|STATE OF THE ART
|Year : 2015 | Volume
| Issue : 1 | Page : 9-14
Evolution, evidence and effect of secondary prophylaxis against rheumatic fever
Rosemary Wyber1, Jonathan Carapetis2
1 Telethon Kids Institute, University of Western Australia, Subiaco, Australia
2 Telethon Kids Institute, University of Western Australia, Subiaco; Princess Margaret Hospital for Children, Perth, Australia
|Date of Web Publication||22-May-2015|
Dr. Rosemary Wyber
Telethon Kids Institute, University of Western Australia, Perth
Source of Support: None, Conflict of Interest: None
The association between group A streptococcal infection and rheumatic fever (RF) was established in the early 20 th century. At the time, RF and subsequent rheumatic heart disease (RHD) were an untreatable scourge of young people in developed and developing countries. Resultingly, research efforts to understand, treat and prevent the disease were widepread. The development of antibiotics in the 1930s offered therapeutic promise, although antibotic treatment of acute RF had little impact. Improved understanding of the post-infectious nature of RF prompted attempts to use antibiotics prophylactically. Regular doses of sulphonamide antibiotics following RF appeared to reduce disease progression to RHD. Development of penicillin and later, benzathine penicillin G, was a further thereputic advance in the 1950s. No new prophylactic options against RF have emerged in the intervening 60 years, and delivery of regularly scheduled BPG injections remains a world wide challenge.
Keywords: Benzathine penicillin G, rheumatic fever, rheumatic heart disease, secondary prophylaxis
|How to cite this article:|
Wyber R, Carapetis J. Evolution, evidence and effect of secondary prophylaxis against rheumatic fever. J Pract Cardiovasc Sci 2015;1:9-14
|How to cite this URL:|
Wyber R, Carapetis J. Evolution, evidence and effect of secondary prophylaxis against rheumatic fever. J Pract Cardiovasc Sci [serial online] 2015 [cited 2020 Nov 29];1:9-14. Available from: https://www.j-pcs.org/text.asp?2015/1/1/9/157554
| Introduction|| |
Rheumatic fever (RF) is prompted by an abnormal immune response to group A streptococcal infection (GAS), typically pharyngitis. RF occurs 2-3 weeks after untreated GAS infection in 3-5% of people during disease outbreaks and likely in a smaller proportion of people in endemic settings. RF presents with musculoskeletal, neurologic, cutaneous and cardiac manifestations.  Susceptibility to RF is a poorly understood interplay between environmental factors, individual genetics and bacterial characteristics. Peak incidence is between 5 and 14 years of age though cases may occur into young adulthood.  Half a million people annually experience an episode of RF, the majority in low-resource settings or vulnerable populations in high-income countries.  The first episode of RF declares an individual susceptible to recurrences of RF. The risk of RF after GAS infection rises to 60% in people who have had a previous episode of RF.  These recurrent RF episodes are associated with chronic damage to the heart valves termed rheumatic heart disease (RHD).  RHD progresses to heart failure and increases the risk of stroke, endocarditis and arrhythmias.
