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Clinical Epidemiology

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The worldwide epidemiology of acute rheumatic
fever and rheumatic heart disease
This article was published in the following Dove Press journal:
Clinical Epidemiology
22 February 2011
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Michael D Seckeler
Tracey R Hoke
Department of Pediatrics, Division
of Cardiology, University of Virginia,
Charlottesville, VA, USA

Abstract: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are significant
public health concerns around the world. Despite decreasing incidence, there is still a significant
disease burden, especially in developing nations. This review provides background on the
history of ARF, its pathology and treatment, and the current reported worldwide incidence of
ARF and prevalence of RHD.
Keywords: rheumatic fever, rheumatic heart disease, group A streptococcus, epidemiology

Introduction
Acute rheumatic fever (ARF) is a postinfectious, nonsuppurative sequela of pharyngeal
infection with Streptococcus pyogenes, or Group A β hemolytic Streptococcus
(GABHS). Of the associated symptoms, only damage to the valve tissue within the
heart, or rheumatic heart disease (RHD), can become a chronic condition leading to
congestive heart failure, strokes, endocarditis, and death. While the incidence and
prevalence of ARF and RHD have been decreasing in developed nations since the
early 1900s, they continue to be major causes of morbidity and mortality among young
people in developing nations. It is estimated that there are over 15 million cases of
RHD worldwide, with 282,000 new cases and 233,000 deaths annually.1
More recent data using echocardiography to screen for RHD in developing nations
have lead to a marked increase in the recognized prevalence in these regions.2–6
With these new data, there has been an increased awareness and interest in ARF and
RHD, which stimulated this review of the literature to provide information on the
pathogenesis, diagnosis, and treatment for ARF and RHD, and an updated estimate
of the worldwide incidence and prevalence.

Background

Correspondence: Michael D Seckeler
PO Box 800386, University of Virginia,
Charlottesville, VA 22908, USA
Tel +1 (434) 924-9119
Fax +1 (434) 924-5656
Email ms3ec@hscmail.mcc.virginia.edu
submit your manuscript | www.dovepress.com

Dovepress
DOI:10.2147/CLEP.S12977

Although physicians in Europe had been describing clinical components of ARF since
the 1500s, it was William Charles Wells’ seminal publication in 1812 that definitively
linked ARF with carditis.7 The entire clinical spectrum of ARF (from tonsillitis to
carditis) was first described by Cheadle in 1889.8 The infectious etiology of ARF was
long suspected, especially given the seasonal variation in outbreaks, and in 1900 Poynton
and Paine described a diplococcus isolated from patients with ARF, which they implicated as a causal organism for the disease.9 Micrococcus (or Streptococcus) rheumaticus
was isolated from a patient with ARF in 1904, and was noted to be “indistinguishable
from strains of Streptococcus pyogenes”.10 Into the 1930s, theories implicating viruses
as causal agents for ARF surfaced,11 and are still being investigated today.12,13
Clinical Epidemiology 2011:3 67–84
67
© 2011 Seckeler and Hoke, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.

18 The Minor criteria are arthralgias. These markers can also be followed as signs of resolution of ARF.16 1984.19. Fever. Sydenham chorea. Having first degree heart block does not predict whether a patient will develop RHD. elevated acutephase reactants. There can also be worsening school performance.14 This year was used as a cutoff to create 2 eras: 1970 through 1990. uncontrolled movements of the trunk or extremities. joints that can change from one location to another as the disease progresses. Arthralgia is pain. Carditis is typically valvulitis and has traditionally been diagnosed by a new murmur suggestive of valvar regurgitation. These data were plotted for the time period 1970 to 2009.18 There has been controversy over the use of Doppler echocardiography in the diagnosis of ARF. Subcutaneous nodules are painless. C-reactive protein. 68 submit your manuscript | www. both of which are expected to be elevated during an episode of ARF. Vitus’ dance. erythema marginatum. Regional incidence and prevalence estimates were not weighted by the underlying population. and Western Pacific. is rapid. Clinical Epidemiology 2011:3 . and first degree heart block. Diagnosis The diagnostic criteria for ARF were first developed by Jones in 194415 and have since been modified in 1965. Sydenham chorea. a patient can have either arthritis or arthralgia as a Jones criterion. usually large. often in multiple joints. either by a pharyngeal swab culture positive for GABHS. serpiginous (snake-like) borders found on the trunk and extremities.20 Many argue Table 1 Major and Minor Jones criteria for the diagnosis of acute rheumatic fever18 Major criteria Minor criteria Migratory polyarthritis Carditis Erythema marginatum Syndenham chorea Subcutaneous nodules Arthralgia Fever First degree heart block Elevated inflammatory markers (ESR. To generate trends of ARF incidence and RHD prevalence over time. Acute-phase reactants are nonspecific laboratory markers of inflammation in the body. and trend lines were calculated with quadratic regression for each WHO region and are reported in the graphs. The last major WHO report on the worldwide prevalence of ARF and RHD reported data through 1990. fleshcolored bumps. or St.Dovepress Seckeler and Hoke Methods An extensive literature search for any articles about “acute rheumatic fever” or “rheumatic heart disease” was performed in August 2010 using PubMed. and intense pain of multiple. plus evidence of recent streptococcal infection. is common in early ARF. data from various countries were clustered by World Health Organization (WHO) region – Africa. usually at least 39°C. ARF incidence and RHD prevalence rates for each reporting country during these eras were graded and plotted on a world map to show the changes in disease burden and geographic location with time in more detail than the trend plots. Data reported from any countries within a WHO region for a given year were averaged together to provide a value for that year. and 1991 through the present.18 and 2002. There may be myocarditis or pericarditis in addition to the valvulitis. Europe. Of note. swelling.19 The criteria are divided into Major and Minor criteria (Table 1). but echocardiography has been used more in recent years to aid in the diagnosis (see below). The typical ones measured are erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).com Dovepress Figure 1 Electrocardiogram demonstrating first-degree heart block in a patient with acute rheumatic fever.dovepress. carditis. without associated redness or swelling. erythrocyte sedimentation rate. Eastern Mediterranean. the Americas. In order to maximize the available information. Jones criteria for each of the WHO regions were compared using one way ANOVA with post-hoc analysis to identify significant differences in criteria between regions.18 The Major criteria are migratory polyarthritis. Erythema marginatum is a transient rash with central pallor and red. ESR. Polyarthitis is redness. Articles reporting data of the incidence of ARF or prevalence of RHD were reviewed. Diagnosis is made by the presence of either 2 Major or 1 Major and 2 Minor criteria. positive rapid GABHS ­antigen test or rising serologic antibody titers (antistreptolysin O [ASO]. but not both.17 1992. The PR interval is noted by the arrows. usually found on the extensor surfaces of the arms and legs. DNAse B. CRP) Abbreviations: CRP. behavioral changes. or streptokinase). and subcutaneous nodules. fever. non-English language articles were included if it was possible to obtain an English translation of either the abstract or the entire article. First degree heart block is diagnosed by prolongation of the PR interval on electrocardiogram (Figure  1). Southeast Asia. and is markedly prolonged at 300 milliseconds (normal for an adult is less than 200 milliseconds). and emotional lability.

