Guidance for Industry

Recommendations for Assessment of

Donor Suitability and Blood and Blood

Product Safety in Cases of Possible

Exposure to Anthrax

Final Guidance

This guidance is being distributed for immediate implementation.

FDA is issuing this guidance without initially seeking comment because the agency has

determined that prior public participation is not feasible or appropriate. Comments and

suggestions regarding this document should be submitted anytime to Dockets Management

Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD

20852. All comments should be identified with the docket number listed in the notice of

availability that publishes in the Federal Register.

Additional copies of this guidance are available from the Office of Communication, Training and

Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Rockville, MD 20852-1448, or by

calling 1-800-835-4709 or (301) 827-1800, or from the Internet at

http://www.fda.gov/cber/guidelines.htm

For questions on the content of this guidance contact the Division of Blood Applications, Office

of Blood Research and Review at (301) 827- 3524.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologics Evaluation and Research (CBER)

October 2001
i

TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 1

III. RECOMMENDATIONS on DONOR DEFERRAL...................................................... 4

A. Proven Anthrax Disease of Any Type or Proven Bacterial Colonization................ 4

B. Undiagnosed Skin Lesions Suspected to be Anthrax................................................. 4

IV. RECOMMENDTIONS on PRODUCT QUARANTINE AND RETRIEVAL............ 5

A. Proven Anthrax Disease of Any Type ......................................................................... 5

B. Undiagnosed Post-donation Illness in Potentially Exposed Individuals.................. 5

V. RECOMMENDATIONS on NOTIFICATION OF PRIOR TRANSFUSION

RECIPIENTS .................................................................................................................... 5

VI. IMPLEMENTATION....................................................................................................... 6

VII. REFERENCES.................................................................................................................. 6

APPENDIX: SIGNS AND SYMPTOMS OF ANTHRAX INFECTION1.............................. 7
1

GUIDANCE FOR INDUSTRY

Recommendations for Assessment of Donor Suitability and Blood

and Blood Product Safety in Cases of Possible Exposure to Anthrax

This guidance document represents the agency’s current thinking on this topic. It does not

create or confer any rights for or on any person and does not operate to bind FDA or the public.

An alternative approach may be used if such approach satisfies the requirements of the

applicable statute and regulations.

I. INTRODUCTION

This guidance document provides the current recommendations of the Food and Drug

Administration (FDA) for assessment of donor suitability and product safety for donors

potentially exposed to Bacillus anthracis, the agent of anthrax. This guidance applies to Whole

Blood, blood components (including recovered plasma) and Source Plasma collections intended

for use in transfusion or for further manufacturing into injectable products. FDA developed the

recommendations in this guidance in consultation with other Public Health Service Agencies and

with the Blood Safety Committee of the Department of Health and Human Services.

At present there are insufficient systematic human data to fully address the possible occurrence

of bacteremia in an asymptomatic individual who is infected with anthrax bacilli. However,

based on the current available scientific data, highly knowledgeable experts agree that such a

possibility is extremely remote. There is no known risk of transmission of anthrax from blood

collected from asymptomatic donors who might have been exposed to the anthrax bacterium.

Moreover, current regulations provide for the deferral of any donor who is not in good health at

the time of donation, and specifically require deferral of a donor with acute respiratory disease or

any infectious skin disease presenting a risk of contamination of the blood. [21 CFR 640.3(b)

and 21 CFR 640.63(c)] Nevertheless, FDA is issuing guidance on prudent measures that should

be taken to reduce any possible risk for transmission of anthrax from blood or blood products.

II. BACKGROUND

Anthrax is caused by the bacterium Bacillus anthracis, a spore forming Gram-positive rod.

Anthrax spores can tolerate dry conditions and stay intact for long periods of time (years),

especially if they are shielded from UV light exposure. When the spores are inoculated,

ingested, or inhaled they germinate to the bacterial (vegetative) form that multiply rapidly and

invade tissues. There are three types of anthrax infection in humans: cutaneous, gastrointestinal,

and inhalational.

Anthrax is reported annually among livestock in the United States. In areas where these animal

cases occur, most human cases are the cutaneous form. Such cases occur among workers who

have handled infected hoofed animals, or products from these animals. Gastrointestinal anthrax
2

has been reported following the ingestion of undercooked or raw meat from infected animals.

Inhalational anthrax, resulting from inhalation of aerosolized spores, was associated with

industrial processing of infected wool, hair or hides in the United States in the past. Prior to

October 2001, no case of inhalational anthrax had been reported in the United States since 1978.

