5
Safety: Case Reports

During the course of the committee’s deliberations, it heard and received in writing considerable testimony from individuals describing adverse events that occurred to them or their family members following vaccination against anthrax. Reports of adverse events have also been featured in newspaper reports and congressional testimony. Some of these events were quite severe, and the committee sympathizes with the presenters and understands their concerns about their illnesses.

These statements and stories in the media are examples of a broader category of information, that is, case reports of adverse events following the use of a vaccine. The committee identified two published case reports related to Anthrax Vaccine Adsorbed (AVA; Kerrison et al., 2002; Swanson-Biearman and Krenzelok, 2001). The most extensive collection of case reports of adverse events following vaccination is contained in the Vaccine Adverse Event Reporting System (VAERS), and the committee focused its attention there. Many of the experiences described to the committee directly were also reported to VAERS. This chapter reviews the characteristics of VAERS and the manner in which VAERS data related to the anthrax vaccine are used by responsible agencies. A summary of the VAERS reports and the committee’s interpretation of this information are also presented.

VACCINE ADVERSE EVENT REPORTING SYSTEM

VAERS is a passive surveillance system begun in 1990 as part of the



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The Anthrax Vaccine: Is it Safe? Does it Work? 5 Safety: Case Reports During the course of the committee’s deliberations, it heard and received in writing considerable testimony from individuals describing adverse events that occurred to them or their family members following vaccination against anthrax. Reports of adverse events have also been featured in newspaper reports and congressional testimony. Some of these events were quite severe, and the committee sympathizes with the presenters and understands their concerns about their illnesses. These statements and stories in the media are examples of a broader category of information, that is, case reports of adverse events following the use of a vaccine. The committee identified two published case reports related to Anthrax Vaccine Adsorbed (AVA; Kerrison et al., 2002; Swanson-Biearman and Krenzelok, 2001). The most extensive collection of case reports of adverse events following vaccination is contained in the Vaccine Adverse Event Reporting System (VAERS), and the committee focused its attention there. Many of the experiences described to the committee directly were also reported to VAERS. This chapter reviews the characteristics of VAERS and the manner in which VAERS data related to the anthrax vaccine are used by responsible agencies. A summary of the VAERS reports and the committee’s interpretation of this information are also presented. VACCINE ADVERSE EVENT REPORTING SYSTEM VAERS is a passive surveillance system begun in 1990 as part of the

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The Anthrax Vaccine: Is it Safe? Does it Work? response to the National Childhood Vaccine Injury Act of 1986.1 It is the nation’s principal system for the collection of reports on adverse events following the use of any vaccine licensed in the United States. The system is coadministered by two federal agencies, the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA), which previously operated two separate surveillance systems. VAERS objectives include the following: (1) detecting previously unrecognized adverse events following the use of licensed vaccines; (2) detecting unusual increases in previously reported events; (3) detecting preexisting conditions that may promote adverse events and contraindicate additional vaccine doses; (4) detecting vaccine lots for which unusual numbers and unusual types of events are reported; (5) serving as a registry for rare vaccine-related adverse events; and (6) providing national data on the numbers of reported adverse events by vaccine type and recipient age (Singleton et al., 1999). It is also intended to trigger further clinical, epidemiologic, or laboratory studies of vaccine safety (Chen, 2000; Mootrey, 2000). VAERS Reporting Process VAERS receives spontaneous reports of adverse events following vaccination. From 1990, when VAERS began, through December 2001, VAERS received more than 126,000 reports on events associated with vaccines of all types (Iskander, 2002). Anyone can submit a report to VAERS, including vaccine recipients or their family members, and more than one report can be submitted about the same adverse event. Reporting is encouraged for any clinically significant event following vaccination, but health care providers are required to report any event listed by the manufacturer as a contraindication to the administration of additional doses of the vaccine as well as certain other specified events (VAERS, 2001). Most reports are submitted by health care providers directly (30 percent) or through the vaccine manufacturer (42 percent; Iskander, 2001b). Figure 5-1 illustrates the flow of information into and through VAERS. Each year, reporting forms along with instructions and a cover letter encouraging reporting are mailed to about 200,000 health care providers (Iskander, 2001a). The forms are also available on the Internet (http://www.vaers.org/, http://www.fda.gov/cber/vaers/vaers.htm, http://www.cdc.gov/nip/). A VAERS report form includes spaces for the reporter to provide demographic information about the vaccine recipient and an open-ended description of the adverse event(s), treatment, outcome, relevant laboratory or diagnostic information, timing of the vaccination and the adverse event, 1   National Childhood Vaccine Injury Act of 1986. P. L. No. 99-660 (1986).