Much of this knowledge about the etiology and outcomes of RF and RHD was compiled between the 1920s and 1960s, an intensive period of discovery of the disease across Europe and North America. The tremendous medical, social and economic burden of RHD generated public and political will to fund research. For example, in the 1920s, RF was the leading cause of death between the ages of 5 and 20 years of age in the United States of America (USA).  By 1930, an estimated 840,000 people in the USA lived with RHD; half of those people were expected to die by the age of 40 years.  With therapeutic options limited to bed rest and aspirin the natural history of the disease was characterized by recurrences of RF and progression to RHD and premature death. However, by the mid-20 th century, the disease-altering effect of long-term prophylactic antibiotics had been identified, and children with RF were no longer condemned to live as "cardiac cripples." ,
Secondary prophylaxis is the administration of antibiotics to people with a history of RF to prevent GAS infection, subsequent RF recurrence and to minimize progression to RHD.  The American Heart Association (AHA) first recommended an antibiotic regimen for secondary prophylaxis against RF in 1955.  Similar guidelines have since been issued by the World Health Organization, World Heart Federation and numerous national organizations. ,,, There have been few substantive changes to secondary prophylaxis guidelines from the original iteration; the first line antibiotic for secondary prophylaxis has remained unchanged for six decades. This relative stasis means that few practicing clinicians have lived through therapeutic innovation or updated treatment guidelines for secondary prophylaxis. Without the publications, conferences and conversations prompted by innovations, the disease-altering effects of secondary prophylaxis may be overlooked. This review revisits historic evidence for secondary prophylaxis and builds the case for persistent careful attention to the delivery of high-quality secondary prophylaxis. The review also highlights outstanding research, clinical and practical questions about delivery of secondary prophylaxis. These questions are of greatest relevance in low-resource settings where the burden of RHD is greatest and historic studies may not be directly applicable to the contemporary challenges.
| Infectious Agent Causing Rheumatic Fever|| |
The association between pharyngitis and RF was identified as early as the 1800s, though observers did not initially attribute sore throat to an infectious agent.  Instead, pharyngitis was considered to be another manifestation of RF, along with characteristic fevers and arthritis. Increased access to microscopy made it possible to identify bacteria in association with pharyngitis, prompting efforts to identify causative organisms. By the early 1900s the idea that pharyngitis was caused by bacterial infection had gained traction. In 1913 Poynton and Paine wrote that "we can now state with confidence that micrococcus gaining access to the system from an inflamed tonsil may produce heart disease with or without the involvement of other systems."  Epidemiologic approaches to outbreaks of RF in the early 1900s provided supplementary evidence that the disease behaved in a characteristically infectious pattern and that discrete outbreaks were clearly correlated with episodes of tonsillitis. Although the 2-3 weeks delay between pharyngitis and RF symptoms was increasingly well documented most observers still considered the cardiac involvement of RF to stem from direct bacterial invasion.
| Streptococci as the Causative Agent in Rheumatic Fever|| |
Streptococci were first named by Rosenbach in 1884 and rudimentary patterns of hemolysis identified by Schottmuller in 1903. , Definitive classification and identification of beta-hemolytic streptococci were developed by Lancefield work in the 1920s.  Concurrently, the pathologic endpoints of GAS were being identified; particularly scarlet fever, erysipelas and puerperal fever. The temporal association between outbreaks of these streptococcal diseases and RF had been identified in the 1800s and were increasingly well defined in the early 20 th -century.  Concurrent but separate work by Coburn (USA) and Collins (England) identified group A β-hemolytic streptococci as the causative agent of RF in 1931 and heralded the concept of RF as an autoimmune response to GAS infection. , Evidence for the autoimmune mechanism was bolstered in 1932 with the demonstration of elevated anistreptolysin O titers (ASOT) in response to pharyngitis and in association with RF.  Although understanding of the immunopathogenesis of RF has progressed substantially in recent years, the exact immunological pathways causing RF remain uncertain and are the subject of ongoing research. 
| Development of Sulfonamide Antibiotics|| |
As the (post) infectious nature of RF was being established, early research into antibacterial therapy was emerging from the field of industrial dyes. A rudimentary antibacterial compound, sulfonamide, was identified in 1908 and later produced as Prontosil in the 1930s. The antibacterial effect of Protosil was powerfully demonstrated against streptococci in 1932.  At the time the sulfonamide class of antibiotics was identified, RF was one of the leading causes of death in children in the USA and the mortality from RHD in adulthood was substantial.  Evidence of sulfonamide efficacy against streptococci naturally led to attempts to intervene in the etiologic pathway from GAS to RHD. Initially, sulfonamides were deployed in the acute treatment of RF. In 1937 Massell and Jones administered "60 grains" of sulfonamide daily to 58 patients with acute RF. Many had febrile reactions and there was no apparent effect on the clinical course of RF.  Swift et al., at the Rockefeller Institute for Medical Research published similar results in 1938 and the quest to "cure" RF with sulfonamides was largely abandoned. 