HLADR7 has been the most frequently associated with ARF and RHD. Patients that recover from the initial ­rheumatic carditis are likely to have permanent valve ­damage.51 Once heart valves have been damaged. these patients require medical ­management for their heart failure. there is concern for overdiagnosis of carditis by relying on Doppler echocardiography. tumor necrosis factor-α (TNF-α). then host cells can be attacked. the foreign antigen is the M-protein and it cross reacts with cardiac myosin. which can be the presenting symptom of ARF. and over time the affected valves can become stenotic in addition to regurgitant. especially among high-risk populations. host tissue without the continued need for streptococci to be present.30 This leads to further inflammation and scarring of heart valve tissue and chronic RHD. Once valve tissue is damaged and inflamed.47 These antibodies could subsequently react to.com Dovepress 69 . and while there have been no universal associations.30 A third factor.25 ARF is believed to be an autoimmune reaction to GABHS infection.19 The current American Heart Association guidelines recommend the use of Doppler echocardiography as a supplement to diagnosis. and damage. binds to various sugar molecules on the cell surface and helps to mark foreign cells for immune cells to eliminate. If the HLA molecules present antigens that resemble both Streptococcus and human tissues. 50 Further study has led to the identification of the M-protein on the GABHS cell membrane as the likely antigen for inducing the production of antibodies that cross-react with human heart tissue. they do not function properly. or regurgitate. but only in the presence of killed streptococci. and subsequently demonstrated that anticardiac and ­antiskeletal muscle antibodies were produced in rats. TNF-α may be upregulated in patients with increased ARF susceptibility.26 Many studies have investigated the role of HLA alleles. and blood is allowed to leak backward. but evidence of valvar regurgitation should not be used as a Major or Minor criterion. this can cause acute congestive heart failure. and subsequent development of ARF.Dovepress that echocardiography can help to diagnosis subclinical RHD. RHD patients with mitral valve damage have been found to have high levels of MBL Clinical Epidemiology 2011:3 Epidemiology of rheumatic fever in their blood. which can then attack the antigen or activate B cells to produce antibodies to the antigen. In severe cases. Figure  2a shows normal cardiac anatomy and Figures  2b and 2c show echocardiograms demonstrating a thickened. which is also located on chromosome 6 near the HLA alleles. a clear understanding of the pathophysiology still eludes modern physicians.21–24 However. they should be equally susceptible to attack from an autoantibody. where all or part of a foreign antigen resembles at least some portion of host tissue. since it is not known how much valvar regurgitation is “normal”. All four heart valves can be involved in rheumatic carditis. which are located on chromosome 6. proteins that are normally intracellular can become exposed to invading immune cells and lead to the development of more autoantibodies directed at different component proteins of valve tissue. however there is a marked predominance of mitral valve involvement. Since all heart valves develop from the same tissue. This is called molecular mimicry and will be discussed more below. and has been supported by outbreaks of ARF following outbreaks of pharyngitis.27–45 While the exact mechanism by which certain genes can confer an increased susceptibility to ARF has not been delineated. regurgitant mitral valve. The role of GABHS infection as an initial event is clear. In addition to the usual treatment for ARF. Another protein that has been associated with ARF and RHD is the inflammatory cytokine.30 The theory of cross-reaction between GABHS and heart tissue has been explored for at least 60 years. leading to an increased inflammatory response in these patients. as well as rising antistreptococcal antibodies in patients with ARF. The cross-reactivity is believed to occur through molecular mimicry. In ARF and RHD. This has recently been associated with higher levels of MBL. HLA molecules process antigens within a host cell and present them on the cell surface to T cells. while those with aortic valve damage have low levels. Pathophysiology Even though ARF has been recognized as a disease entity for at least 150 years. Cavelti first identified anticardiac autoantibodies in ARF in 1945.30 but is not clear why more MBL leads to damage of the mitral valve.48 In 1962. Severe valve stenosis or ­regurgitation can eventually warrant surgical repair or replacement of submit your manuscript | www. especially given the tendency for outbreaks to occur within families and the relatively few cases of ARF that develop given the high prevalence of GABHS pharyngitis and pharyngeal carriage. in ARF susceptibility.dovepress. which induces T-cell mediated attack of the heart tissue and valves. mannose-binding lectin (MBL).46. Genetically determined host susceptibility has long been presumed. Kaplan and colleagues demonstrated a cross-reactivity between human heart tissue and GABHS 49 and later anticardiac antibodies in patients with ARF. there are theories about the roles played.

