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Rapid Responses: Rapid Responses published:
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The medical response to terrorism
- Ian Roberts (6 September 2004)
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Vaccinating to Keep Troops Healthy
- John D. Grabenstein, William Winkenwerder, Jr. (17 September 2004)
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Scientific evidence and its political use
- Tom Jefferson (27 September 2004)
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Bioterrorism and compulsory vaccination revisited: arguments for current vaccines based on inadequate support for older vaccines
- Walter R Schumm (29 September 2004)
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Ian Roberts, Professor of Epidemiology and Public Health London School of Hygiene & Tropical Medicine
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Bloodbath was the word most of the reporters used. Nevertheless, the day that over 200 women and children died in Russia’s worst hostage crises the BMJ published yet another editorial on bio-terrorism. Terrorism, whether governmental or non-governmental is, and always has been, about bombs and bullets. It is not about anthrax or smallpox. The only recent use of an infectious agent in a terrorist attack killed about six people using anthrax sourced from a US military establishment. Every day of the year hundreds of people bleed to death following bullet wounds and bomb blasts. So why the fuss about bio-terrorism? The answer is politics. Doctors, just like the public, respond to the signals sent out by governments and bio-terrorism serves an important political function. It causes fear among the domestic population which enables governments to restrict civil liberties, attack foreign states and justify huge spending on armaments, all of which increase the risk of real terrorism like the kind that was metered out in Middle School No 1 in Beslen yesterday. A responsible medical reaction to terrorism would emphasize that most of the victims die of traumatic injury for which there are currently few effective treatments. For most practical medical purposes deaths from terrorism are much the same as those from unintentional injuries such as road traffic crashes. This means that finding better ways to treat trauma will benefit not only the victims of terrorism but trauma patients more generally. World-wide, for people at ages 5 to 45 years, trauma is second only to HIV/AIDS as a cause of death and each year about three million people die from trauma, many after reaching hospital. Among those who survive to reach hospital, exsanguination is the most common cause of death, accounting for nearly half of in-hospital trauma deaths. Head injury and multi-organ failure account for most of the remainder. Apart from surgical intervention, which is the mainstay of the emergency management of bleeding, trauma patients are routinely exposed to a panoply of untested treatments. Bleeding patients invariably receive some kind of fluid replacement but there is no reliable evidence about how much fluid should be given or what fluid should be used. For nearly half a century doctors replaced blood loss with colloids and albumin but the recent evidence from the SAFE trial, albeit from a somewhat different medical context, suggests that saline may be equally effective at a fraction of the cost. Few if any of the treatments currently used in the intensive care management of head injury have ever been shown to be effective and the existing evidence from clinical trials shows that these treatments could easily do more harm than good. So why is trauma care the poor relation of medical research? Perhaps because trauma is a disease of poor people in poor countries and because the pharmaceutical companies, which set the agenda for biomedical research, make their profits from treating rich people in rich countries. The result is that trauma care is an evidential wasteland. The US Department of Defense policy of compulsory vaccination of military personnel (poor people from a rich country) against anthrax and smallpox, may have important political benefits, but even if the vaccines are effective, and according to the editorial there is some doubt about this, the threat of biological attack is remote and most combat deaths are from uncontrolled bleeding. The twist in the tale is that even bio-terrorism is about bombs. Because the ability to cause infection is the defining aspect of a biological weapon, it follows that any malevolent intervention that causes infection in the civilian population constitutes an attack with a biological weapon. Real bio-terrorism is about epidemics of diarrhea like that which killed thousands of Iraqi children after Anglo-American forces bombed Iraqi water supplies and sanitation plants. BMJ editorials on bio- terrorism lend credibility to a lie while the victims of real terrorism are faced with bombs, bullets and untested healthcare. Competing interests: None declared |
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John D. Grabenstein, Deputy Director, Military Vaccine Agency 5113 Leesburg Pike, Suite 402; Falls Church, VA 22041 USA, William Winkenwerder, Jr.