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The Anthrax Vaccine: Is it Safe? Does it Work? FIGURE 5-1 VAERS information flowchart. AVEC is unique to the anthrax vaccine. vaccine type and lot number, and preexisting conditions. (See Appendix E for a copy of the form.) Reports can be submitted by mail or fax, or the information can be provided over the telephone. Reports are submitted to the VAERS contractor, who acknowledges their receipt with a letter to the reporter (Chen et al., 1994; Singleton et al., 1999). The contractor assigns a unique identifier to each report, assigns codes to the adverse events reported, and enters the data into a computer database. Duplicate reports are removed or linked if the different reports provide different information (Iskander, 2001a). Certain adverse events are classified as serious2: a death, a life-threatening illness, or an illness that results in a permanent disability, hospitalization, or prolongation of a hospital stay (Singleton et al., 1999). Manufacturers are also required to report “other medically important conditions” (Iskander, 2001b). Within 5 days of the receipt of a report of a serious event, nurses working for the VAERS contractor initiate follow-up inquiries to the vaccine recipient or reporter to gather more information, including medical or autopsy records, if they are available (E. Miller, CDC, 2   Postmarketing Reporting of Adverse Drug Experiences. 21 C.F.R. § 314.80 (2000).

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The Anthrax Vaccine: Is it Safe? Does it Work? personal communication, May 24, 2001). As a result of the additional information, the medical coding of the event may be changed. Review of VAERS Data by FDA and CDC Both FDA and CDC regularly review data from VAERS reports for patterns in the data that suggest the possibility of previously unrecognized adverse events. For regulatory purposes, FDA reviews individual reports to assess whether the reported events are adequately reflected in product labeling (FDA, 2001). FDA also reviews all reports of serious adverse events soon after receipt by the VAERS contractor and may occasionally investigate other events as well. All reports of deaths are investigated to determine the official cause of death and to obtain any autopsy information. FDA staff examine VAERS data to look for unusual or unexpected patterns or trends associated with a vaccine or a vaccine lot and meet weekly to discuss any newly identified patterns observed. FDA does not attempt to evaluate whether the reported events have a causal association with the vaccine in question, but the agency is empowered to recall any vaccine or vaccine lot found to be associated with an unacceptably high rate of reports of adverse events (FDA, 2001). VAERS reports are routinely reviewed carefully after a vaccine has been on the market for a few years and data based on experience with the vaccine have been collected. The accumulated VAERS reports are also summarized and discussed in journal articles. FDA does not have a priori thresholds or numbers of reports of a particular adverse event that trigger additional follow-up but instead relies on a constellation of data including, among other factors, the seriousness of the reports, the similarities of case descriptions, and the size of the vaccine lot in question. In the case of the anthrax vaccine, data on the number of doses administered are available from the Department of Defense’s (DoD’s) Defense Medical Surveillance System (DMSS) and inform FDA’s interpretation of the adverse events reports. CDC focuses on collective reports and attempts to determine unusual epidemiologic trends and associations (FDA, 2001). For each vaccine, aggregated data from VAERS reports are evaluated weekly for unusual numbers of cases, types of adverse events, or other unexpected features. CDC also receives information about cases flagged during FDA’s weekly review of reports. As at FDA, CDC analysts generally rely on clinical judgment rather than specific quantitative thresholds of adverse events to initiate additional follow-up. If VAERS reports raise concerns, studies are undertaken to develop more definitive information.