One of the ­earliest reports of brain MRI findings in acute ­Sydenham chorea demonstrated increased signal intensity in the caudate nucleus. or juvenile rheumatoid arthritis) among 261 North American patients from 1985 to 2005 found that 55% of the surgeries were for RHD (160 patients. and degenerative changes in ­recurrent chorea. 61 This appeared to ­correlate with pathologic findings seen in ­varying case series which show blood vessel inflammation. a component of the basal ganglia. speech and behavioral issues. neonatal lupus.62 Subsequent case series have ­demonstrated acute changes in the caudate nucleus (some of which progressed to cystic changes on subsequent studies)63 and others with lesions in the subcortical white matter. demonstrating the left atrium connected to the left ventricle via a mitral valve. Not only 70 submit your manuscript | www.60 One function of the basal ganglia is inhibition of motor impulses. which may be the cause of speech and behavioral symptoms. demonstrating a thickened anterior leaflet of the mitral valve.54–57 The cost of surgical intervention for RHD is approximately US$25. There appears to be molecular mimicry involved in the development of Syndeham chorea as well. ­neuronal pathways can be disrupted as well.64 Clinical Epidemiology 2011:3 . with mortality from endocarditis ranging from 29% to 36%. Numerous studies have provided evidence for anti-neuronal antibodies to the basal ganglia in patients with Sydenham chorea.58 Early detection of ARF and RHD through screening programs can reduce the morbidity of chronic RHD and surgeries for heart valve repair or replacement. but since gangliosides are involved in cell signaling. Investigators have used MRI to examine the brains of patients with Sydenham chorea to determine the ­etiology of the movement. Kawasaki disease. 200 procedures) with 3  in-hospital deaths.Seckeler and Hoke Dovepress Figure 2 a) Artist rendition of normal left heart anatomy.6% of cases.com Dovepress does this cause inflammation and damage neurons. Damage to this area can explain the unusual movements associated with Sydenham chorea. demonstrating moderate-to-severe mitral valve regurgitation (blue jet). which is enough to fund 1 year of an RHD screening program in a small developing nation.61.000. A recent review of 361 cardiac ­surgeries for rheumatic disease (RHD. with ­a ssociated edema and shifting of brain matter. systemic lupus.53 In various series of patients with endocarditis. c) Two-dimensional echocardiogram with color Doppler.52 b) Two-dimensional echocardiogram of the left heart.59 Kirvan and colleagues recently found a carbohydrate ­component of the streptococcal cell wall that cross-reacts with gangliosides in the cell membrane of neurons in the basal ganglia. RHD was the underlying cause in 15% to 76. the affected heart valves.dovepress. occlusion and necrosis in early disease.