Cutaneous anthrax has an incubation period that ranges from 1 to 12 days. The skin lesions of

cutaneous anthrax typically are found on the hands, arms or feet. The early infection is

localized, appearing first as a papule that progresses over a few days to a 1-2 cm. vesicle that

ruptures leaving a black, necrotic ulcer. The cutaneous infections usually can be cured with

antibiotics.

Gastrointestinal anthrax is considered to have an incubation period that ranges from 1 to 7 days.

Gastrointestinal anthrax includes anthrax of the mouth and throat (“oropharyngeal”) and anthrax

of the lower gastrointestinal tract (“abdominal”). Involvement of the oropharynx is characterized

by lesions at the base of the tongue, sore throat, dysphagia, fever, and regional

lymphadenopathy. Lower gastrointestinal tract involvement usually causes nausea, loss of

appetite, vomiting and fever, followed by abdominal pain, vomiting blood, and the occurrence of

bloody diarrhea.

The most serious form of anthrax occurs when someone inhales spores (inhalational anthrax),

leading to a fulminant infection in the chest (necrotizing mediastinitis) and septicemia. This

disease is rapidly fatal in almost all cases unless therapy is begun before the disease becomes

advanced. The incubation period of inhalational anthrax among humans is unclear, but it is

reported to between 1 and 7 days, and possibly sometimes as long as 60 days.

While ciprofloxacin, doxycycline and penicillin are the antibiotics most often recommended by

infectious diseases experts and public health authorities, susceptibility testing is critical in

guiding antibiotic therapy for anthrax, particularly for treating presumed intentional infections.

Clinicians should consult the Centers for Disease Control and Prevention (CDC) or local public

health authorities for further guidance.

Standard infection control precautions (handwashing, wearing gloves for handling contaminated

materials) are sufficient when treating patients with anthrax. Inhalational anthrax is not

contagious from person to person, obviating a need for respiratory precautions. Bacillus

anthracis is very resistant to common environmental conditions that would destroy non-sporeforming organisms. However, household bleach, diluted 1:10 and applied for 30 minutes will

eliminate the spore form as well as the bacterial form of B. anthracis. Steam sterilization,

autoclaving, or burning may also be employed for destruction of the spores and bacteria.

Limited amounts of a vaccine for anthrax have been produced but are not currently available for

general use.

Blood Donor and Blood Product Issues

The FDA has received inquiries about procedures for blood collection in reaction to reports of

exposures to B. anthracis. To date, these reports have involved small numbers of persons either
3

with anthrax infection (disease) or well individuals from whom the anthrax bacillus could be

cultured or otherwise detected (colonization). In these cases, anthrax apparently was acquired in

circumscribed locations after direct contact with contaminated materials. Inquiries have focused

on the safety of blood donation by other individuals living or working in the same general area

who might also have been exposed. In response, FDA is issuing guidance on prudent measures

that should be taken to reduce any possible risk for transmission of anthrax from blood or blood

products.

In most cases of cutaneous anthrax, the bacteria are localized at the site of inoculation of the skin

where they cause development of a necrotic ulcer. The organisms usually do not enter the

bloodstream unless the individual remains untreated. Although clinical experience with

gastrointestinal anthrax is extremely limited, bacteremia is known to occur in the fulminant stage

of the abdominal form of gastrointestinal anthrax. In inhalational anthrax, the bacteria initially

are localized to the mediastinal lymph nodes. After a generally brief incubation period, a

fulminant illness develops that is characterized by necrotizing mediastinitis and bacterial sepsis.

The appearance of anthrax bacteria in the blood of an infected person is thought to coincide very

closely with the onset of fever and other symptoms of a serious illness in any form of anthrax.

Thus, the likelihood of anthrax bacteremia in a person who feels well enough to donate is

extremely remote. For this reason, standard screening procedures that exclude sick persons from

donating blood are expected to result in deferral of donors who otherwise might transmit the

disease due to bacteria in their blood. In addition, the apparently limited number of individuals

exposed in these recent episodes makes transfusion transmission of anthrax even less likely to

occur.

After consulting with scientific experts at the CDC, the National Institutes for Health (NIH), and

the United States Army Medical Research Institute for Infectious Diseases (USAMRIID) about

the possible transmission of anthrax by blood transfusion, the FDA is not recommending any

changes to standard donor screening and blood collection procedures to identify or otherwise

query donors who may have been exposed to anthrax. This policy is based on the assessment

that there is not known or suspected to be a significant risk of transmission of anthrax from blood

collected from asymptomatic donors who might have been exposed to the anthrax bacterium or

its spores, and the fact that standard blood collection procedures that already are in place include

deferral of any donor who is not in good health at the time of donation.