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The Anthrax Vaccine: Is it Safe? Does it Work? Limitations of VAERS As the only system for the collection of information on adverse events reported in association with the use of all U.S. licensed vaccines after they are marketed, VAERS is an essential resource for the monitoring of vaccine safety. An unexpected increase in the numbers of reports about a product or a series of reports of an unexpected or unusual adverse event can catalyze additional information gathering and investigation. However, VAERS also has certain critical limitations (Chen, 2000; Ellenberg and Chen, 1997; IOM, 1994a,b). Adverse events that occur soon after a vaccination may be reported to VAERS whether or not they are causally related to the vaccination. Duplicate reports of the same case may be submitted, and the medical information provided may be incorrect or incomplete. The complexity of the information that comes into the system (e.g., multiple exposures and multiple outcomes) also makes analysis difficult. In addition, VAERS provides no information on the incidence of similar events among persons who have not been vaccinated. Because VAERS is a passive system that relies on spontaneous reporting, adverse events are likely to be underreported to an unknown extent, and underreporting may also vary over time and among various kinds of adverse events. One analysis found that the “reporting efficiency” of VAERS ranged from 68 percent for vaccine-associated poliomyelitis following administration of oral polio vaccine to <1 percent for rash following administration of the measles-mumps-rubella vaccine (Rosenthal and Chen, 1995). Moreover, for most vaccines there are no data about the number of doses actually administered, although there may be data from other sources on the number of doses distributed. As a result of these limitations, it is nearly impossible to calculate accurate rates of adverse events from VAERS data. A numerator based on the number of reports can be assumed to differ from the true number of events, and there are no data on the total number of doses administered for the denominator (Mootrey, 2000; Singleton et al., 1999; Tilson, 1992). In the case of AVA, however, DoD has maintained records on vaccine doses administered since the start of the Anthrax Vaccine Immunization Program (AVIP) in 1998. This information provides a denominator that is useful in the interpretation of changes in the frequencies of conditions reported to VAERS. In addition, the availability of data from DMSS on diagnoses for hospitalizations and outpatient visits (see Chapter 6) gives DoD a unique opportunity to evaluate the completeness of reporting to VAERS. Adverse events for which medical attention was received can be systematically identified within DMSS, and efforts can be made to determine whether those events are included in VAERS. However, it is important to recognize that increased reporting is not a

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The Anthrax Vaccine: Is it Safe? Does it Work? goal in and of itself. For VAERS, like any other spontaneous reporting system, there is no expectation or possibility of complete reporting. This inherent characteristic of spontaneous reporting systems must be recognized to properly interpret the data that they produce. Only in the context of an extremely organized health care system, such as that administered by DoD, can exposures be truly quantified and outcomes more completely reported. Even then, determination of true rates of reactions requires formal epidemiologic studies that provide complete ascertainment of numerators and denominators (see Chapter 6). For spontaneous reporting systems, then, the goal should be not simply more complete reporting but more detailed and insightful reporting, including more clinical data on each case and the selective reporting of cases that are novel, serious, or both. Increasing the numbers of reports of poorly documented events is unlikely to be helpful in determining which events are truly vaccine related. Finding: The presence or absence of VAERS reports (or other case reports) cannot be considered in and of itself to provide adequate evidence of causal association or its absence. Reports may suggest hypotheses for further investigation, but it must be borne in mind that many different factors beyond the presence of health symptoms can influence whether a report is filed. DoD AND VAERS Because most recipients of the anthrax vaccine are U.S. military personnel, DoD has two roles in connection with VAERS. First, military health care providers who administer AVA and other vaccines also prepare and submit VAERS reports on adverse events that follow vaccinations. Second, DoD has an interest in learning from VAERS data of any signals of possible safety concerns. “Signals” are the earliest indication of a possible causal relationship between an exposure and a health event. Such signals can come from the anecdotal experiences of patients suffering an adverse event following the exposure or from preliminary analyses of data. A signal does not mean that a causal relationship exists, as there may be other explanations for the apparent association. Instead, a signal is merely an indication that further investigation is needed. For AVA, DoD has also sought a special independent mechanism for review of VAERS reports, the Anthrax Vaccine Expert Committee (AVEC). Submission of VAERS Reports DoD, which administers most of the anthrax vaccine used in the United States, has a central role in the reporting of any adverse events that occur following vaccination. Since 1995, DoD policy has required submission of