including erythromycin.27 kg) 50 mg/kg by mouth daily Drug-dependent 10 days Benzathine penicillin G Amoxicillin Cephalosporina (first generation) Clindamycina Clarithromycina Azithromycina 20 mg/kg/day divided in 3 doses by mouth 15 mg/kg/day divided in 2 doses by mouth 12 mg/kg by mouth daily Once 10 days 10 days 10 days 10 days 5 days Notes: aIn penicillin-allergic patients. The first line is primary prevention through the recognition of GABHS pharyngitis and treatment with appropriate antibiotics. a single intramuscular dose of benzathine penicillin G (BPG) can be given at the time of GABHS pharyngitis diagnosis. and there are currently 4 vaccines in development targeting the M-protein. and azithromycin. but as many as 5% may also be allergic to cephalosporins. Source: American Heart Association. Inc. Note. Patients that have a hypersensitivity to penicillin may be treated with a first-generation cephalosporin. ­tetracyclines. While there are many potential vaccine candidates.66 Treatment Primary prevention There are several approaches to reduce the impact of ARF. and sulfonamides are not recommended to treat GABHS pharyngitis. clarithromycin. and there has never been documentation of GABHS isolates that are resistant to penicillin.66 Full details of antibiotic treatments for GABHS pharyngitis are shown in Table 2. are another alternative. Macrolides. For patients in whom compliance with an oral regimen is a problem.000 units intramuscular (.66 Oral penicillin V is still the first line treatment in patients whom compliance can be expected. Antibiotic therapy initiated within 9 days of onset of pharyngitis is effective in preventing ARF.Dovepress Epidemiology of rheumatic fever Table 2 Antibiotic regimens for treatment of group A streptococcal pharyngeal infections.68 Part of the complexity in vaccine development is the high ­variability Clinical Epidemiology 2011:3 Figure 3 Schematic drawing of the M-protein structure with the conserved (blue).27 kg) 600. Another intriguing area of research for the past 40 years in ARF prevention is GABHS vaccine development.com Dovepress 71 . Note that the conserved region is closest to the cell membrane. although there have been GABHS strains that demonstrate macrolide resistance. up to 5% of patients allergic to penicillin may also be allergic to cephalosporins. submit your manuscript | www.65. Antibiotic Dose Duration Penicillin V 250 mg by mouth 2 to 3 times daily (#27 kg) or 500 mg by mouth 2 to 3 times daily (. Fluoroquinolones. the extracellular M-protein on the surface of GABHS cells has become the primary target.dovepress. variable (red).200. 67.000 units intramuscular (#27 kg) or 1.65. and hypervariable (green) regions.

the progression to degenerative changes seen in recurrent chorea makes corticosteroids less likely to be of any benefit in this group. naproxen has been used as an alternative anti-inflammatory agent. Secondary antibiotic prophylaxis is only effective when there is high compliance. usually 4 to 6 weeks.61. these can be equally effective.79 Given the higher likelihood of side effects from steroid treatment.21 Treatment with aspirin usually causes marked improvement in the joint manifestations of ARF within 24 to 48 hours. if they had not already. including irradiation of the heart.77 While aspirin has remained the mainstay of ARF therapy.70. Secondary prophylaxis Those patients who develop ARF are at high risk to develop subsequent attacks when infected with GABHS.73 Since then.Dovepress Seckeler and Hoke of the M-proteins. variable.81 Some groups do recommend the use of corticosteroids for carditis in patients who are in severe heart failure. However. and are likely to provide protection against a wider range of M-types. but 3 of 21 also developed ARF. They found that there was no difference in final outcomes. Table 3 Antibiotic regimen for secondary prophylaxis of acute rheumatic fever. The other three M-protein-based vaccines in development target the conserved region of the M-protein. ­Figure 3 shows a schematic of the structure of the M-protein. For those who cannot tolerate aspirin.78 A more recent meta-analysis confirmed these results and found no significant reduction in the development of RHD with corticosteroids compared to aspirin.5 g by mouth daily (#27 kg) or 1 g by mouth daily (. there is concern that vaccination could actually cause ARF.76 and prolonged confinement to a hyperoxic chamber. There have been studies showing decreased ­severity and duration of chorea with prednisone therapy. The hypervariable region is exposed to the host immune system and is the portion that distinguishes each M subtype. and found a quicker resolution of chorea symptoms in the treatment group. people living in crowded conditions Clinical Epidemiology 2011:3 .84 If patients are compliant with oral regimens.83 so many healthcare providers prescribe intramuscular BPG every 4 weeks to ensure adequate serum penicillin levels.66 72 submit your manuscript | www. This has prompted the study of other anti-inflammatory medications.82 Paz and colleagues82 performed a placebo-controlled study on a group of 37 children with Sydenham chorea. up to 5% of patients allergic to penicillin may also be allergic to cephalosporins. but at the cost of higher recurrence rates.72.000 units intramuscular (#27 kg) or 1.200.com Dovepress A large multi-center study in the United States and United Kingdom in 1955 compared the efficacy of aspirin. the hormonal treatments caused more rapid resolution of some symptoms. or worsen existing valve damage.69 It is important to note that these strains are based only on data from the United States. The 26 chosen strains were those associated with pharyngitis. cortisone.66. the exact action of effect is unclear. Note.75 or heparin. Secondary antibiotic prophylaxis should be given to individuals most at risk for GABHS pharyngeal infections.000 units intramuscular (. This was seen in an early M-protein vaccine trial in the 1960s where all patients receiving the vaccine developed antistreptococcal antibodies. with over 150 M-types identified. compared to 5 of 447 controls.71 Acute treatment Salicylate therapy for the symptoms of ARF was first attempted successfully by Maclagan in 1876. Patients who have recurrences of ARF are at risk to develop carditis. Inc. aspirin has remained the first line treatment for uncomplicated ARF. Studies in areas highly endemic for ARF have found that BPG dosed every 3 weeks provides better prevention of recurrent ARF. and ARF. These include children.22 Anti-inflammatory medications are given until the inflammatory markers normalize. with conserved.27 kg) Drug-dependent Penicillin V Sulfadiazine Macrolidea Notes: aIn penicillin-allergic patients.21. the decision about which M-types to include was based on the United States Centers for Disease Control’s Active Bacterial Core Surveillance of the Emerging Infections Program Network. Source: American Heart Association. which can help distinguish ARF from other arthritides which do not resolve as quickly.80. which will be discussed more later.62 corticosteroid treatment for chorea is a logical choice. a variety of treatments have also been attempted for ARF. so-called “rheumatogenic” strains. and adrenocorticotropic hormone for the acute treatment of the symptoms of ARF. Antibiotic choices are similar to those for GABHS pharyngitis. and hypervariable regions. invasive disease.74 administration of ascorbic acid and orange juice. treated 22 with prednisone.27 kg) Every 4 weeks (3 weeks in high-risk areas/populations) 250 mg by mouth twice daily 0. Antibiotic Dose Benzathine penicillin G 600. and so this population is best treated with secondary antibiotic ­prophylaxis after their initial attack (Table 3). For the 26-valent GABHS vaccine.68 Since ARF is thought to be due to an autoimmune response to the M-protein and molecular mimicry of the heart valve tissue. Given the inflammatory changes seen on pathologic specimens. but seems to be related to the anti-inflammatory properties.dovepress.