| The Concept of Prophylaxis|| |
Anecdotal evidence had long suggested that the number of recurrences of RF was associated with disease progression to RHD.  Empiric evidence for the hypothesis came from the United States, where Bland and Jones followed a cohort of 1000 young people (<20 years) diagnosed with RF, chorea or RHD between 1921 and 1931. The mean age of enrollment was 8 years with an artificially high proportion (70.9%) of female patients for hospital administrative reasons. Follow-up at both 10 and 20 years revealed a clear association between the number of RF recurrences and mortality.  Similarly, a Swedish cohort of over 500 children in the early 1950s demonstrated a tight correlation between the number of episodes of RF and the proportion progressing to RHD on auscultation in later years. 
The association between RF recurrence and disease progressions implied that prevention of recurrence had the potential to change disease outcomes. Increasing recognition of the postinfectious nature of RF encouraged some researchers to consider novel antibiotics as prophylactic agents.  Medical management of RF and RHD in the early 20 th -century was based on prolonged bedrest in an attempt to minimize heart strain during acute carditis. Convalescent facilities were opened in England and the United States to provided dedicated care for children with RF and RHD. Prolonged inpatient convalescence was also intended to minimize domestic exposure to bacteria and to provide a health promoting environment with nutritious food, appropriate ventilation and reduced overcrowding.  Institutions established for the care of rheumatic patients became a natural hub for research into potential therapies. Thus, the existence of inpatient convalescent facilities potentiated research to minimize recurrences of RF through antibiotic prophylaxis.
| Sulfonamide Prophylaxis|| |
In 1936, two separate groups duly began experimental work to explore the role of prophylactic sulfanilamide. In New York Coburn and Moore conducted a series of experiments. In the most comprehensive study, they administered 2 g of sulfanilamide daily to 30 outpatient girls with a history of RF between 8 and 14 years over the course of 7 months.  20 girls were described as having "good compliance," 10 girls had "poor compliance" (controls). Participants were examined clinically every 2 weeks including throat cultures, erythrocyte sedimentation rate and drug serum concentration. None of the 20 girls receiving sulfanilamide was diagnosed with GAS infection. Of the 10 girls not taking sulfonamide, there were 6 episodes of GAS infection, three of which were followed by rheumatic recurrences.
In Baltimore, Thomas and France enrolled 122 patients 7-37 years (majority 14-26 years) with a history of RF/RHD to receive 1 g of sulfonamide daily. A cohort of healthy controls was recruited and matched on age, sex and ethnicity. All participants underwent regular throat swabs and clinical examination for evidence of pharyngitis. None of the prophylaxis group had pharyngeal GAS infections or recurrences. Nine of the control group had positive cultures, and there were 15 recurrences of RF. , By 1952 a meta-analysis of over 3000 patients by Rammelkamp (reproduced in Stollerman  ) indicated that sulfonamide prophylaxis could reduce the absolute risk of recurrence from 16% to 9%; a startling 50% relative risk reduction for a disease previously without therapeutic interventions. Although this approach showed promise for widespread prophylaxis, difficulties in long-term administration of sulfonamide drugs emerged. Agranulocytosis was a troublesome problem, occasional episodes of antibiotic resistance were noted, the sulfur drugs were contraindicated in pregnancy and sulfonamides demonstrated limited action against pharyngeal carriage of GAS. , Despite these challenges, any opportunity to alter the disease trajectory of RHD was welcomed, with Dr. Caroline Thomas writing in 1945 "It is clearly far better to take sulfonamide prophylactically for years and remain well, than to be forced to take digitalis for years after all recovery is lost." 
