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.
- 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.
Table of Contents
- 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 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-spore-
forming 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 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.
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.
Table of Contents
- 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.
- Proven Anthrax Disease of Any Type or Proven Bacterial Colonization
- 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.
- 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.
- 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:
- the lesion is later shown not to be due to anthrax (and is not
otherwise considered to be a cause for deferral), or
- 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.
Table of Contents
- 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:
- 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.
- 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.
Table of Contents
- 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.
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.
Table of Contents
- 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.
Table of Contents
- 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.
Table of Contents
- 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.