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The Anthrax Vaccine: Is it Safe? Does it Work? VAERS reports for any adverse event that results in the loss of time from duty of more than 24 hours or any period of hospitalization (Department of the Air Force, 1995). This requirement has been reiterated with specific emphasis for the anthrax vaccine: [A] Form VAERS-1 must be completed and submitted using Service reporting procedures for those events resulting in a hospital admission or time lost from duty for greater than 24 hours or for those events suspected to have resulted from contamination of a vaccine lot. Further, health care providers are encouraged to report other adverse events that in the provider’s professional judgment appear to be unexpected in nature or severity. In addition, the patient or a health care provider may submit a Form VAERS-1 directly to the Food and Drug Administration (FDA) for any possible adverse event. (Bailey, 1999, p. 1) Reports from Navy and Air Force health care providers are to be submitted directly to VAERS, whereas reports from Army health care providers are to be submitted through a military treatment facility’s Pharmacy and Therapeutics Committee, which forwards them to VAERS. Copies of VAERS reports must also be submitted to a service’s reportable disease officer within 7 days of an adverse event. Concerns About Reporting to VAERS Some service members have expressed concern that they have been discouraged from submitting VAERS reports regarding the anthrax vaccine. According to service member testimony to the U.S. Congress as well as statements made to this Institute of Medicine (IOM) committee, reporting to VAERS has at times “met reluctance” or taken place only after delays (U.S. Congress, House of Representatives, Committee on Government Reform, 2000, p. 36; Irelan, 2000; Nietupski, 2001). In at least one Air Force squadron there is a perception that seeking care for symptoms of unknown origin or filing a VAERS report carries the risk of being labeled as a malingerer or as depressed or could jeopardize a service member’s flight status (Tanner, 2001; U.S. Congress, House of Representatives, Committee on Government Reform, 2000, p. 39). In a General Accounting Office survey of National Guard and Air Force Reserve pilots and aircrew members (GAO, 2000), 60 percent of those who reported experiencing reactions that they attributed to the anthrax vaccine had not discussed those reactions with military health care personnel or their supervisors. In addition, 71 percent of those surveyed were unaware of VAERS, representing a substantial opportunity for underreporting. (The level of awareness of VAERS among the general public is not known.) Testimony to the committee indicated that at the start of AVIP at least some military physicians had little knowledge of VAERS and VAERS reporting procedures (Buck, 2001).

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The Anthrax Vaccine: Is it Safe? Does it Work? In response to such concerns, the acting assistant secretary of defense for health affairs requested in October 2000 that the surgeons general of the services remind medical personnel of the need for high-quality, empathetic medical care for vaccinees and of policies for submission of VAERS reports (Clinton, 2000). The surgeon general of the Army’s memorandum of October 27, 2000 (Peake, 2000) noted that DoD policy for reporting to VAERS (Bailey, 1999; Department of the Air Force, 1995) set the minimum requirements for submissions of reports (i.e., if vaccine-related reactions result in hospitalization or the loss of time from duty of more than 24 hours or if contaminated or dangerous lots are suspected). The memorandum also urged submission of reports “for any event that may be related to a vaccination. If a patient wants to submit a VAERS report, help him or her submit one” (Peake, 2000). Memoranda to Navy and Air Force medical personnel provided similar messages, noting that it is not the provider’s responsibility to determine the causality of the adverse event (Carlton, 2000; Surgeon General of the Navy, 2000). A potential additional step to facilitate reporting to VAERS was described to the committee in July 2001. Plans were noted to provide new guidelines for military health care providers for coding a health event as vaccine related. Finding: Concerns of service members that reporting to VAERS is some-times discouraged within the military setting have been responded to appropriately with reminders to physicians that DoD policy requires submission of a VAERS report for postvaccination health events that result in hospitalization or the loss of time from duty of more than 24 hours. Additional steps, however, are possible to facilitate reporting to VAERS, including improvements in the coding of health care visits that are potentially vaccine related. Recommendation: DoD should develop and implement a system to automate the generation of VAERS reports within the military health care system, using codes to identify from automated records those health care visits that are potentially vaccine related. Use of these codes should generate an automatic filing of a VAERS report that includes the specific diagnoses for the clinical event(s) that prompted the health care visit. However, the submission of reports to VAERS should not be restricted to visits assigned codes that identify them as potentially vaccine related. DoD Access to and Use of VAERS Data The AVIP Agency, which is part of DoD, monitors VAERS reports related to the use of AVA. The Army Medical Surveillance Activity pro-