| Development of Penicillin Antibiotics|| |
In 1940, the seminal publication "penicillin as a chemotherapeutic agent" demonstrated the efficacy of penicillin against a range of bacteria in rats.  Evidence of improved efficacy and reduced toxicity of penicillin relative to sulfonamide spurred rapid investigation into its role in secondary prophylaxis. A large number of sites began trials using various regimens of oral penicillin. The superiority of penicillin over sulfonamide was speedily demonstrated. By 1954, a meta-analysis of 1672 patient-years indicated that oral penicillin prophylaxis could reduce the absolute risk of recurrence from 8.6% to 0.67%.  However, outpatient adherence to frequent oral penicillin doses was challenging. Intravenous and intramuscular injectable forms of penicillin were rapidly developed, however, these early injectable penicillins also required frequent administration. Attempts to increase the dosing interval included use of icepacks to slow absorption and suspension of penicillins in a beeswax before injection. These interventions provided scant benefit; reformulation would be required before an effective form of long-acting penicillin could provide lasting protection from GAS infection. 
| Development of Benzathine Penicillin G|| |
In 1951, Sazabo, Edwards and Bruce synthesized a new penicillin salt N, N'- dibenzylethylenediamine dipenicillin, later known as benzathine penicillin G (BPG).  The salt was strikingly poorly soluble and when administered intramuscularly (IM) produced prolonged and low serum concentration of penicillin. This pharmacokinetic profile was ideally suited for prophylaxis. The biography of the late Gene Stollerman recalls a call from the pharmaceutical company Wyeth asking for assistance with clinical trials to demonstrate the efficacy of the new BPG as novel prophylactic agent against RF the same year.  Dose finding was based on the known range of in vitro sensitivity of GAS to penicillin and the assumption that comparable serum penicillin concentrations would be protective against GAS infection in vivo.  A convenience sample of existing patients already receiving oral penicillin or oral sulfadiazine was compared with those receiving the new BPG formulation. Preliminary results were published speedily in 1952, with more comprehensive data in 1955. , In 242 patient-years of monthly BPG injection, only one episode of GAS pharyngitis occurred and there were no recurrences of RF. In patients receiving oral penicillin for 170 patient-years, two recurrences of RF were noted whereas in those receiving sulfadiazine, five recurrences occurred over 130 patient-years. Although recurrence rates were not statistically significantly different between the groups, results were bolstered by additional information on ASOT, GAS pharyngeal carriage and progression of detectable heart murmurs. Patients receiving BPG appeared to have globally better outcomes than those on oral prophylaxis regimens. Stollerman concluded: "Single monthly injections of 1,200,000 units of benzathine penicillin confer a high degree of continuous protection against infection with group A streptococci and afford a reliable means of protecting the patient against recurrences of RF."  In 1955, the AHA Committee on the Prevention of RF and Bacterial Endocarditis produced the first formal guidelines for secondary prophylaxis of RF, including IM BPG. 
The AHA guidelines enshrined secondary prophylaxis in standard clinical practice. Researchers began to use differential adherence with antibiotic regimens and varied antibiotic formulations as natural experiments to understand the efficacy of secondary prophylaxis. The 1964 publication from Wood et al., exemplifies this approach; describing a cohort of 431 children and adolescents receiving secondary prophylaxis and disaggregating outcomes according to adherence (good, questionable, poor) and formulation (BPG, oral penicillin, sulfadiazine).  The study demonstrated those receiving BPG had 0.4 recurrences of RF per 100 patient-years with BPG, relative to oral penicillin (5.5/100 patient-years) or oral sulfadiazine (2.8/100 patient-years). Streptococcal infections were significantly reduced (P < 0.01) in those with good adherence compared to those with poor adherence to prophylaxis.
Toward the end of the 20 th -century research attention to RHD in high resource declined, reflecting a declining burden of RHD and increasing burden of ischemic disease. Research activity continued in developing settings with a small number of investigators exploring the influence of secondary prophylaxis on progression and disease severity of RHD. Echocardiography was increasingly available from the 1970s but researchers in low-resource settings remained limited to diagnosis of RHD through cardiac auscultation.  In Kuwait, Majeed et al., followed 126 children after their first episode of RF and demonstrated that those with mild carditis during RF were significantly less likely to progress to RHD with regular BPG prophylaxis than with irregular BPG prophylaxis (P < 0.02).  In India, Sanyal et al., demonstrated that 15 of 45 (33%) children with RF and carditis had resolution of cardiac murmurs after 5 years of BPG secondary prophylaxis. 
