The October 2001 domestic anthrax attacks affected 22 people, resulting in 5 fatalities. The added global terrorist threats have created an increasing need for homeland protection, as well as protection of our widely deployed forces battling terrorism. It is now relevant for physicians to be familiar with both clinical anthrax and adverse vaccine-related events associated with the resumption of the anthrax vaccine program. Dermatologists played a lead role in the initial response to the anthrax attack. We must be the lead providers most familiar with the cutaneous reactions that may be seen with the preventive vaccination. This article reviews the latest recommended evaluation and management of anthrax vaccine adverse events.
Case Reports Patient 1—A 36-year-old white male active duty military fighter pilot developed recurrent, localized urticaria after receiving his sixth anthrax vaccination (Figure 1). Results of a skin biopsy showed a superficial perivascular dermatitis with eosinophils consistent with urticaria. The urticaria continues to recur 21/2 years after his last vaccination and remains localized to the vaccinated arm.
Patient 2—A 33-year-old black male military member developed erythema multiforme one day after receiving his fifth anthrax vaccination. He had been treated for pharyngitis with a 10-day course of oral penicillin, which had been completed 2 days prior to receiving the vaccination. Target lesions were present on both arms and hands but were more prominent on the arm that received the vaccination (Figure 2). Results of a skin biopsy revealed a superficial perivascular and interface lymphocytic dermatitis, with vacuolar changes along the dermoepidermal junction compatible with erythema multiforme.
Patient 3—A 28-year-old white male military member presented with a pruritic rash that had developed on his face approximately 12 hours after receiving his fifth anthrax vaccination. The rash had spread to his torso (Figure 3) and lower extremities. Results of a punch biopsy revealed a superficial and deep lymphocytic infiltrate with interface changes and some extravasated red blood cells, findings felt to be consistent with an erythema multiforme reaction (Figure 4). The patient was treated with a 2-week course of prednisone and intramuscular diphenhydramine (Benadryl®), and clearing of symptoms was noted within 10 days.
Comment
The threat of anthrax is deadly and real, as shown by the domestic attacks via the US Postal Service in October 2001. In all, there were 11 confirmed cases of inhalation anthrax, resulting in 5 fatalities. In addition, there were 7 confirmed cases and 4 suspected cases of cutaneous anthrax. Twenty of the 22 cases were unquestionably linked to mail contaminated with a single strain of Bacillus anthracis.1 Anthrax is easy and cheap to produce and can be stored for prolonged periods, with spores survivable for decades in ambient conditions.2 The spores are resistant to dryness, heat, UV light, gamma radiation, and many disinfectants.3 In addition, anthrax is odorless, colorless, tasteless, and difficult to detect, thus making it a likely choice for future biological attacks. After the first gulf war, Iraq admitted to producing and deploying weaponized anthrax in missiles.4 The Sverdlovsk anthrax outbreak in the former Soviet Union occurred after the accidental release of aerosolized anthrax spores from a bioweapons facility and resulted in as many as 250 cases with 100 deaths.2 Fortunately, we have a vaccine that has been judged safe and effective by the US Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and National Academy of Sciences. Protecting the health of US military forces who defend our vital interests is a national obligation.5 The trade-off for force protection of our military personnel involves a small incidence of vaccine-related adverse events (AEs), the most common being local type injection site reactions or skin reactions.
Natural cutaneous anthrax manifests within a few days as a painless, pruritic papule that progresses to a blister and evolves to a painless ulcer, with a black central eschar and surrounding local edema. In contrast, vaccine-related events manifest differently, and the vaccine cannot cause clinical anthrax infections. An algorithm for the evaluation of suspected cutaneous anthrax has been published by the American Academy of Dermatology Ad Hoc Task Force on Bioterrorism.6 Additional guidelines for clinical and laboratory diagnoses, specimen handling, and postexposure prophylaxis are available from the US Centers for Disease Control and Prevention.7
The vaccine itself is made from a noninfectious, cell-free sterile filtrate of an attenuated, nonencapsulated, nonproteolytic strain of B anthracis.8 It is considered an inactivated vaccine and is unable to cause infection. The anthrax vaccine has been approved by the FDA since 1970 and is safely administered to veterinarians, laboratory workers, woolen mill workers, and livestock handlers.8 In 1997, it was mandated that all US military personnel receive it. Full protection requires a schedule of 6 injections over 18 months (specifically, at 0, 2, and 4 weeks and 6, 12, and 18 months), with an annual booster thereafter. In the event of anthrax exposure, the vaccine also can be offered as postexposure prophylaxis with 3 doses at 2-week intervals, along with postexposure antibiotics.2 Contraindications to the anthrax vaccine include hypersensitivity reaction to a prior dose or vaccine component, human immunodeficiency virus positivity or immune suppression (active corticosteroid or other immunosuppressive treatment), any active infection or acute illness, pregnancy (confirmed or suspected), and age younger than 18 years or older than 65 years.