If an asymptomatic donor (other than those donors known to have proven bacterial colonization)

mentions use of antibiotics to prevent anthrax, medical directors may exercise their own

discretion whether to defer donors who are taking antibiotics. If an otherwise healthy and

asymptomatic potential donor is taking antibiotics solely because medical or public health

authorities recommended this after possible exposure to anthrax, donation is acceptable if all

other criteria are met.

Nevertheless, as a prudent measure to address the possible increased risk of anthrax bacteremia

in cases of active disease or proven bacterial colonization (as opposed solely to potential

exposure), FDA is providing recommendations on criteria for donor deferral, and on criteria for

product quarantine and retrieval related to reports of post-donation illnesses.
4

The FDA is continuing to consult with experts on anthrax at the CDC, NIH, and USAMRIID to

ensure the greatest possible safety of the blood supply. In addition, the situation and

epidemiology of this and other potential biological threats are rapidly changing. Any new data or

experience related to this issue will be evaluated rapidly and further updates will be provided as

appropriate.

III. RECOMMENDATIONS ON DONOR DEFERRAL

Consistent with existing regulations and applicable guidance, donors should be in good health

and free of acute respiratory illnesses and of infectious skin disease presenting a risk of

contamination of the blood. [21 CFR 640.3(b) and 21 CFR 640.63(c)] Standard procedures that

already are in place should be adequate to defer potential donors who may have gastrointestinal

or inhalational anthrax at the time of donation since such persons are expected to be

symptomatic. However, additional considerations are needed to address bacterial colonization in

an asymptomatic donor. Also, special consideration is needed to address confirmed or suspected

cutaneous anthrax because the skin lesions usually are painless. At this time, FDA is not

proposing revisions to standard donor questions. However, a donor may report such lesions, or

in the performance of routine donor screening and preparation for phlebotomy, a skin lesion

compatible with cutaneous anthrax may be found.

The following recommendations apply to cases of known or suspected anthrax disease or proven

bacterial colonization at the time of donation.

A. Proven Anthrax Disease of Any Type or Proven Bacterial Colonization

1. FDA recommends that a potential donor with a current confirmed medical diagnosis of

anthrax of any form should be deferred until the person subsequently completes a full

course of an appropriate treatment and the condition is considered to be resolved.

2. Although there is no evidence that proven bacterial colonization in well persons indicates

an increased risk for transmission of anthrax by transfusion, as a prudent measure FDA

recommends that such persons should be deferred from donation until they have

completed a full course of prophylaxis with an appropriate antibiotic.

B. Undiagnosed Skin Lesions Suspected to be Anthrax

FDA recommends that a potential donor with a skin lesion suspected to be anthrax should be

deferred until either:

a) the lesion is later shown not to be due to anthrax (and is not otherwise considered to be a

cause for deferral), or

b) the lesion is confirmed as cutaneous anthrax and the person subsequently completes a full

course of an appropriate treatment and the infection is considered to be resolved.
5

IV. RECOMMENDTIONS ON PRODUCT QUARANTINE AND RETRIEVAL

The FDA is recommending that blood establishments quarantine and retrieve previously

collected in-date units of blood and blood components intended for transfusion, as well as

unpooled units of Source Plasma and recovered plasma intended for fractionation to make

injectable products under the following circumstances:

A. Proven Anthrax Disease of Any Type

FDA recommends that the in-date blood components from prior collections should be

quarantined and retrieved promptly if a donor later reports a confirmed medical diagnosis of

anthrax (i.e., clinical disease of anthrax and not solely bacterial colonization). Product

quarantine and retrieval should date back to the known time of potential donor exposure to B.

anthracis or 60 days prior to the onset of illness, whichever is the shorter period.

B. Undiagnosed Post-donation Illness in Potentially Exposed Individuals

In cases of undiagnosed post-donation illnesses among donors who were in areas under

investigation for anthrax exposures, FDA recommends that medical directors should exercise

judgment regarding product quarantine and retrieval. Factors that may be considered include

the character and severity of the illness (index of suspicion for anthrax), the likelihood of

anthrax exposure for the specific individual, and whether or not the donor subsequent to an

anthrax exposure received an appropriate course of antibiotic therapy recommended by

public health authorities as effective prophylaxis against anthrax in the setting of likely

exposure to the anthrax bacterium. In general, quarantine and retrieval would not be expected

in response to undiagnosed illnesses unless there were felt to be strong epidemiologic and/or

clinical evidence raising the suspicion of active anthrax disease.

If a decision is made to quarantine and retrieve prior collections, then product quarantine and

retrieval should be performed promptly and should date back to the known time of potential

donor exposure to anthrax or 60 days prior to the onset of illness, whichever is the shorter

period.

