratory in time for testing.The blood must be incubated with the test antigens <12 hours after collection, while the lymphocytes are viable.After the blood is incubated with antigens for 16-24 hours, plasma must be collected and either properly stored or tested promptly by ELISA.Collecting the required 5-mL blood sample from younger children might not be possible or acceptable. # Additional Considerations and Recommendations in the Use of QFT-G in Testing Programs QFT-G can be used in all circumstances in which the TST is used, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB screening of health-care workers and others undergoing serial evaluation for M. tuberculosis infection.QFT-G usually can be used in place of (and not in addition to) the TST. A positive QFT-G result should prompt the same public health and medical interventions as a positive TST result.No reason exists to follow a positive QFT-G result with a TST.Persons who have a positive QFT-G result, regardless of symptoms or signs, should be evaluated for TB disease before LTBI is diagnosed.At a minimum, a chest radiograph should be examined for abnormalities consistent with TB disease.Additional medical evaluation would depend on clinical judgment on the basis of findings from history (including exposure to infectious TB), physical examination, and chest radiography.HIV counseling, testing, and referral is recommended because HIV infection increases the suspicion for TB and the urgency of treating LTBI.After TB has been excluded, treatment of LTBI should be considered (6). The majority of healthy adults who have negative QFT-G results are unlikely to have M. tuberculosis infection and do not require further evaluation.However, for persons with recent contact with persons who have infectious TB, negative QFT-G results should be confirmed with a repeat test performed 8-10 weeks after the end of exposure, as is recommended for a negative TST result.Studies to determine the best time to retest contacts with negative QFT-G results have not been reported.Until more information is available, the timing of QFT-G testing should be the same as that used for the TST (17,18). When "window period" prophylaxis (i.e., treatment for presumed LTBI) is indicated for contacts aged <5 years or severely immunocompromised persons who are exposed to highly contagious TB, repeat testing for LTBI is recommended 8-10 weeks after contact has ended (18).With either TST or QFT-G, negative results of the test at the end of the window period should be interpreted by considering all available epidemiologic, historic, clinical, physical, and diagnostic information, including the findings for the other contacts in the investigation.A full course of treatment should be considered even with a negative result from either test at the end of the window period when the rate of M. tuberculosis transmission to other contacts was high or when a false-negative result is suspected because of a medical condition (18). A greater rate of positive results has been reported with TST than with QFT-G in persons with and without recognized risks for M. tuberculosis infection, except for patients who have culture-confirmed TB disease (5,8).This tendency might be explained by either greater specificity with QFT-G, greater sensitivity with TST, or both.For this reason, all information must be considered when making treatment decisions for persons with increased risk for progression from LTBI to TB or in whom TB disease is associated with increased risk for severe illness or poor outcomes. An indeterminate QFT-G result does not provide useful information regarding the likelihood of M. tuberculosis infection.The optimal follow-up of persons with indeterminate QFT-G results has not been determined.The options are to repeat QFT-G with a newly obtained blood specimen, administer a TST, or do neither.For persons with an increased likelihood of M. tuberculosis infection who have an indeterminate QFT-G result, administration of a second test, either QFT-G or TST, might be prudent.The potential for TST to cause boosting and the need for two-step testing in settings conducting serial testing should be considered.For persons who are unlikely to have M. tuberculosis infection, no further tests are necessary after an indeterminate QFT-G result.Laboratories should report the reason that the QFT-G result was indeterminate (e.g., high background levels of IFN-γ in the nil sample or inadequate response to mitogen).In one report, inadequate response to mitogen was associated with immunosuppressive conditions (9). As with the TST, if TB disease is suspected, additional diagnostic evaluations should be performed before or at the same time as the QFT-G and should not be delayed while awaiting QFT-G results.These evaluations should include chest radiography, bacteriologic studies, serology for HIV, and, as indicated by the illness, additional tests and studies.At present, as with the TST, the results of indirect tests for M. tuberculosis (e.g., QFT-G) usually would not influence the selection of additional tests and studies in such patients. TB control programs can use QFT-G for investigating contacts of persons with potentially infectious TB disease.Because QFT-G does not require a second visit to complete, test results probably will be available from a greater percentage of contacts than would be available using TST.Because of its greater specificity, QFT-G is expected to indicate a smaller proportion of contacts as infected than the TST would indicate.Public health resources that previously were devoted to completion of testing can instead be concentrated on full evaluation and complete treatment of contacts who have positive QFT-G results.In contrast to the TST, initial QFT-G testing of contacts will not boost subsequent test results, which avoids uncertainty about interpreting follow-up results.
