Prevention of Rheumatic Fever, Today and Tomorrow
Disclosure: Dr. Bisno has modest consultant relationships with Advancis Pharma (now Middlebrook), Cornerstone Biopharma, Merck, Schering-Plough, and Targanta Therapeutics.
Pub Date: Thursday, February 26, 2009
Author: Alan L. Bisno, MD, FACP
Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation 2009; published online before print February 26, 2009, 10.1161/CIRCULATIONAHA.109.191959.
Acute rheumatic fever (ARF) is a major cause of cardiovascular morbidity and mortality in the developing world. The global prevalence of rheumatic heart disease has been estimated to be 15.6 million cases, with 282,000 new cases and 233,000 deaths each year. Although focal outbreaks of ARF still occur in the United States , for the most part, the disease has become extremely rare in this country.[3,4] The reasons for this phenomenon are incompletely understood, but likely involve the interplay of socioeconomic development, changes in prevalence of highly rheumatogenic streptococcal strains [2,5,6], and possibly, to a lesser extent, the utility of primary prevention strategies such as advocated in the American Heart Association (AHA) statement.
There is no evidence, however, of a parallel decline in the prevalence of group A streptococcal (GAS) pharyngitis, the antecedent infection responsible for the development of ARF. Indeed, GAS remains the most common bacterial cause of acute pharyngitis. It is estimated to account for approximately 15% to 30% of cases of acute pharyngitis in children and 10% in adults. Antimicrobial therapy of strep throat accomplishes a number of desirable goals: prevention of suppurative complications, improvement in clinical signs and symptoms, and rapid decrease in infectivity to reduce transmission of GAS to close contacts. However, a major impetus for such treatment on the part of primary care practitioners is the fear of leaving untreated a potentially rheumatogenic infection. It is, therefore, paradoxical that much professional time, energy, and expense is directed toward preventing a disease so rarely seen in everyday medical practice.
The new AHA scientific statement, "Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis," updates the previous 1995 statement on this subject. In formulating its conclusions, the members of the committee had to deal with certain issues that remain both complex and controversial.
Upper respiratory infections, including pharyngitis, are among the most common causes of visits to primary care practitioners, and appropriate diagnosis and management of these illnesses has both clinical and major public health implications. Sore throat accounts for 1% to 2% of all patient visits to office-based primary care practitioners, hospital outpatient departments, and emergency departments in the United States. Data from the National Medical Care Survey indicate approximately 7.3 million annual visits for children  and 6.7 million such visits for adults. Numerous studies have documented that the percentage of patients presenting to primary care practitioners who receive antimicrobial prescriptions for the complaint of a sore throat greatly exceeds the proportion of such patients with true streptococcal pharyngitis. For example, between 1989 and 1999, 73% of the 6.7 million US adults visiting primary care providers annually, with the complaint of sore throat, received a prescription for an antibiotic.
Given these facts, the task facing the primary care physician is to identify and appropriately treat the minority of sore throat patients suffering from strep throat and to avoid unnecessary and potentially deleterious treatment for the remainder, who likely suffer from self-limited viral pharyngitis. The most appropriate methods to accomplish this task are, in my opinion, well enunciated in the AHA statement, as well as in practice guidelines promulgated by the American Academy of Pediatrics (AAP)  and the Infectious Diseases Society of America (IDSA). The reader should be aware, however, that these recommendations in the AHA statement are not without controversy, both as regards the most appropriate method of diagnosis and the optimal therapeutic agents.
Issues in Diagnosis
For example, one published practice guideline [7,12] has suggested that in adults with features strongly suggestive of streptococcal pharyngitis, empirical antimicrobial therapy without microbiologic confirmation is an acceptable alternative. A subsequent cost-effectiveness analysis  and two prospective clinical studies [14,15] have concluded that such empirical therapy is neither the most effective nor the least expensive strategy for diagnosis of strep throat in adults. Furthermore, empirical therapy in adults leads to considerable overuse of antibiotics.