­Overall. Table  6  shows the percentages of patients with the Major and Minor criteria for each WHO region and for all reported studies combined. and healthcare workers. 85 utilized population-based screening.049). The reported incidence of ARF is decreasing in all WHO Regions except for the Americas where it appears to be increasing slightly and the Western Pacific.com Dovepress 73 .Dovepress Epidemiology of rheumatic fever Table 4 Reported incidence of acute rheumatic fever (ARF) (per 100. Those with RHD should be treated until 40 years of age or 10 years after their last attack. carditis occurred in 60% of cases. The Americas also had more cases of chorea than the Eastern Mediterranean (P = 0.002. surgical series. The most important component of these guidelines is the need to assess each patient’s clinical situation to determine if they have continued high-risk exposure to GABHS which could warrant lifelong prophylaxis.8 1. and the only significant difference between regions was a higher male predominance in Southeast Asia compared to the Western Pacific (P = 0. where it appears to be steadily increasing. whichever is longer.4 Fijians Indians Papago tribe 78 21.6 → 2. Figures 8 and 9 are graphs of the trend of ARF incidence and RHD prevalence for each WHO Region. or autopsy series.5–55 12–14 120 27 112 15. national health registries.019 and 0. respectively).7 4. The American Heart Association guidelines state that individuals who have had ARF without carditis should be treated until the age of 21 years or 5 years after their last attack. where it appears to be decreasing. as any of the four cardiac valves can be affected by ARF. and ESR elevation was less in Southeast Asia than in the Eastern Mediterranean and Western Pacific (P = 0.dovepress. There were more cases of erythema marginatum in the Americas than in Southeast Asia (P  =  0.1 10–30 1.9 1. prospective disease surveillance. It is also recommended to continue prophylaxis after heart valve Table 5 Reported prevalence of rheumatic heart disease (RHD) (per 1000 persons) from 1935 through 1970 Years Country RHD (/1000) 1935–1964 1949–1951 1958–1961 1961 1964–1965 1966 1970 1970 United States (Minnesota)86 United States (Colorado)88 Japan98 USSR99 Pakistan (Karachi)100 India (Chandigarh)101 Taiwan (Taipei)102 Uruguay103 20.6 4. The literature review revealed data on the incidence and/or prevalence of ARF and RHD in 100 countries around the world. Europe and the Eastern Mediterranean (P = 0. Fever and an elevated ESR were reported less often in Africa than any of the other regions. respectively).013.041. Tables 4 and 5 show the reported incidence of ARF and prevalence of RHD for the era before 1970.019.4 African Americans Puerto Ricans 47 Whites 23 African Americans Whites 44. Figures 4 through 7 present the incidence of ARF and prevalence of RHD during the 1970 to 1990 and 1991 to present eras.65.005 and 0.000 persons) from 1930 through 1970 Years Country 1930–1964 1935–1949 Sweden United States (Minnesota)86 England (Bristol/Sheffield)87 United States (Colorado)88 Costa Rica89 Peru90 Sri Lanka91 United States (Maryland)92 United States (Utah)93 United States (New York)94 United States (New York)94 United States (New York)94 United States (Tennessee)95 United States (Tennessee)95 Denmark85 Fiji96 Fiji96 United States (Arizona)97 1948–1953 1949–1961 1950 1952 1952–1957 1960–1964 1960–1964 1963–1965 1963–1965 1963–1965 1963–1969 1963–1969 1966 1965–1966 1965–1966 1970 Subgroup ARF (/100.003.011 and 0.015 and 0. 0. data from specialty referral clinics.025). teachers. all studies were included. or studies from which the data collection methods could not be determined.8 1. respectively).66 Results Of the 164 articles reviewed for ARF incidence and RHD prevalence data.7–6.000) 25 → 1. whichever is longer. and in the Western Pacific than in both the Eastern Mediterranean and Southeast Asia (P = 0. college students).6 → 12 6.3 35–65 85 25. Arthritis also occurred in 60% of all cases and Southeast Asia had significantly fewer cases than the Americas. The reported prevalence of RHD is increasing in all regions except for Europe.015). respectively). Seventy-nine studies were retrospective reviews of hospital admissions or discharges for ARF or RHD. In order to maximize the available data. parents. Elevated submit your manuscript | www. There was a slight male predominance in all ARF cases.5 13 140 92 (military recruits.4 1 Clinical Epidemiology 2011:3 replacement surgery. but the Americas had significantly fewer cases than the Western Pacific or Southeast Asia (P = 0.