However, QFT-G might be less sensitive for LTBI than the TST, and its ability to predict subsequent development of TB disease is undetermined. QFT-G might represent a cost-effective alternative to the TST in testing programs which are part of the TB infection control program in institutions such as health care settings, correctional facilities, or homeless shelters.In these settings, false-positive reactions to the TST pose a problem.This problem is compounded in settings with BCG-vaccinated persons born in countries where TB is prevalent.Follow-up visits for reading the TST also pose substantial operational challenges; the second visit for reading requires extra effort and leads to inefficiency.The greater specificity of the QFT-G and the requirement for only one visit are compelling advantages.General recommendations on the use of QFT-G as part of the infection control program in health-care settings have been included in the most recent revision of the TB infection control guidelines (19).In situations with serial testing for M. tuberculosis infection, initial two-step testing, which is necessary with the TST, is unnecessary with QFT-G and is not recommended. TB control programs or institutions that elect to use QFT-G should consult and collaborate with laboratories in their system to ensure that specimens are properly obtained, handled, and processed prior to and after arrival in the laboratory. gov/mmwr/cme/conted.html.3.Select which exam you want to take and select whether you want to register for CME, CEU, or CNE credit.4.Fill out and submit the registration form.5.Select exam questions.To receive continuing education credit, you must answer all of the questions.Questions with more than one correct answer will instruct you to "Indicate all that apply."6.Submit your answers no later than December 16, 2008.7 # 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 2.75 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 0.25 continuing education units to participants who successfully complete this activity. # Continuing Nursing Education (CNE). This activity for 3.2 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. # National Commission for Health Education Credentialing (NCHEC). CDC is a designated provider of continuing education contact hours in health education by the NCHEC.This program is a designated event through which a certified health education specialist can receive 2.5 category I contact hours in health education.CDC's provider number is GA0082. # Goal and Objectives This report provides expanded guidelines concerning the investigation of tuberculosis (TB) exposure and transmission and prevention of future cases of TB through contact investigations.The goal of this report is to provide standard and comprehensive guidance for this public health activity that will lead to improved outcomes for persons exposed to infectious TB.Upon completion of this educational activity, the reader should be able to 1) discuss when to initiate a contact investigation; 2) discuss how to prioritize the evaluation of contacts; 3) discuss the diagnostic evaluation of contacts, including children aged <5 years old and immunocompromised contacts; 4) discuss the medical treatment of contacts who have latent tuberculosis infection ; and 5) discuss when to expand a contact investigation.To receive continuing education credit, please answer all of the following questions. # The infectious period is usually determined to be 3 months before the diagnosis of TB. A. True.B. False. # The most important characteristics of contacts for assigning priority are age and immune status. A. True.B. False. # Two-step tuberculin skin tests (TSTs) are recommended for the evaluation of foreign-born contacts. A. True.B. False. # Contacts with TST reactions >5 mm should undergo further medical evaluation, including a chest radiograph. A. True.B. False. # Which contacts should be considered for window prophylaxis? A. Correct answers for questions 1-7. 1.E; 2.T; 3.T; 4.F; 5.T; 6.G; 7.F. # The availability of continuing education credit influenced my decision to read this report. A # S. Food and Drug Administration as an aid for diagnosing Mycobacterium tuberculosis infection.This test detects the release of interferon-gamma (IFN-γ) in fresh heparinized whole blood from sensitized persons when it is incubated with mixtures of synthetic peptides representing two proteins present in M. tuberculosis: early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10).These antigens impart greater specificity than is possible with tests using purified protein derivative as the tuberculosis (TB) antigen.In direct comparisons, the sensitivity of QFT-G was statistically similar to that of the tuberculin skin test (TST) for detecting infection in persons with untreated culture-confirmed tuberculosis (TB).The performance of QFT-G in certain populations targeted by TB control programs in the United States for finding latent TB infection is under study.Its ability to predict who eventually will have TB disease has not been determined, and years of observational study of substantial populations