In 2002, a Cochrane meta-analysis on the efficacy of secondary prophylaxis identified 11 relevant papers published between 1959 and 1996.  One analysis of the review focused on the relative efficacy of oral penicillin versus intramuscular BPG. In aggregate, intramuscular BPG reduced the incidence of GAS pharyngitis by 71-91% and RF recurrence by 87-96% in comparison to oral penicillin prophylaxis. It is telling that Cochrane review has been revisited 5 times since the original publication without new papers being suitable for inclusion. The review is no longer being revised, a situation indicative of the stasis in secondary prophylaxis research.
In most of the world, the formulation of BPG is largely unchanged from the original powder for suspension. A number of different generic lyophilized powdered products are used in low-resource settings. These formulations are cold-chain independent and relatively low cost but difficult to mix into a suspension prior to administration. A number of safety, quality and supply issues have been identified as barriers to use of powdered forms of BPG.  In a small number of high resource settings a branded, cold-chain, relatively high-cost liquid formulation of BPG is used.  Most guidelines recommend administration of 1.2 IU (900 g) of BPG between every 2 and 4 weeks.  However, adherence to these regimens is a global challenge, with few settings able to demonstrate delivery of than more than half of scheduled injections.  Unless BPG can be delivered at regular intervals, the opportunity to see the disease-altering benefits of BPG is lost. Sustained programs to improve the delivery of secondary prophylaxis are needed improve adherence, perhaps drawing on important case studies from New Zealand,  Samoa  and emerging research from Australia.  Alternatively, reformulation of BPG to prolong the dose interval or reduce pain on administration may address the vexed challenge of adherence.
| The Future of Secondary Prophylaxis|| |
The history of secondary prophylaxis for RF is of incrementally better antibiotics providing incrementally better protection from GAS infection and RF recurrence. However, the rate of innovation has slowed dramatically as the burden of RF and RHD has reduced in high resource settings. Important research questions remain unanswered, hampering contemporary efforts to control RHD. Robust studies with echocardiographic endpoints for secondary prophylaxis regimens are needed. Historical studies have largely relied on pharyngitis (± a rise in serologic markers of GAS infection) or recurrences of RF to quantify the efficacy of prophylaxis.  However, the most important clinical outcome is progression to chronic valvular RHD, and this has been relatively underexplored in the echocardiographic era. New studies with portable echocardiography should better quantify the effect of prophylaxis on progression from mild, moderate and severe disease at a valvular level. These clinical outcomes should be better correlated with pharmacokinetic data to confirm the presumed association between a protective serum minimal inhibitory concentration and inhibition of GAS infection. Future studies also need to include data on the quality of drugs, particularly BPG, used for secondary prophylaxis given concerns about the quality and safety of generic formulations currently available. , Broader questions about the persistent susceptibility of GAS to penicillins also remain unanswered and may yet become critical to the durability of the secondary prophylaxis approach. 
| Conclusion|| |
The comparatively staid therapeutic interventions for RF and RHD belie important and novel innovations in the early 20 th -centuary. Bacteriologic and epidemiologic advances elucidated GAS as the causative organism of RF; clinical observation and serologic studies identified the postinfectious nature of the disease. The advent and optimization of antibiotics facilitated an increasingly robust schedule of secondary prophylaxis with potential to avert RF and slow progression to RHD. Thus, secondary prophylaxis has transformed RF from a feared and often fatal condition of childhood to a manageable, chronic condition of adulthood. However, the benefits of secondary prophylaxis are inequitably accrued to people living in settings with access to high-quality BPG and health systems capable of delivering the therapy. Continued attention to delivering, understanding and optimizing secondary prophylaxis is required to control progression to RHD, and associated mortality, for individuals and for populations.
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