133 (10) Qatar.013. and 0. . Eastern Mediterranean. 120.120 (7) Kuwait.Seckeler and Hoke Dovepress ARF (/100.182 (8) New Caledonia.178 (5) Jordan.dovepress. and both combined (Figure 10c).199 74 submit your manuscript | www. and in the Americas and Eastern Mediterranean than in Southeast Asia (P  =  0.112 (9) Northern Mariana Islands. arthralgia. respectively). and Southeast Asia (P = 0.025. showing M-types from developing nations (Figure 10a).40.049).136 (12) Trinidad.179 (6) Kosrae.86.152 (24)Utah.123-125 (8) New Caledonia.133 (10) Samoa.112 (3) French Antilles.026 and 0.104-156 (1) Barbados.112 (5) Federated States of Micronesia.147 (20) Navajo Reservation.005. Africa had fewer recurrences than Southeast Asia (P = 0. There was no difference in subcutaneous nodules. Western Pacific.93 (25) Virginia. 111. developed nations (Figure 10b). and Western Pacific than in Africa (P = 0.97 (15) California.175 (4) Israel.0. 151 (23) Tennessee. For ARF (/100. 0. Federated States of Micronesia.com Dovepress Clinical Epidemiology 2011:3 . or first-degree heart block between all 6 regions. The reported M-types are presented in Figure 10.113 (4) French Polynesia. 156-200 (1) American Samoa.185 (9) Northern Mariana Islands.036.159.86 (19) Mississippi. 139. respectively).112. 115.114 (6) Israel.190 (11) West Virginia.181 (7) Lebanon.155 (27) Wyoming. and 0.112 (11) Tonga.97 ASO titer was more common in the Americas. respectively).142 (16) Florida. There were not enough data available to compare differences in Major and Minor criteria between the two eras to evaluate for changes in presenting Jones criteria over time.000 persons) <5 5–20 20–40 40–100 >100 Figure 4 Map showing reported worldwide incidence of ARF from 1970 through 1990.022.141. Regional ARF recurrence rates ranged from 8% to 34%.143 (17) Hawaii.153 (26) West Virginia.001.140 (14) Arizona.001.105 (2) Fiji.144-146 (18) Minnesota.169-171 (3) Grenada.150 (22) Rhode Island. Europe.148 (21) Ohio. with Europe having significantly fewer recurrences than the Americas.004.000 persons) <5 5–20 20–40 40–100 >100 Figure 5 Map showing reported worldwide incidence of ARF from 1991 through present.149.97. 108.137 (13) Alabama.192 (2) Fiji. 0.120.002.154.104. Eastern Mediterranean. 0.

only 50% of patients diagnosed with ARF had laboratory evidence of a recent streptococcal infection demonstrated by an elevated or rising ASO titer.136. where public health resources are limited. As might be expected.112.112 (9) Tonga. in Figure  10 the 26 M-types present in the GABHS vaccine currently being tested are noted by an asterisk.228 (2) Samoa.99.177.86 comparison.191. In Africa.111.com Dovepress 75 .168.000 persons) <1 1–2 2–4 4–10 >10 Figure 6 Map showing reported worldwide prevalence of RHD from 1970 through 1990. RHD (/1.118.112 (5) French Polynesia.102-104. especially those presenting data from specialty referral clinics or hospital admissions.112.169. practice patterns for ARF diagnosis vary across countries.21. However. All patients diagnosed with ARF were treated accordingly.202 (7) Puerto Rico. which is a disappointment from a public health standpoint.192 (3) Tonga. The inherent limitations to the methods of many reviewed studies.3 Clinical Epidemiology 2011:3 submit your manuscript | www.202 (4) Fiji.Dovepress Epidemiology of rheumatic fever RHD (/1.21 (3) El Salvador.189. do not allow calculation of exact incidence rates.103 (8) Samoa.132.169.201-216 (1) Barbados.21. these data make clear that ARF and RHD still exist in significant numbers around the world.197.86.112 (6) Jamaica.104 (2) Cook Islands.176.128.90.69.000 persons) <1 1–2 2–4 4–10 >10 Figure 7 Map showing reported worldwide prevalence of RHD from 1991 through present.217-240 (1) Fiji.14.111.241 Discussion This is the most comprehensive review of the incidence and prevalence of ARF and RHD in the English literature to date.2-6.136 (10) Minnesota.160.dovepress.192.