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In a recent editorial, Jefferson questions military use of anthrax and smallpox vaccines licensed as safe and effective by the U.S. Food & Drug Administration (FDA).(1) The Department of Defense is concerned about the safety of U.S. servicemembers, so we vaccinate them to keep them healthy. Vaccination provides the only round-the-clock protection against the malicious use of microbes as weapons. Our vaccination programs are based on a credible military threat, recognized by multiple government agencies and multiple administrations. Given that a few cubic meters could hide a grievous quantity of anthrax spores or variola virus, the unsuccessful hunt for weapons of mass destruction in Iraq does little to reassure. That anthrax and smallpox infections are not circulating naturally is irrelevant when these microbes can be targeted willfully at our troops. Anthrax spores are all too easy to deliver, as our nation learned in fall 2001. The values of anthrax vaccine and smallpox vaccine are established in the medical literature, which is more extensive and more accurate than cited in the editorial. The National Academy of Sciences published a comprehensive review of anthrax vaccine safety and efficacy in March 2002.(2) The FDA recently affirmed that human and animal evidence show that anthrax vaccine protects regardless of route of exposure.(3) It was the modern military safety surveillance system that first identified the rare risk of myo-pericarditis after smallpox vaccination,(4) something otherwise unrecognized in America, and then described the extent of recovery from this condition.(5) The rigorous screening program adopted in the U.S. civilian and military smallpox vaccination programs resulted in serious adverse event rates at or below historical expectations.(6-7) Military units work and fight as teams. One service member’s health affects his or her teammates. Survival of individual troops and the success of units each depend on troops working together. We vaccinate to protect mutually dependent people, reaching a collective decision based on the best available science. We look forward to improved vaccines, as with all medical progress. Until such products are licensed, multiple years from now, we will not risk our troops’ lives against lethal biological weapons. We use today’s vaccines to shield our service members so they can succeed in their mission to protect our nation, and return home healthy. William Winkenwerder, Jr, MD; Assistant Secretary of Defense (Health Affairs); Washington, DC Colonel John D. Grabenstein, RPh, PhD; Deputy Director, Military Vaccine Agency; Falls Church, Virginia 1. Jefferson T. Bioterrorism and compulsory vaccination. BMJ 2004;329:524-525. 2. Joellenbeck LM, Zwanziger L, Durch JS, Strom BL, ed. The Anthrax Vaccine: Is it Safe? Does it Work? Washington, DC: National Academy Press, 2002. www.nap.edu/catalog/10310.html 3. Food & Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review. Fed Reg 2004;69(Jan 5):255-67; errata 7114-5. 4. Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, Poland GA, Gray GC, Ostroff S, Eckart RE, Hospenthal DR, Gibson RL, Grabenstein JD, Arness MK, Tornberg DN, DoD Smallpox Vaccination Clinical Evaluation Team. Myopericarditis following smallpox vaccination among vaccinia-naïve US military personnel. JAMA 2003;289:3283-89. 5. Eckart RE, Love SS, Atwood JE, Arness MK, Cassimatis DC, Campbell CL, Boyd SY, Murphy JG, Swerdlow DL, Collins LC, Riddle JR, Tornberg DN, Grabenstein JD, Engler RJM, DoD Smallpox Vaccination Clinical Evaluation Team. Incidence and follow-up of inflammatory cardiac complications following smallpox vaccination. J Am Coll Cardiol 2004;44:201-205. 6. Grabenstein JD, Winkenwerder W Jr. US military smallpox vaccination experience. JAMA 2003;289:3278-82. 7. Department of Defense. Smallpox Vaccination Safety Summary, 25 August 2004. www.smallpox.mil/event/SPSafetySum.asp (accessed 13 Sep 2004). Competing interests: None declared |
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Tom Jefferson, Coordinator Cochrane Vaccines Field
