Military and civilian medicine have always been intertwined, but nothing compares to the strange tale of Warren Air Force base in the 1940’s. Perched on the high plains outside of Cheyenne, Wyoming, the combat training center was, mysteriously, a bacterial cauldron. For more than a decade virulent strains of group A streptococcus caused unprecedented rates of pharyngitis among the trainees, and history’s worst epidemic of rheumatic fever.

A small cadré of military researchers at the base seized the moment, executing a provocative series of trials that tested the potential of antibiotics to prevent post-streptococcal rheumatic fever. Roughly 2% of the trainees given placebo in their studies developed rheumatic fever, while under 1% of trainees given antibiotics experienced the disease. For every 50-60 trainees treated with antibiotics, the researchers had successfully prevented one case of rheumatic fever. It was a small, but decisive victory.

Prior to the epidemic at Warren Air Force base there was little interest in ‘strep throat’. During the twenties and thirties in the Unites States, sore throat care focused on diphtheria, “the strangling angel.” The characteristic ‘bull neck’ and the dreaded grey pseudomembrane led to a gruesome, asphyxiating death for thousands of children each year. Comparatively, strep throat was a minor nuisance that often received little more attention than the common cold. But by the 1940s vaccination programs had nearly eradicated diphtheria, and antibiotics were becoming widely available. When the Air Force studies were reported in the early 1950s, they resonated. Rheumatic heart disease was common among adults, making its prevention seem immediate and intuitively important, and antibiotics for a bacterial infection made good sense. Identifying and treating ‘strep throat’ quickly became a staple of medical education, and little has changed.

The problem, of course, is that one can only prevent rheumatic fever where it may plausibly occur. Outside of Warren Air Force base in the 1940s, is rheumatic fever a plausible risk? Apparently not. There have been only two other cases of rheumatic fever ever reported in a pharyngitis study, both in 1961. In fact, despite large, contemporary studies tracking tens of thousands of strep throats in the general community, many of whom received placebos or no treatment, there hasn’t been a case of rheumatic fever reported in a study for nearly fifty years. When the incidence dropped to less than one per million in the general population in 1994, the Centers for Disease Control and Prevention stopped tracking rheumatic fever entirely.

At Warren Air Force base only 50-60 recruits were treated to prevent one case. Today, preventing one case would likely require antibiotic treatment for hundreds of thousands of strep throats, making it a mathematical certainty that antibiotics will do more harm than good. For each case of rheumatic fever prevented in modern practice, a few dozen patients either die or suffer near-fatal anaphylaxis, toxic epidermal necrolysis, colitis, or other antibiotic reactions, and many thousands more suffer diarrhea, rashes, and yeast infections.

Fortunately, rheumatic fever has been declining for a century, starting well before the introduction of antibiotics. While strep throat is no less common today, ‘rheumatogenic’ strains have dwindled, leading epidemiologists to conclude that antibiotics have little or nothing to do with rheumatic fever’s disappearance. Changes in hygiene, nutrition, population crowding, access to care, and changes in the bacterium are all felt to be important factors, which explains why the disease is now typically seen most in third world settings.

There are, arguably, other reasons to consider antibiotics for pharyngitis, but the evidence does not rise to support them. The Cochrane group estimates a 16-hour reduction in symptoms with antibiotics, but ibuprofen, acetaminophen, or a single dose of corticosteroids is as good or better, with fewer side effects. And while peritonsillar abscess may be minimally reduced by antibiotics, abscesses typically present primarily rather than after strep throat, and in most cases are easily treated. No studies have shown that antibiotics reduce the transmission of strep or reduce other complications.

The administration of antibiotics for strep throat, endorsed universally by practice guidelines and professional societies, is based exclusively on data from the world’s most concentrated epidemic of rheumatic fever. Using this to guide modern therapy is like administering antibiotics to prevent bubonic plague.

The essence of evidence is its ability to point us toward truth, and we must first understand what truth we seek. We do not ask whether antibiotics may be useful during a military epidemic of rheumatic fever. We ask a different question. We ask if antibiotics are beneficial for every day strep throat. Those who have written our guidelines and crafted our recommendations have, unfortunately, failed us. The strange tale of Warren Air Force base is a lesson in evidence: The only way to get an answer right is to pay attention to the question.