V. RECOMMENDATIONS ON NOTIFICATION OF PRIOR TRANSFUSION

RECIPIENTS

In the case that subsequent to donation, a donor is reported to have a confirmed medical

diagnosis of anthrax (clinical disease of anthrax and not solely bacterial colonization), FDA

recommends that medical directors consider the need for prompt record tracing and notification

to the treating physicians of prior recipients of blood and blood components collected from that

donor. FDA considers relevant units to be those dating back to the known time of potential

donor exposure to anthrax, or 60 days from onset of illness, whichever is the shorter period.
6 

Because the chance of anthrax transmission from transfusion is highly unlikely, FDA is not 

recommending lookback notification of blood and blood component recipients in cases of prior 

donation by a person who later reports an undiagnosed illness compatible with anthrax. 

VI. IMPLEMENTATION

The recommendations in this guidance should be implemented immediately and do not require 

prior approval from the FDA. Under 21 CFR 601.12 licensed establishments implementing 

these recommendations should submit by official correspondence a statement in their annual 

reports indicating the date that the revised standard operating procedures, consistent with these 

recommendations have been established and implemented.

VII. REFERENCES

1. A.M. Friedlander, Anthrax, In: F.R. Sidell, E.T. Takafuji, D.R. Franz, eds. Textbook of 

 Military Medicine: Medical Aspects of Chemical and Biological Warfare, Washington, DC:

 Office of the Surgeon General, Dept. of the Army, 1997, 467-478. 

2. T.V. Inglesby, D.A. Henderson, J.G. Bartlett, M.S. Ascher, E. Eitzen, A.M. Friedlander, J. 

Hauer, J. McDade, M.T. Osterholm, T. O’Toole, G. Parker, T.M. Perl, P.K. Russel, K. Tonat, 

Anthrax as a Biological Weapon; Medical and Public Health Management, JAMA (1999) 

281; 1735-1745. 
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APPENDIX: SIGNS AND SYMPTOMS OF ANTHRAX INFECTION1

Inhalational anthrax: A brief prodrome resembling a viral respiratory illness followed by

development of hypoxia and dyspnea, with radiographic evidence of mediastinal widening.

This, the most lethal, form of anthrax results from inspiration of 8,000-40,000 spores of B.

anthracis. The incubation of inhalational anthrax among humans is unclear, but it is reported to

range between 1 and 7 days possibly ranging up to 60 days. Host factors, dose of exposure and

chemoprophylaxis may play a role. Initial symptoms include sore throat, mild fever, muscle

aches and malaise. These may progress to respiratory failure and shock. Meningitis frequently

develops. Case-fatality estimates for inhalational anthrax are based on incomplete information

regarding exposed populations and infected populations in the few case series and studies that

have been published. However, case-fatality is extremely high, even with all possible supportive

care including appropriate antibiotics. Records of industrially acquired inhalational anthrax in the

United Kingdom before antibiotics were available reveal that 97% of cases were fatal. With

antibiotic treatment the fatality rate is estimated to be at least 75%. Estimates of the impact of

the delay in post-exposure prophylaxis or treatment on survival are not known. It has been

suggested that each day of delay in initiating treatment may significantly increase morbidity and

mortality from anthrax infection.

Gastrointestinal anthrax: Severe abdominal distress followed by fever and signs of septicemia.

This form of anthrax usually follows the consumption of raw or undercooked contaminated meat

and is considered to have an incubation period of 1-7 days. An oropharyngeal and an abdominal

form of the disease have been described in this category. Involvement of the pharynx is usually

characterized by lesions at the base of the tongue, sore throat, dysphagia, fever, and regional

lymphadenopathy. Lower bowel inflammation usually causes nausea, loss of appetite, vomiting

and fever, followed by abdominal pain, vomiting blood, and bloody diarrhea. The case-fatality

rate is estimated to be 25-60%, and the effect of early antibiotic treatment on that case-fatality

rate is not defined.

Cutaneous anthrax: A skin lesion evolving from a papule, through a vesicular stage, to a

depressed black eschar. This is the most common naturally occurring type of infection (>95%)

and usually occurs after skin contact with contaminated meat, wool, hides, or leather from

infected animals. Incubation period ranges from 1-12 days. Skin infection begins as a small

papule, progresses to a vesicle in 1-2 days followed by a necrotic ulcer. The lesion is usually

painless, but patients also may have fever, malaise, headache and regional lymphadenopathy.

The case-fatality rate for cutaneous anthrax is 20% without, and less than 1% with, antibiotic

treatment.

1

See “CDC Guidelines for State Health Departments, Revised October 14, 2001.”