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Editor, Winkenwerder and Grabenstein question the scientific basis of my editorial. I repeat my statement that the only available field evidence in humans comes from a badly-reported 1950s trial of a vaccine similar to AVA. This vaccine was probably effective against cutaneous anthrax but the researchers specifically concluded that no such claims could be made regarding inhalation anthrax. The Institute of Medicine (IoM) report cited by Winkenwerder and Grabenstein concludes that such evidence exists as follows: Finding: The committee finds that the available evidence from studies with humans and animals, coupled with reasonable assumptions of analogy, shows that AVA as licensed is an effective vaccine for the protection of humans against anthrax, including inhalational anthrax, caused by any known or plausible engineered strains of B. anthracis". (http://books.nap.edu/books/0309083095/html/10.html#pagetop accessed 25 September 2004) In other words as I stated in my editorial, at present there is no field evidence of AVA’s effectiveness against inhalation anthrax in humans. In my view no amount of political window-dressing can change this fact. Winkenwerder and Grabenstein believe that laboratory evidence from animals and humans using surrogate outcomes such as antibody responses coupled with “reasonable assumptions” are enough to justify forced vaccination of 2.4 million souls. It is unclear to me whether informed consent is being obtained from military personnel prior to immunisation and if so on what basis. As evidence from field trials is lacking it would appear that US military personnel are being used as involuntary guinea pigs. I also note that neither authors have declared conflicts of interest. Does being politically responsible for an immunisation programme not create a conflict of interest when the basis for decision-making is questioned? Finally I would like to express my gratitude to Dr Enrico Materia for his help with my editorial. Content and opinions remain my sole responsibility. Competing interests: None declared |
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Walter R Schumm, Professor Kansas State University, Manhattan, KS 66506-1403
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Bioterrorism and compulsory vaccination revisited Arguments for current vaccines based on inadequate support for older vaccines Numerous concerns about the U.S. anthrax vaccine have been raised, as summarized recently by Nass.1 Most recently, BMJ recently featured an editorial on the merits of compulsory vaccination in which some of the flaws of the Brachman et al study2 were discussed, including uncertainties concerning how random assignment to treatment and control groups was performed.3 Winkenwerder and Grabenstein4 replied to Jefferson2 arguing that “The values of anthrax vaccine and smallpox vaccine are established in the medical literature, which is more extensive and more accurate than cited in the editorial.” However, Jefferson did not question the use of the vaccines per se, only the mandating of selected current vaccines. Allowing vaccination to be voluntary would allow the coverage of the vaccine to attain a level proportional to the accepted veracity of Department of Defense education on the merits and risks of the vaccines. Notably, Winkenwerder and Grabenstein did not even attempt to rebut Jefferson’s cited limitations of the Brachman et al. study. I will address five additional shortcomings. First, Brachman et al’s statistics leave much to be desired.5 The often reported rate of 92.5% effectiveness for the anthrax vaccine sounds impressive, but should be considered against the actual results in which 99.7% (378/379) of vaccinated workers avoided anthrax infection compared to 96.4% (399/414) of placebo workers. In truth, the vaccine actually protected an additional 3.3% of workers compared to no treatment. Essentially, anthrax infection was uncommon even among the unvaccinated workers despite exposure to hundreds of anthrax spores in their working environment for periods of several months to several years.6 Brachman et al. did not report a multivariate analysis in which mill location, risk levels, level of vaccination (full, partial, none), age, race, and gender of workers or other factors of interest might have been assessed statistically. They used a regular chi-square test7 (p. 14) that yielded a significant (p < .05) treatment effect, but use of the more