David H. Newman is the author of
Hippocrates Shadow (Scribner $26)
Find more by Dr. Newman in upcoming issues of Emergency Physicians Monthly

 

Studies that captured rheumatic fever cases at WAF base:
Denny FW, Wannamaker LW, Brink WR. Prevention of rheumatic fever.  Treatment of the preceding streptococcic infection. JAMA. 1950;143(2):151-3.
Bennike T, Kjaer E, Skadhauge K, al e. Penicillin therapy in acute tonsillitis, phlegmonous tonsillitis, and ulcerative tonsillitis. Acta Media Scandinavia. 1951;139:253-74.
Brink WR, Rammelkamp CH, Denny FW, Wannamaker LW. Effect of penicillin and aureomycin on the natural course of streptococcal tonsillitis and pharyngitis. Am J Med. 1951;10:300-8.
Denny FW, Hahn E. Comparative effects of penicillin, aureomycin, and terramycin on streptococcal tonsillitis and pharyngitis. Pediatrics. 1953;11:7-14.
Catanzaro F, Morris A, Chamovitz R, al e. Symposium on rheumatic fever and rhuematic heart disease. The role of Streptococcus in the pathogenesis of rheumatic fever. Am J Med. 1954;17:749-56.
Chamovitz R, Stetson C, Rammelkamp CH. Prevention of rheumatic fever by treatment of previous streptococcal infection. New Engl J Med. 1954;251:466-71.

CDC document last reporting the incidence of Acute Rheumatic Fever:
Centers for Disease Control and Prevention. Summary of notifiable diseases, United States, 1997. Mor Mortal Wkly Rep CDC Surveill Summ. 1998;46:1-87

Rudolph AH, Price EV. Penicillin reactions among patients in venereal disease clinics: a national survey. JAMA. 1973;223:99-108.
Neugut A, Ghatak A, Miller R. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Int Med. 2001;161(1):15-21.
Idsoe O, Guthe T, Wilcox R, al e. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull WHO.1968; 38(2):159-88.
Roujeau J. Drug-induced toxic epidermal necrolysis II: Current aspects. Clin Derm. 1993;11:493-500.
Bachot N, Roujeau J. Physiopathology and treatment of severe drug eruptions. Current Op All Clin Imm. 2001;1(4):293-8.

Bronze MS, Dale JB. The reemergence of serious group A streptococcal infections and acute rheumatic fever. Am J Med Sci. 1996;311(1):41-54.
Stollerman GH. Rheumatic fever in the 21st century. Clin Inf Dis. 2001;33(6):806-14.
Quinn R. Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease, and scarlet fever: the decline of rheumatic fever. Rev Inf Dis. 1989;11(6):928-53.
Gordis L. The virtual disappearance of rheumatic fever in the United States: lessons in the rise and fall of disease. T. Duckett Jones memorial lecture. Circulation. 1985;72(6):1155-62.
Olivier C. Rheumatic fever - is it still a problem? J Antimic Chemo. 2000; 45:13-21.
Markowitz M. The decline of rheumatic fever: role of medical intervention. J Ped. 1985;106:545-50.

Middleton D, D’Amico F, Merenstein J. Standardized symptomatic treatment versus penicillin as initial therapy for streptococcal pharyngitis. J Ped. 1988;113(6):1089-94.
Bertin L, Pons G, d’Athis P, al e. Randomized, double-blind, multicenter, controlled trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment of symptoms of tonsillitis and pharyngitis in children. J Ped. 1991; 119(5):811-4.
Watson N, Nimmo W, Charlesworth C, al e. Relief of sore throat with the anti-inflammatory throat lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy and safety. Int J Clin Pract. 2000;54(8):490-6.
O’Brien J, Meade J, Falk J. Dexamethasone as adjuvant therapy for severe acute pharyngitis. Ann Emerg Med. 1993;22:212-15.
Marvez-Valls E, Ernst A, Gray J, al e. The role of betamethasone in the treatment of acute exudative pharyngitis. Acad Emerg Med. 1998;5:567-72.
Wei J, Kasperbauer J, Weaver A, al e. Efficacy of a single-dose dexamethasone as adjuvant therapy for exudative pharyngitis. Laryngoscope. 2002;112:87-93.
Kiderman A, Yaphe J, Bregman J, et al. Adjuvant prednisone therapy in pharyngitis: a randomised controlled trial from general practice. Br J Gen Pract. 2005; 55(512): 218-21.
Olympia RP, Khine H, Avner JR. Effectiveness of oral dexamethasone in the treatment of moderate to severe pharyngitis in children. Arch Ped Adol Med. 2005; 159(3): 278-82.
Hahn R. Clinical evaluation of flurbiprofen alone and plus ampicillin in chronic pharyngitis in acute phase. International J Clin Pharm Res. 1986;6(1):81-6.

Cooper RJ, Hoffman JR, Bartlett JG, et al. Principles of appropriate antibiotic use for acute pharyngitis in adults: Background. Ann Emerg Med. 2001; 37(6): 711-719.
Savolainen S, Jousimies-Somer H, Makitie A, al e. Peritonsillar abscess: clinical and microbiologic aspects and treatment regimens. Arch Otol Head Neck Surg. 1993;119:521-4.
Passy V. Pathogenesis of peritonsillar abscess. Laryngoscope. 1994;104:185-90.