would be needed to acquire this information.In July 2005, CDC convened a meeting of consultants and researchers with expertise in the field to review scientific evidence and clinical experience with QFT-G. On the basis of this review and discussion, CDC recommends that QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control (e.g., those for health-care workers).This report provides specific cautions for interpreting negative QFT-G results in persons from selected populations.This report is aimed at public health officials, health-care providers, and laboratory workers with responsibility for TB control activities in the United States. (CFP-10).ESAT-6 and CFP-10 are secreted by all M. tuberculosis and pathogenic M. bovis strains.Because these proteins are absent from all Bacille Calmette-Guérin (BCG) vaccine strains and from commonly encountered nontuberculous mycobacteria (NTM) except M. kansasii, M. szulgai, and M. marinum (1), QFT-G is expected to be more specific for M. tuberculosis than tests that use tuberculin purified protein derivative (PPD) as the antigen. QFT-G represents one type of IFN-γ release assay (IGRA) (2).Tests such as QFT-G measure the IFN-γ released by sensitized white blood cells after whole blood is incubated with antigen.Tests such as ELISpot enumerate cells releasing IFN-γ after mononuclear cells recovered from whole blood are incubated with similar antigens.Two IGRAs have been approved by FDA for use in the United States: the original QuantiFERON ® -TB test (QFT) and the recently approved QFT-G. The two tests use different antigens to stimulate IFN-γ release, different methods of measurement, and different approaches to test interpretation.QFT was approved as an aid for diagnosing LTBI, whereas QFT-G is approved as an aid for diagnosing both LTBI and TB disease.QFT is no longer commercially available.Information concerning the assay is in the package insert (13).Training of laboratory staff will be necessary.Certain facilities might elect to refer specimens for testing.The Clinical Laboratory Improvement Amendments (CLIA) regulations for quality systems of all phases of the total testing process (preanalytic, analytic, and post-analytic) and for general laboratory systems must be followed, including, but not limited to, the requirements for test system, equipment, instruments, reagents, materials and supplies (42 CFR Part 493.1252), and the establishment or verification of performance specifications (42 CFR Part 493.1253) (20).In addition, under CLIA, documentation of all quality systems, including laboratory proficiency and staff competency, is required. # Background # Future Research Needs Additional studies to assess the performance of the QFT-G test under program conditions should be conducted.Further research is needed regarding use of QFT-G in multiple clinical circumstances.Studies of test performance should assess specificity, sensitivity, reproducibility, and association of test results with risk for infection and risk for progressing to TB disease.Comparisons among different IGRAs and TSTs are encouraged.Questions to be addressed include the following: - performance of QFT-G in young children, especially those aged <5 years; - performance of QFT-G in persons with impaired immune systems, including persons with HIV/AIDS, those who will be treated with TNF-α antagonists, and others; - performance and practicality of use of QFT-G in substantial numbers of persons who undergo periodic screening; - determination of the subsequent incidence of TB disease after LTBI has been either diagnosed or excluded with QFT-G; - length of time between exposure, establishment of infection, and emergence of a positive QFT-G test result; - economic evaluation and decision analysis comparing QFT-G with TST; - changes in QFT-G results during therapy for both LTBI and TB disease; - ability of QFT-G to detect reinfection after treatment for both LTBI and TB disease; and - performance of QFT-G in targeted testing programs (e.g., for recent immigrants from high-incidence countries) and contact investigations.In collaboration with FDA and the manufacturer, CDC will establish mechanisms for postmarketing surveillance.Providers should use FDA's MedWatch (available at .accessdata.fda.gov/scripts/medwatch) to report instances of a contact having all of the following criteria: - a negative QFT-G or TST result >6 weeks after the end of exposure, - culture-confirmed TB disease <2 years after the end of exposure, and - an M. tuberculosis isolate that has a genotype identical to that of the presumed source case.Certain instances consistent with these criteria might require further study of the circumstances.However, reliance on postmarketing surveillance is not a substitute for research targeted at the above-noted questions.Research in these areas and others should therefore be conducted through prospective studies. The optimal methods for ensuring quality in laboratory implementation of QFT-G testing should be determined.Educational materials are needed that can be widely disseminated to educate physicians regarding the use of the QFT-G assay.CDC will work with partners and the manufacturer to ensure the development of such materials. Other IGRA tests and test formats might become available in the United States over the next several years (21,22).Users of any of these products should anticipate the need for periodic modifications in practice, with resulting improvements in utility of these testing technologies.