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The Anthrax Vaccine: Is it Safe? Does it Work? duces weekly summaries from the copies of VAERS reports that DoD health care providers submit to the services’ disease reporting systems. Monthly cross-checks with VAERS managers ensure that the AVIP Agency learns, in a redacted manner, of reports sent directly to VAERS without a report through military channels (Grabenstein, 2001b). DoD also receives information about VAERS reports through AVEC, a committee of civilian experts convened to review VAERS reports related to AVA (see below for a further discussion of AVEC). As a liaison member of AVEC, the AVIP Agency receives copies of all AVA-related VAERS reports (with identifiers removed) and of the additional records sought by AVEC for a substantial fraction of cases (Grabenstein, 2001c). In addition, DoD has access to the redacted information in the AVEC database. A contractor to the AVIP Agency maintains this database and codes and enters data for use by AVEC (Grabenstein, 2001c). An AVEC medical reviewer audits the accuracy of the data entered. DoD may not disclose information from individual reports because the data belong to AVEC and because of the restrictions that are part of the Privacy Act (Grabenstein, 2001b). Anthrax Vaccine Expert Committee The Department of Health and Human Services (DHHS) convened AVEC in 1998 in response to a request from the Army surgeon general (Sever et al., in press). It is a committee of civilian physicians and scientists and was formed to provide ongoing independent expert medical review of VAERS reports related to anthrax vaccination. DHHS recruited the committee members through the Expert Witness Program of the Vaccine Injury Compensation Program (http://bhpr.hrsa.gov/vicp/INDEX.HTM). Committee members have expertise in neurology, infectious diseases, rheumatology, epidemiology, and statistics, as well as experience and interest in vaccine-related adverse events. The committee includes liaison members from DoD’s AVIP Agency, FDA’s Center for Biologics Evaluation and Research, and CDC’s National Immunization Program. AVEC has staff support from the DHHS National Vaccine Injury Compensation Program. DoD provides DHHS with funding to support the activities of the committee, but the agreement between the two departments gives DHHS full independence in the selection of AVEC members and in all activities of the committee (Grabenstein, 2001c; Sever et al., in press). AVEC reviews AVA-related VAERS reports individually to assess the probability of a causal relationship between the reported adverse event and the anthrax vaccine and in aggregate to determine if any patterns are evident from the reports. AVEC and its procedures were modeled after the Advisory Committee on Causality Assessment (ACCA), an expert advisory group convened by the Canadian government in 1994 to review all reports

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The Anthrax Vaccine: Is it Safe? Does it Work? of serious and unusual vaccine-associated adverse events from both active and passive monitoring systems in Canada (Collet et al., 2000). Both ACCA and AVEC use the criteria of the World Health Organization to assign categories of “very likely/certain,” “probable,” “possible,” “unlikely,” “unrelated,” or “unclassifiable” to the likelihood of a causal relationship between the adverse event and the vaccine (Caserta, 2000; Collet et al., 2000; Sever et al., in press). The review of individual reports begins when the VAERS contractor provides redacted copies of reports to AVEC as they are received. A single AVEC member makes a preliminary review and assessment of each case using a case assessment form (Appendix F). Additional medical records are sought as needed through VAERS to provide more information on the adverse event and its resolution or longer-term outcome. At intervals of 3 to 6 weeks, batches of the reports with preliminary assessments are sent to the full committee and a teleconference is held to discuss each case (Weibel, 2001). On the basis of that discussion, the committee may modify the preliminary categorization of a case or decide to seek additional information. Information from the case assessment form, including the conclusions of the committee, is entered into an AVEC database (Caserta, 2000). Further evaluation takes place as part of the preparation of manuscripts for publication. The causality assessments involve only the medically qualified civilian members of AVEC. The nonmedical members, liaison members from government agencies, and other support personnel play no role in the process (Grabenstein, 2001c; Sever et al., in press). The aggregate review is an ongoing process operating in parallel with the case reviews. The statistician and epidemiologist on AVEC compile and analyze information from the database in an effort to discern any patterns that relate to specific symptoms, severity, lot numbers, or other factors. They also use information available from DMSS to estimate the number of vaccine doses administered during the time period in question. This added information provides some ability to look at trends in reporting rates for adverse events. AVEC gives additional scrutiny to adverse events that appear in 1 percent or more of the reports it receives and particularly to any repeated serious and “other medically important” adverse events, taking into account the committee’s previous classifications of the likelihood of a causal association between the particular adverse event and the vaccine. No formal protocols have been established to determine the number of reports of a given adverse event over a specified period of time that would initiate additional action. To date, AVEC has not observed a cluster of events that it believed warranted concerns about the safety of the vaccine (Sever et al., in press). Should information from VAERS reports raise such concerns, AVEC would inform the National Vaccine Injury Compensation Program, which would