These countries have small. E) Western Pacific. Similar practice patterns can be noted in the other poorer WHO regions – Western Pacific and Southeast Asia. which has contributed to an increased prevalence of RHD.000 1986 1984 1982 1980 0 Year E 1988 20 1978 2008 2006 2004 2002 2000 1998 1996 1994 1992 1990 1988 1986 1984 1982 1980 1978 1976 1974 1972 0 40 1976 50 60 1974 100 80 1972 150 100 1970 D Incidence per 100. C) Africa. A) The Americas.000 persons for each WHO region.000 Year 200 1970 C Incidence per 100. The reported incidence is only now approaching an average 100/100. which is likely what the true incidence has been. Given that the incidence of ARF has been decreasing in most regions.000 people.dovepress. Because of the endemic nature of ARF in these regions and the marked impact of progression to chronic RHD. This trend has been attributed to improved living conditions. RHD is also more rigorously sought out.2–6 Recognition of subclinical carditis will identify those children who would benefit from secondary antibiotic prophylaxis and hopefully prevent the progression to clinically significant RHD. Points represent reported incidence from the literature. The apparent increase in incidence in the Western Pacific is more likely improved recognition and reporting of ARF in this region. their increased likelihood Clinical Epidemiology 2011:3 . Nevertheless. One possibility for the high incidence of ARF in the Western Pacific region is that many of the countries are small island nations.000 Year 1986 1984 1982 1980 1978 1976 1974 1972 400 350 300 250 200 150 100 50 0 1970 2008 2006 2004 2002 2000 1998 1996 1994 1992 1990 1988 1986 1984 1982 1980 1978 1976 1974 1972 Incidence per 100. and so even a small outbreak of ARF can be calculated as a high incidence level. The decrease in ARF incidence is consistent with prior studies that have shown the incidence to be decreasing since the early 20th century. relatively 76 submit your manuscript | www.133.161 The prevalence of RHD appears to be increasing worldwide.000 B 700 600 500 400 300 200 100 0 1970 A Incidence per 100.Dovepress Year 2008 2006 2004 2002 2000 1998 1996 1994 1990 1992 1992 1994 1996 1998 2000 2002 2004 2006 2008 1992 1994 1996 1998 2000 2002 2004 2006 2008 1990 1988 50 1990 1988 1986 1984 1982 1980 0 1978 2008 2006 2004 2002 2000 1998 1996 1994 1992 1990 1988 1986 1984 1982 1980 1978 1976 1974 1972 0 100 1976 50 150 1974 100 200 1972 150 250 1970 F 200 Incidence per 100. it is not likely due to increases in the disease. ­Population-wide echocardiographic screenings may be subject to length time bias or pseudodisease. The upward trend in our calculated incidence of ARF in the Americas is likely due to the high incidence reported from Mexico in 1995.000 Year 250 1970 Incidence per 100. given relatively small denominators. it is reasonable to be aggressive with ARF diagnosis and treatment. and F) Southeast Asia.com Dovepress isolated populations. Major advances in medical and surgical treatments for RHD have led to increased survival. the use of antibiotics for GABHS pharyngitis and possibly shifting GABHS serotypes. B) Europe. and the children diagnosed are likely to be among the majority of ARF patients in whom carditis resolves within a year of initial attack.000 Seckeler and Hoke Year Figure 8 Trends of acute rheumatic fever incidence per 100. which is easily seen as an outlier in the maps in Figures  4 and 6. D) Eastern Mediterranean. and newer studies relying on echocardiography to enhance the diagnosis of RHD have shown that subclinical carditis exists at rates up to 10 times higher than that diagnosed by examination alone.