precise Fisher’s Exact Test would have yielded a non-significant result (p < .13). Only one of the four mills demonstrated statistical significance (p < .05) for preventing anthrax infection. As late as 1999,8 2000,9and 200210, researchers were admitting that the Brachman et al study per se had failed to prove the efficacy of the vaccine against inhalation anthrax, even though the latter reference accepted the conclusions of the 2002 IOM report11 that the vaccine was effective against inhalation anthrax. Even the 2002 IOM report11 (p. 59) concluded that “the small number of inhalational cases in those studies provides insufficient information to allow a conclusion to be made about the vaccine’s efficacy against inhalational infection.” However, since then, efficacy has been claimed for all routes of infection, including inhalational, even without very much additional supporting evidence.10,12 Second, the way in which the design of the Brachman et al study was reported leaves much to be desired.13 Even the number of subjects involved is uncertain. Brachman et al reported 313 treatment group workers at the Arms Mill but had earlier based their statistical analyses on 300 subjects (p. 14).7 Some subjects received partial vaccinations (n = 116, 9.3% of total) but Brachman et al did not distinguish between vaccine and placebo groups among partial vaccinees. The low and high risk departments at the mills were never identified, though it may be possible to deduce them from careful analysis. By the end of the Brachman et al study over 75% of the workers had dropped out of the tests; it has never been determined how such attrition may have influenced the statistical outcomes of the study. The variation in attrition rates across the total experimental group (76%), the partial vaccination group (37%), and the refusal group (93%) raise concerns. Nor did Brachman et al provide information on differential attrition rates between the placebo and treatment groups, within the total experimental group. The strain of inhalation anthrax encountered at the Arms Mill in Manchester, New Hampshire was never identified, whether it was one of the U.S. military strains or a wild strain. The latter is unlikely because the strain was noted (p. 11) as having been as virulent as “the most virulent laboratory- selected strain.”7 Attrition rates varied substantially among the four textile mills in the study, from as low as 8% to as much as 85%. Refusal rates varied considerably among the mills, ranging from less than one percent to nearly 45%. The study was probably not double blind (p. 282).8 Three of the four mills involved in the study have never been identified. One 1999 report14 identified all four mills as from the state of New Hampshire, but it is likely that at least one mill was actually from the Philadelphia area. Regardless of their location, the time periods in which the mills participated in the study varied from a few months to more than three years. Third, with respect to safety of the anthrax vaccine, even the 2002 IOM report11 admitted that in the Brachman et al. study, “events following vaccination were monitored in only two of the four mills and were monitored only for the first 48 hours following inoculation (pp. 142- 143).” Even so, it is not clear how the percentages were calculated for reaction rates after vaccination in the Brachman et al. study. As many as seven percent of workers experienced severe, edema-producing reactions after their sixth inoculation, but only 265 of the initial 793 workers from all four mills in the experimental groups remained in the study after six inoculations. We are left clueless about how many workers from the two mills remained in the study after each inoculation. The total number of workers who ever experienced edema-producing reactions was only 21. However, the two mills involved, the attrition rates for each mill as of each inoculation, and the denominator of workers after each inoculation were never provided, rendering data interpretation difficult, if not meaningless. Thus, the Brachman et al study, the first holy grail of efficacy and safety for the defenders of the current anthrax vaccine, suffers from multiple design flaws, incomplete reporting, and relatively weak statistics. Fourth, recent research adds further