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The Anthrax Vaccine: Is it Safe? Does it Work? convey the information to DoD and the AVIP Agency. AVEC can also provide a public alert through a rapid publication, such as a letter to a journal editor. REPORTS TO VAERS RELATED TO AVA As of November 29, 2001, roughly 2.1 million doses of AVA had been administered in the United States since 1990. AVEC has reviewed a total of 1,623 unique VAERS reports about adverse events following receipt of the anthrax vaccine. This section provides summary information about the nature of the events reported to VAERS, the conclusions reached by AVEC as to the likelihood of a causal association between vaccination with AVA and the reported adverse event, allergic reactions reported through VAERS, and the IOM committee’s conclusions from its own review of the VAERS reports concerning serious adverse events (i.e., a death, a life-threatening illness, or an illness that results in a permanent disability, hospitalization, or prolongation of a hospital stay). AVEC Conclusions Regarding Reports to VAERS Of the 1,623 VAERS reports reviewed by AVEC as of October 2, 2001, 57 involved hospitalization, 161 involved a loss of time from duty of 24 hours or more without hospitalization, and the remainder involved neither hospitalization nor loss of time from duty for 24 hours or more (AVIP, 2001). AVEC found that 10 of the 57 hospitalizations were “very likely/certainly” or “probably” caused by receipt of the anthrax vaccine. All 10 involved allergic inflammation reactions at the injection site. Table 5-1 presents the diagnoses and AVEC classifications of the other 47 hospitalizations reported to VAERS. Of the 161 VAERS reports that involved a loss of time from duty of 24 hours or more without hospitalization, 89 were classified by AVEC as “certainly” or “probably” caused by anthrax vaccination. The events included in these 89 reports are listed in Table 5-2. Acute Allergic Reactions Following Vaccination with AVA DoD reexamined VAERS reports to identify reports of acute allergic (anaphylactic) reactions following vaccination with AVA. These were defined as reactions (1) that had an onset within 2 hours of receipt of AVA (usually within minutes) and (2) that involved either airway and cardiovascular collapse (anaphylactic shock) or less severe anaphylactic symptoms such as generalized itching, symptoms of chest tightness with or without evidence of hives, and reactions for which epinephrine or antihistamines

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The Anthrax Vaccine: Is it Safe? Does it Work? TABLE 5-1 AVEC Classification of Hospitalizations Reported to VAERS (as of October 2, 2001) Following Anthrax Vaccination and Not Classified as “Very Likely/Certainly” or “Probably” Caused by Anthrax Vaccine Adsorbed   Number of VAERS Reports Diagnosis Unclassifiable Unrelated Unlikely Possible Abdominal pain 1   Acute encephalitis   1   Angioedema   1   Aplastic anemia 1   Atrial fibrillation 1   1   B-cell lymphoma involving central nervous system   1   Bipolar psychiatric disorder 1 1   Blackout episode   1   Cardiac arrest   1   Cardiomyopathy with atrial fibrillation   1 1   Diabetes mellitus, insulin requiring 1   Diabetes mellitus, non-insulin requiring   1   Dysesthesias (T1 and below) 1   Dyspnea 2   Endocarditis with perirectal abscess   1   Fatigue and injection-site inflammation   1 Febrile illness   1   Guillain-Barré syndrome 3 2   Idiopathic thrombocytopenic purpura 1   Inflammation over olecranon process   1   Intestinal surgery (appendectomy)   1   Liver abscess with Escherichia coli septicemia   1   Meningitis, aseptic   1   Meningitis, viral 1   Meningitis, unspecified   1   Multiple sclerosis   1   Neurological symptoms (facial weakness, slurred speech)   1   Neutropenia, fever 2   Pemphigus vulgaris   1   Progressive paralytic neurological disease   1   Rash   1 Scleritis, bilateral   1   Seizure   1   Syncope   1   Systemic lupus erythematosus   1   Toxic epidermal necrolysis syndrome   1   Viral-like syndrome   2   Total 15 23 7 2   SOURCE: AVIP (2001).