Efficacy and Safety
The vaccine's efficacy against aerosolized anthrax was shown in studies on nonhuman primates. Sixty-two (95%) of the 65 primates vaccinated with the anthrax vaccine adsorbed (AVA) survived a lethal aerosol challenge, whereas all 18 unvaccinated controls died.8 In actively monitored studies on the safety of AVA, mild local reactions occurred in 3% to 20% of doses, moderate reactions in 1% to 3% of doses, and severe reactions in less than 1% of doses.8 Acute systemic reactions were reported in 0.06% of doses and consisted of transient symptoms of fever, chills, nausea, and general body aches.8
The current system for reporting AEs is the Vaccine Adverse Event Reporting System (VAERS), and the FDA reviews 100% of these reports. In addition, a US Department of Defense directive requires its military providers to initiate a report for any event following AVA that results in hospitalization, any loss of duty of more than 24 hours, or for suspected vaccine contamination.9 Reporting of other reactions suspected because of vaccination is encouraged, especially those that are clinically significant or unusual. The form can be obtained on the Web at http://www.vaers.org or via telephone at 800-822-7967. Electronic reporting is available on the Web at http://secure.vaers.org/VaersDataEntryintro.htm. The VAERS is a passive surveillance system, and determining causal associations between vaccines and AEs is not always possible.10 Other concurrent infections or exposures may precipitate a given symptom that may simply coincide with the receipt of a vaccine.11 For example, patient 2 may have had vaccine-associated erythema multiforme but because he had recently completed a course of penicillin, we cannot exclude the possibility of a concurrent antibiotic association.
The Anthrax Vaccine Expert Committee reviewed 602 VAERS reports filed from 1998 through 1999.12 Nearly one half of reports noted a local injection site AE, 33% of which were noted to be moderate to large. A subcutaneous nodule was cited in 5.3% of reports. Although three fourths of reports noted a "systemic" AE, these covered a broad spectrum, with 34 types cited at a frequency of more than 1%. The most common AEs, in declining order of incidence, were flulike symptoms, 20.8%; malaise, 13.3%; rash, 14.2%; arthralgia, 12%; headache, 10.1%; with the remainder of AEs all affecting fewer than 10% of patients. Among the reported 45 total "serious or medically important AEs," one report of each of the following was noted: systemic lupus erythematosus, angioedema, anaphylactoid reaction, and toxic epidermal necrolysis. None of these AEs were judged to be causally (defined as likely, certain, or probable) related to the vaccine itself.12 According to Friedlander et al,8 the "FDA continues to view the anthrax vaccine as safe and effective for individuals at risk of exposure to anthrax."
Management of Adverse Events
Adverse reactions after vaccination can be divided into local and systemic.
Cutaneous Reactions—The cutaneous manifestations and the latest recommendations from the Walter Reed National Vaccine healthcare center network9 are summarized partially in Tables 1 and 2.
Local reactions involve the injection site or have contiguous spread and are graded based on the measured size of the local redness or swelling (Table 1). Most local anthrax vaccine reactions require no treatment and resolve within 72 hours, though topical or oral steroids and oral antihistamines can be used to help manage symptoms. Unless the local reaction is very large or complicated, the patient can usually proceed with subsequent doses. Although some of these reactions may mimic cellulitis, antibiotic therapy for postvaccination inflammation is not warranted. Allergy consultation is recommended for a large or complicated reaction, especially if this occurs after the second dose. In this instance, the patient may be immune (a hyperresponder) and may not require further series (with the exception of the yearly booster).9 When a significant local type reaction has occurred, pretreatment to help prevent future large local reactions is indicated.