concerns about the Brachman et al report and the validity of using that report as a foundation for the compulsory vaccination program of the U.S. Department of Defense. Colonel Grabenstein accuses Jefferson of omitting favorable evidence about the efficacy and safety of the anthrax vaccine, but on his own part omits evidence to the contrary. For instance, many of the symptoms reported by members of the U.S. Air Force at Dover Air Force Base in a survey conducted there in January 2000 (and cited in the 2002 IOM report, pp. 126, 132-133) match the definitions of Gulf War illness used by the CDC and Steele. Nearly 19% of the members of Captain Jean Tanner’s squadron met the CDC definition of Gulf War illness.15 Finally, U.S. Department of Defense officials have simply ignored the published critique16 my colleagues and I made of the 2002 Institute of Medicine report. We observed that at least three major studies in England, Canada, and the United States had found problems with the anthrax or other vaccines among military veterans.17,18,19 In addition, our own research found that recipients of anthrax vaccine reported lower levels of subjective health several years after the Gulf War than did non- recipients.21 The 2002 IOM report mentioned (p. 93) some of those studies17,20 but appears to have dismissed them largely because they were based on self-reports or cross-sectional data. Yet, the same IOM report hails the Millenium Cohort Study, based largely on self-report, as an important asset for studying the long-term safety of the anthrax vaccine, even though relatively little information has been asked about anthrax vaccination in that study. Furthermore, the RAND Corporation’s report on immunizations as a factor in Gulf War illness had been due out in 200216,21 but as of September 28, 2004 had not yet been published, although the most recent anticipated publication date is October 15, 2004. It is not clear why it would take so long for DoD to approve the release of a scientific text on vaccines and Gulf War illness, especially when it was being published by such a capable and distinguished organization as the RAND Corporation. Such a long delay could only heighten concerns, first raised over two years ago,16,21 about the potential role of politics in the timing of the release of that report. Of course, vaccines are by no means the only concern we have ever raised with respect to long term health problems. Our publications include assessments of nerve agent exposure22 and pyridostigmine bromide pills23,24 as possible factors in the health outcomes of Gulf War veterans; our most recent unpublished research implicates overdoses of insecticide as perhaps the best predictor of declines in the long term subjective health of veterans. Perhaps the best approach to vaccine education is not found in pretending that certain scientific results are irrelevant merely because they do not fit the desired paradigms. Given all of these considerations and uncertainties, until better evidence or a better anthrax vaccine is available, Jefferson is correct – “the choice of whether to be vaccinated or not should be left to the individual.”3 Walter R. Schumm Colonel, U.S. Army Reserve (retired) and Professor School of Family Studies and Human Services, Kansas State University, Justin Hall, 1700 Anderson Avenue, Manhattan, Kansas USA 66506-1403 (Schumm@humec.ksu.edu) Competing interests: WRS at age 60 (2011) will be in receipt of retired pay from the U.S. Department of Defense for his 30 years of service in the U.S. Army Reserve and Army National Guard (1972-2002). WRS provided expert testimony on behalf of the Plaintiffs in the case of John Doe #1 et al. v. Donald Rumsfeld, et al. (U.S. District Court for the District of Columbia, Civil Action No. 03-707), as did Dr. Winkenwerder and Colonel Grabenstein on behalf of the Defendants. REFERENCES 1 Nass M. Anthrax vaccine: caveat emptor (let the buyer beware). Current Treatment Options in Infectious Diseases 2003; 5: 361- 364. 2 Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin M, Ingraham NR. Field evaluation of a human anthrax vaccine. American Journal of Public Health 1962; 52: 632-645. 3 Jefferson T. Bioterrorism and compulsory vaccination: better vaccines are needed if vaccination is to be made compulsory. BMJ 2004; 329: 524-525. 