Given the need for microbiologic confirmation, clinical decision-making in the primary care setting is greatly facilitated by the availability of rapid antigen detection tests (RADTs) to establish the presence of GAS on a swab of the posterior pharynx of a patient with acute pharyngitis. Such tests are highly specific, and a positive test in the appropriate clinical setting allows the practitioner to rapidly initiate appropriate therapy.
Unfortunately, RADTs are somewhat less sensitive than conventional throat cultures, thus raising the issue of the necessity of backing up negative RADTs with a throat culture. Doing so adds cost and complexity to the management of this extremely common disorder. On this issue, the 2009 guideline equivocates. The authors state that “some experts believe that physicians who use a RADT without culture backup in children and adolescents” should first compare the results with those of throat culture in their own practice to confirm adequate sensitivity. The authors have thus left some flexibility as regards mandatory culture backup of negative RADTs, but the practicality of this stance might be questioned. The results might depend upon a number of factors such as the stringency with which the individual practitioner decides which patients to culture. Moreover, the statement does not indicate what should be considered “adequate sensitivity.” This is admittedly a tough issue on which to draw hard and fast lines in a national statement. I am pleased to note that the interdisciplinary writing group concurs with the 2002 IDSA recommendation that backup of negative RADTs is unnecessary in adults. The rationale here is that the incidence of strep throat and the risk of an initial attack of ARF are considerably lower in adults. Neither the AHA nor the IDSA statements, however, indicate the age at which culture backup can be abandoned.
Issues in Therapy
Ten days of oral penicillin or a single injection of benzathine penicillin G remain the recommended drugs of choice by the AHA, AAP, and IDSA for the reasons succinctly enunciated in the AHA statement. Again, respected authorities take issue with this statement, believing that oral cephalosporins, some of which are Food and Drug Administration (FDA)-approved for a shorter duration of treatment, result in superior outcomes. A recent metaanalysis suggests, however, that even for oral cephalosporins, a 10-day course is superior to shorter courses in eradication of GAS from the pharynx. Despite the fact that streptococcologists argue over these issues, all authorities agree that the most important quality of care issue from a public health standpoint is using strategies that minimize promiscuous antimicrobial prescribing to patients at minimal risk of actually having group A streptococcal infection.
The utility of oral macrolides or azalides in treatment of penicillin-allergic patients depends upon local patterns of streptococcal resistance to these agents. National data suggest that the percentage of resistant GAS remains low , but this is a moving target, influenced primarily by the quantity of these antimicrobials used in the general community. Thus, clinicians who elect these agents for this indication (a quite reasonable choice at present) will need to be kept informed of susceptibility patterns in their particular area. Narrow-spectrum cephalosporins (in patients without immediate-type hypersensitivity to beta-lactam antibiotics) and clindamycin are acceptable alternatives, as outlined in the statement.
Hopes for the Future
Finally, it is clear that our strategies for both primary and secondary prevention of ARF are imperfect, both in the United States and the developing world. Much progress has been made, however, in our understanding of GAS virulence factors at the molecular level and of host factors critical to the protective response. Cloning and sequencing of the genomes of several prevalent GAS types have identified a number of potential vaccine candidates. These include type-specific multivalent M protein constructs as well as common protective antigens expressed by many or all GAS genotypes. Although we still have not unraveled the riddle of the ultimate pathogenesis of ARF, a number of groups are actively attempting to develop a safe and effective GAS vaccine that could have a profound effect on the worldwide burden of this ancient scourge as well as, perhaps, circumvent many of the dilemmas involved in diagnosis and therapy of streptococcal sore throat in our own country. A streptococcal vaccine is not around the corner, but it is definitely achievable, given an appropriate public health priority.
- Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005;5(11):685-694.