9% 75.7% 50.8% 8.0% 7.5% 40.7% 2. ↑ PR.7% 28.7% 54.8% 5.7% 48.9% 48. ESR. increased erythrocyte sedimentation rate.9% 63.6% 24.243 These are similar to Gordis’ findings from the 1970s in Baltimore.000 Year 35 30 25 20 15 10 5 0 1970 Prevalence per 1. Abbreviations: EM.5% 4.6% 33.7% 20.4% 3. c) Africa.3% 84.2008 2006 2004 2002 2000 1998 1996 1994 1992 1992 1994 1996 1998 2000 2002 2004 2006 2008 1992 1994 1996 1998 2000 2002 2004 2006 2008 1990 50 40 30 20 10 Year 1990 1988 1986 1984 1982 1980 1978 1976 1974 0 1972 2008 2006 2004 2002 2000 1998 1996 1994 1992 1990 1988 1986 1984 1982 1980 1978 1976 1974 1972 60 1970 F Prevalence per 1. especially in endemic areas.7% 68.5% 34.243 A recent meta-analysis of the treatment of GABHS pharyngitis to prevent ARF concluded that there would be an approximately 60% reduction in cases of ARF if pharyngitis was appropriately treated.3% 46.8% 1.4% 22.dovepress. ASO.0% 4.9% 35.9% 24.000 Dovepress Year Figure 9 Trends of rheumatic heart disease prevalence per 1000 persons for each WHO region.242.1% 55. or even ARF without a clinically apparent preceding sore throat as missed opportunities to prevent ARF. and worsening of prior valvar lesions. prolonged PR interval on ECG. makes it appropriate that these children receive secondary antibiotic prophylaxis.3% 60. of recurrent ARF.3% 64.9% 11.4% 71.4% 74. b) Europe.5% 1.7% 22.4% 72. a) The Americas.2% 81. elevated antistreptolysin O titer.7% 35.4% 53.1% 54. Points represent reported prevalence from the literature.9% 43.3% 60.9% 52.9% 68. there is little excuse for hundreds of thousands of new cases of ARF annually.9% 90.8% 8.9% 67.3% Note: Proportions are restricted to acute rheumatic fever patients.1% 45. d) Eastern Mediterranean.3% 48.5% 7. poor compliance with antimicrobial regimens.3% 8.3% 12.4% 12.8% 5.5% 63. Clinical Epidemiology 2011:3 submit your manuscript | www.8% 15.6% 40.3% 65.5% 66. e) Western Pacific.0% 3.4% 78.0% 71.000 Epidemiology of rheumatic fever 1970 A Prevalence per 1.8% 62.0% 59. Authors cite varying reasons such as patients not seeking care for pharyngitis.3% 26.5% 52.9% 81.5% 79.9% 21.000 Year 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 C Prevalence per 1.5% 54.4% 65.com Dovepress 77 . erythema marginatum.1% 91.3% 22.7% 15. and f) Southeast Asia.9% 17.242 Implementing systematic sur- Table 6 Percentage of major and minor criteria by WHO region and for all reported studies WHO region Males Recurrences Major criteria Minor criteria Carditis Arthritis EM Chorea Nodules Arthralgia Fever ↑ PR ESR ASO The Americas Europe Africa Eastern Mediterranean Western Pacific Southeast Asia All 54.7% 86.2% 57.0% 63. Given the relative ease and low cost of GABHS pharyngitis treatment to prevent ARF occurrence.000 Year 1988 1986 1984 1982 1980 1978 1976 1974 1972 2008 2006 2004 2002 2000 1998 1996 1994 1992 1990 1988 1986 1984 1982 1980 1978 1976 1974 1972 40 35 30 25 20 15 10 5 0 1970 B 40 35 30 25 20 15 10 5 0 Prevalence per 1.9% 1.3% 11.0% 59.000 1988 1986 1984 1982 1970 0 Year E 1990 5 1980 0 10 1978 5 15 1976 10 20 1974 15 1972 D 20 Prevalence per 1.9% 27.0% 0.8% 23.

244 In highly endemic areas. veillance and treatment of GABHS pharyngitis.2 2 3 4 5 6 8 9 10 11 12 13 14 15 17 18 19 22 24 25 26 28 29 33 41 42 43 44 46 48 49 52 53 54 55 56 57 58 59 60 62 63 65/69 66 67 68 71 73 74 75 76 77 78 81 82 83 85 86 87 89 92 93 94 95 98 100 101 102 103 104 105 106 108 109 110 112 114 116 118 120 122 123 NT C Number of countries reporting M-type M-type Figure 10 Number of reported occurrences of each streptococcal M-type in a) developing nations. given the increased occurrence of ARF among families and monozygotic twins. personal communication).Dovepress 12 * 10 8 * * * 6 * * * * * * * * * 4 * * 2 * * 0 * * * * * * * * * 1 1.2 2 3 4 5 6 8 9 10 11 12 13 14 15 17 18 19 22 24 25 26 28 29 33 41 42 43 44 46 48 49 52 53 54 55 56 57 58 59 60 62 63 65/69 66 67 68 71 73 74 75 76 77 78 81 82 83 85 86 87 89 92 93 94 95 98 100 101 102 103 104 105 106 108 109 110 112 114 116 118 120 122 123 NT B Number of countries reporting M-type 18 * 16 14 * 12 * 10 8 * 6 * * * * * * * * * 0 * * 4 2 * * * * * * * * * * * 1 1. some providers choose to empirically treat patients in the 5. it is hard Clinical Epidemiology 2011:3 .D. is crucial to the control and prevention of ARF.to 15-year age range with fever and complaints of sore throat.245 The variability in reported HLA alleles associated with ARF and RHD could be due to genetic differences in the populations studied or differences in local streptococcal strains. Note: *denotes M-types contained in 26-valent GABHS vaccine. Given the current state of the literature.27–45. but there are still many other HLA alleles that are identified in only single studies.2 2 3 4 5 6 8 9 10 11 12 13 14 15 17 18 19 22 24 25 26 28 29 33 41 42 43 44 46 48 49 52 53 54 55 56 57 58 59 60 62 63 65/69 66 67 68 71 73 74 75 76 77 78 81 82 83 85 86 87 89 92 93 94 95 98 100 101 102 103 104 105 106 108 109 110 112 114 116 118 120 122 123 NT A Number of countries reporting Seckeler and Hoke 8 7 * 6 5 * 4 * * * 2 0 * * * 3 1 * * * * * * ** * * ** * * * * * * 1 1. With the low risk of side effects or induction of antibiotic resistance with penicillin therapy compared with the significant risk associated with ARF. even without any laboratory evidence of GABHS infection (M.dovepress. nontypeable. Abbreviation: NT. this strategy may be justified.28..S. b) developed nations. particularly through school-based programs. 78 submit your manuscript | www. and c) both combined.245 The HLA-D8/17 and HLADR7 types are the most represented in the literature among patients with ARF and RHD.com Dovepress The likelihood of genetic susceptibility to ARF is high.

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