4 Winkenwerder W Jr, Grabenstein, J. Vaccinating to keep troops healthy. BMJ 2004; 329: 5 Schumm WR, Brenneman RL, Arieli B, Mayo-Theus, S, Muhammad, J. A statistical reanalysis of Brachman et al.’s 1962 study of a human anthrax vaccine. Medical Veritas 2004; 1: 171-178. 6 Dahlgren CM, Buchanan LM, Decker HM, Freed SW, Phillips CR, Brachman PS. Bacillus anthracis aerosols in goat hair processing mills. American Journal of Hygiene 1960; 72: 24-31. 7 Brachman PS, Plotkin SA, Bumford FH, Atchison MM. An epidemic of inhalation anthrax: the first in the twentieth century. II. Epidemiology. American Journal of Hygiene; 72: 6-23. 8 Inglesby TV, Henderson DA, Bartlett JG, Ascher, MS, Etizen E, Friedlander AM, Hauer J, McDade J, Osterholm MT, O’Toole T, Parker G, Perl TM, Russell PK, Tonat K. Anthrax as a biological weapon: medical and public health management. JAMA 1999; 281: 1735-1745. 9 Fulco CE, Liverman CT, Sox HC. Gulf War and health: depleted uranium, pyridostigmine bromide, sarin, vaccines. (Vol. 1). Washington, DC: National Academy Press, 2000. 10 Inglesby TV, O’Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Friedlander AM, Gerberding J, Hauer J, Hughes J, McDade J, Osterholm MT, Parker G, Perl TM, Russell PK, Tonat K. Anthrax as a biological weapon, 2002: Updated recommendations for management. JAMA 2002; 287: 2236-2252. 11 Joellenbeck LM, Zwanziger LL, Durch JS, Strom BL. The anthrax vaccine. Is it safe? Does it work? Washington, DC: National Academy Press, 2002. 12 Brachman PS, Adimora AA, Berry SH, Bush T, Eickhoff TC, Ferrieri P. An assessment of the CDC anthrax vaccine safety and efficacy research program. Washington, DC: National Academies Press, 2003. 13 Schumm WR, Brenneman RL. How “adequate and well-controlled” was the “clinical trial” of a human anthrax vaccine, 1955-1959? Medical Veritas 2004; 1: 166-170. 14 Friedlander AM, Pittman PR, Parker GW. Anthrax vaccine: evidence for safety and efficacy against inhalational anthrax. JAMA 1999; 282: 2104 -2106. 15 Schumm WR. Anthrax vaccine and Gulf War illness symptoms in Captain Jean Tanner’s Dover Air Force Base survey. Medical Veritas 2004; 1: 163- 165. 16 Schumm WR, Webb FJ, Jurich AP, Bollman SR. Comments on the Institute of Medicine’s 2002 Report on the safety of anthrax vaccine. Psychological Reports 2002; 91: 187-191. 17 Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, MacFarlane GJ. Health and exposures of United Kingdom Gulf War veterans: Part II. The relation of health to exposure. Occupational & Environmental Medicine 2001; 58: 299-306. 18 Gilroy G. Health study of Canadian forces personnel involved in the 1991 conflict in the Persian Gulf. Vol. 1. Ottawa, Ontario: Department of National Defense, 1998. 19 Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. American Jouornal of Epidemiology 2000; 152: 992-1002. 20 Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. Role of vaccinations as risk factors for ill health in veterans of the Gulf War: cross sectional study. BMJ 2000; 320: 1363-1367. 21 Schumm WR, Reppert EJ, Jurich AP, Bollman SR, Webb FJ, Castelo CS, Stever JA, Sanders D, Bonjour GN, Crow J, Fink CJ, Lash JF, Brown BFC, Hall CA, Owens BL, Krehbiel M, Deng LY, Kaufman M. Self-reported changes in subjective health and anthrax vaccination as reported by over 900 Persian Gulf War era veterans. Psychological Reports 2002; 90: 639-653. 22 Schumm WR, Webb FJ, Bollman SR, Jurich AP, Reppert EJ, Castelo CS, Stever JA. Predicting self-reported exposure to nerve agents by Reserve Component personnel during the first Persian Gulf War. Psychological Reports 2004; 94: 989- 992. 23 Schumm WR, Reppert EJ, Jurich AP, Bollman SR, Castelo CS, Sanders D, Webb FJ. Pyridostigmine bromide and the long-term subjective health status of a sample of female Reserve Component Gulf War veterans: a brief report. Psychological Reports 2001; 88: 306-308. 24 Schumm WR, Reppert EJ, Jurich AP, Bollman SR, Webb FJ, Castelo CS, Stever JA, Kaufman M, Deng LY, Brown BFC, Lash JF, Fink CJ, Crow JR, Bonjour GN. Pyridostigmine bromide and the long-term subjective health status of a sample of over 700 male Reserve Component Gulf War era veterans. Psychological Reports 2002; 90: 707-721. Competing interests: As noted in the manuscript |
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