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The Anthrax Vaccine: Is it Safe? Does it Work? TABLE 5-2 Adverse Events Reported to VAERS (as of October 2, 2001) Involving Loss of Time from Duty of 24 Hours or More and Considered by AVEC as Certainly or Probably Caused by Anthrax Vaccine Adsorbed Reported Adverse Event Number of Events Injection-site reactions 52 Various rashes 9 Acute allergic reactions 9 Virus-like symptoms 9 Itching 2 Gastroenteritis 2 Muscle aches 2 Bronchiolitis obliterans 1 Tingling sensation 1 Photophobia 1 Swollen lymph nodes 1 Total 89   SOURCE: AVIP (2001). were given. As of October 2, 2001, no cases of anaphylactic shock had been reported to VAERS. There were 16 cases (7.6 per 1 million doses) of less severe anaphylactic reactions, all of which resolved without sequelae (Grabenstein, 2001a). IOM Review of Serious VAERS Reports The IOM committee reviewed the extent, nature, and quality of the information available in VAERS to inform its analysis of VAERS and AVEC. A subcommittee of the IOM committee reviewed all VAERS reports related to AVA that were defined as serious under VAERS criteria and that had been submitted through October 30, 2001—a total of 120 reports. The subcommittee also discussed with AVEC its process for causality assessment. The IOM subcommittee was satisfied with the approach described by AVEC and did not replicate the causality assessments for the cases that the subcommittee reviewed. The subcommittee undertook a qualitative review and discussion of the collection of cases reported to VAERS in a search for patterns or suggestions of similar clinical pictures or possibly related underlying pathophysiology. For all events or symptoms that appeared in two or more reports of serious events, the subcommittee checked the rates of these (or related)

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The Anthrax Vaccine: Is it Safe? Does it Work? diagnoses among those who had and those who had not been immunized with AVA in the DoD analyses of DMSS data that had previously been presented to the entire committee (see Chapter 6 and Appendix G). No confirmatory increases in the rates of these events in the immunized population were found. Finding: The committee has reviewed the case materials and the methods applied by VAERS and AVEC to evaluate those materials and concurs with their conclusions that those materials present no signals of previously undescribed serious adverse reactions associated with exposure to AVA. REFERENCES AVIP (Anthrax Vaccine Immunization Program). 2001. Section J: Reports involving anthrax vaccine submitted to the FDA/CDC Vaccine Adverse Event Reporting System (VAERS) and Evaluated by the Anthrax Vaccine Expert Committee. Detailed Safety Review of Anthrax Vaccine Adsorbed. [Online.] Available: http://www.anthrax.osd.mil/Sit_Files/articles/INDEXclinical/safety_reviews.htm [accessed January 18, 2001]. Bailey S. 1999. Policy for reporting adverse events associated with the anthrax vaccine. Memorandum to Surgeon General of the Army, Surgeon General of the Navy, and Surgeon General of the Air Force. Department of Defense, Washington, D.C. Buck J. 2001. Written statement. Presentation to the Joint Meeting of the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine and the Institute of Medicine Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program, Meeting III, Washington, D.C. Carlton PK Jr. 2000. Vaccine Adverse Events Reporting System (VAERS). Memorandum for See Distribution. Department of the Air Force, Washington, D.C. Caserta V. 2000. Anthrax Vaccine Expert Committee (who, what, when, where, and how). Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting I, Washington, D.C. Chen RT. 2000. Special methodological issues in pharmacoepidemiology studies of vaccine safety. In: BL Strom, ed. Pharmacoepidemiology. 3rd ed. West Sussex, England: John Wiley & Sons, Ltd. Pp. 707–732. Chen RT, Rastogi SC, Mullen JR, Hayes SW, Cochi SL, Donlon JA, Wassilak SG. 1994. The Vaccine Adverse Event Reporting System (VAERS). Vaccine 12(6):542–550. Clinton JJ. 2000. Reactions of the anthrax vaccine. Memorandum to Surgeon General of the Army, Surgeon General of the Navy, and Surgeon General of the Air Force. Department of Defense, Washington, D.C. Collet JP, MacDonald N, Cashman N, Pless R. 2000. Monitoring signals for vaccine safety: the assessment of individual adverse event reports by an expert advisory committee. Advisory Committee on Causality Assessment. Bulletin of the World Health Organization 78(2):178–185. Department of the Air Force. 1995. Immunizations & Chemoprophylaxis—Air Force Joint Instruction 48-110 (U.S. Army Regulation 40-562; Navy Bureau of Medicine & Surgery Instruction 6230.15; Coast Guard Commandant Instruction M6230.4E). Department of the Air Force, Washington, D.C. Aerospace Medicine. [Online]. Available: http://afpubs.hq.af.mil/pubfiles/af/48/afji48-110/afji48-110.pdf [accessed February 20, 2002]. Ellenberg SS, Chen RT. 1997. The complicated task of monitoring vaccine safety. Public Health Reports 112(1):10–20.

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