- Veasy LG, Tani LY, Daly JA, et al. Temporal association of the appearance of mucoid strains of Streptococcus pyogenes with a continuing high incidence of rheumatic fever in Utah. Pediatrics 2004;113(3 Pt 1):e168-e172.
- Ferguson GW, Shultz JM, Bisno AL. Epidemiology of acute rheumatic fever in a multi-ethnic, multi-racial U.S. urban community: the Miami-Dade experience. J Infect Dis 1991;164:720-725.
- Land MA, Bisno AL. Acute rheumatic fever: a vanishing disease in suburbia. JAMA 1983;249:895-898.
- Bisno AL. The concept of rheumatogenic and non-rheumatogenic group A streptococci. In: Read SE, Zabriskie JB, eds. Streptococcal diseases and the immune response. New York: Academic Press, 1980:789-803.
- Shulman ST, Stollerman G, Beall B, et al. Temporal changes in streptococcal M protein types and the near-disappearance of acute rheumatic fever in the United States. Clin Infect Dis 2006;42(4):441-447.
- Snow V, Mottur-Pilson C, Cooper RJ, Hoffman JR. Principles of appropriate antibiotic use of acute pharyngitis in adults. Ann Intern Med 2001;134:506-508.
- Linder JA, Bates DW, Lee GM, Finkelstein JA. Antibiotic treatment of children with sore throat. JAMA 2005;294(18):2315-2322.
- Linder JA, Stafford RS. Antibiotic treatment of adults with sore throat by community primary care physicians: a national survey, 1989-1999. JAMA 2001;286(10):1181-1186.
- Committee on Infectious Diseases. Group A streptococcal infections. In: Pickering LK, ed. Red Book: 2006 Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics, 2006:610-620.
- Bisno AL, Gerber MA, Gwaltney JM, Jr., et al. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Diseases Society of America. Clin Infect Dis 2002;35(2):113-125.
- Cooper RJ, Hoffman JR, Bartlett JG, et al. Principles of appropriate antibiotic use for acute pharyngitis in adults: background. Ann Intern Med 2001;134(6):509-517.
- Neuner JM, Hamel MB, Phillips RS, et al. Diagnosis and management of adults with pharyngitis. A cost-effectiveness analysis. Ann Intern Med 2003;139(2):113-122.
- McIsaac WJ, Kellner JD, Aufricht P, et al. Empirical validation of guidelines for the management of pharyngitis in children and adults. JAMA 2004;291(13):1587-1595.
- Humair JP, Revaz SA, Bovier P, Stalder H. Management of acute pharyngitis in adults: reliability of rapid streptococcal tests and clinical findings. Arch Intern Med 2006;166(6):640-644.
- Bisno AL. Diagnosing strep throat in the adult patient: do clinical criteria really suffice? Ann Intern Med 2003;139(2):150-151.
- Casey JR, Pichichero ME. The evidence base for cephalosporin superiority over penicillin in streptococcal pharyngitis. Diagn Microbiol Infect Dis 2007;57(3 Suppl):39S-45S.
- Falagas ME, Vouloumanou EK, Matthaiou DK, et al. Effectiveness and safety of short-course vs long-course antibiotic therapy for group a beta hemolytic streptococcal tonsillopharyngitis: a meta-analysis of randomized trials. Mayo Clin Proc 2008;83(8):880-889.
- Linder JA, Chan JC, Bates DW. Evaluation and treatment of pharyngitis in primary care practice: the difference between guidelines is largely academic. Arch Intern Med 2006;166(13):1374-1379.
- Richter SS, Heilmann KP, Beekmann SE, et al. Macrolide-resistant Streptococcus pyogenes in the United States, 2002-2003. Clin Infect Dis 2005;41(5):599-608.
- Bisno AL, Rubin FA, Cleary PP, Dale JB. Prospects for a group A streptococcal vaccine: rationale, feasibility, and obstacles--report of a National Institute of Allergy and Infectious Diseases workshop. Clin Infect Dis 2005;41(8):1150-1156.
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --