“The chain that binds the heart to the throat…”
— Wannamaker LW
(Circulation. 1973;48:9)
INTRODUCTION
Acute rheumatic fever (ARF) is a systemic inflammatory autoimmune disease that follows throat infection with Lancefield group A beta-hemolytic streptococci [GABHS (GAS: Group A Streptococcus pyogenes)]. ARF is believed to involve the triad of a genetically susceptible individual, infection with a rheumatogenic strain of GAS, and a host immune response.
AGENT
Beta-hemolytic streptococci, according to its cell-wall polysaccharide antigen, can be divided in number of serological groups, such as Group A, B, C, G, and F. GAS, most commonly, have been related to human infection. Group C and G can cause infection and evoke an antigenic response including streptolysin-O. However, pharyngitis caused only by GAS has been linked with ARF and rheumatic heart disease (RHD). GAS can be subdivided in 130-myeloma (M) types.
Group A Streptococcus is the most common pathogen to cause bacterial pharyngitis with its peak incidence in children 5–15 years of age.1 At this age, in any episode of pharyngitis, GAS is responsible in 15–20% cases and viral pathogens in 80% cases.2 Its incidence is uncommon in children below 3 years of life and in adult population. About of 10% of sore throats in adults are due to GAS infections. GAS is droplet spread with a cross-infection rate of 19–50% within a household.
Over years, incidence of GAS pharyngitis has remained at a steady rate. Interestingly, though incidence of ARF has come down remarkably in developed country, incidence of GAS pharyngitis has not declined.3 What happened over 20 years in GAS is the emergence of more virulent type of strains and non-M types.
Usually, GAS pharyngitis may lead to rheumatic fever (RF). Occasionally GAS skin infection can lead to RF in certain population such as Aboriginal communities of central and northern Australia.4
HOST
Acute rheumatic fever is equally common in male and female population. However, RHD is more common in female, with a relative risk of 1.6–2 in comparison to male. Not all GAS pharyngitis episodes are associated with RF. Other than agent factor, host factor plays an important role. This is evidenced from the facts that certain ethnic races and individual with certain genetic marker are more susceptible to RF.4
Hereditary Susceptibility
As only 0.3–3% of individuals affected by streptococcal pharyngitis may develop ARF, host factor including a genetic factor may be the determinable factor. The genetic rule does not follow Mendelian inheritance but follows the rule of polymorphism, which occurs in genes coding for immune-related protein. The proteins include:
- Mannose-binding protein C2
- Ficolin-2
- Toll-like receptor 2
- Tumor necrosis factor
- Interleukin-1 receptor antagonist
- Transforming growth factor β1
- T-lymphocyte protein 4
A new technology, genome-wide association studies (GWAS) by which millions of variants can be tested for any association in thousands of individuals. Early reports are very hopeful and implicate not only human leukocyte antigens (HLA), but also the immunoglobulin heavy chain locus, including IGHV4-61 gene segment, on chromosome 14.
Most studies5 have shown an association of HLA with ARF. DR7 and HLA*B5 are the most common allele. In Indian context, important association is among HLA-A33, DR2, DR3, and ARF. HLA-DR4 and DR7 are important associations in Pakistan, Brazil, and Turkey. Among B-cell alloantigen, D8/17 is an important association to ARF.
There are other evidences in favor of genetic role. First, children raised separately from their parents who had RHD are more prone to ARF with a relative risk of 2.93.6 The largest meta-analysis of 175 monozygotic and 260 dizygotic twin pair, the largest meta-analysis showed that the risk of ARF in a monozygotic twin with a history of ARF in the co-twin is increased by more than six times in comparison to dizygotic twins. Thus, the estimated heritability was 60%, implicating genetic factor as playing a significant role in RF.7
Ethnic Susceptibility
Prevalence of RHD is highest in Samoa in Hawaii and reported8 to be 77.7 per 1,000 Aboriginal population, Maori in New Zealand, south central Asia, and sub-Saharan Africa have also a high prevalence rate. Crowding, hygiene practice, carrier of rheumatogenic strains, and genetic predispositions are the presumption of this ethnic susceptibility. All of these population have high rate of pyoderma, which may be another causative factor.9
Environment
Poverty and economic disadvantage are the two most important responsible factors, deciding the environmental background. Household overcrowding is the most important environmental risk factor. Rural area is more susceptible, as overcrowding is more common in poor rural community, along with poor medical service. War leading to social disruption, displacement, overcrowding, and unhygienic living condition is an important environmental factor.
Is RF abating globally: Genetic and environmental perspective factor?
CARRIER2
Isolation of GAS in upper respiratory tract indicates either true infection or a carrier state. True infection is associated with rising antibody titer, whereas carrier state is not. Thus, beta-hemolytic streptococci carrier is defined as isolation of GAS without rising titer of antistreptococcal antibodies. Its rate is 10–50% in asymptomatic schoolchildren. In temperate countries, 50–60% of carriers harbor GAS, whereas in tropical countries, 60–70% harbor group C and G streptococci. Though carriers harbor organisms, they do not develop ARF or spread infection.10 About of 25% of patients with GAS pharyngitis remain culture-positive even after optimum antibiotic therapy. They are GAS carriers. The Infectious Disease Society of America (IDSA) does not recommend routine eradication of GAS carrier because of low risk of spreading infection.11 However, in area where RHD is of highly prevalent, routine eradication of GAS carrier has been advised.12 In certain situations, committee on infectious disease13 recommends eradication of GAS carrier (Box 1).
There are several treatment options including clindamycin, amoxicillin, and intramuscular penicillin plus 4 days of rifampicin. Therapy of choice is a 10-day course of clindamycin.135
EPIDEMIOLOGY
India14
India contributes to 25–50% of the global burden of newly diagnosed case, deaths, and hospitalization from RHD.15,16 Historically, one of the early reports of ARF and RHD in India was from Kolkata. Basu reported, in 1925, the incidence of rheumatic carditis 8.5% in his series of 446 patients of acquired heart disease.17
Incidence and prevalence of ARF and RHD in India can be assessed from hospital admission data (Table 1), population-based studies and school survey. In 1941, Kutumbiah from Chennai reported 39% of hospital admission as RHD.18 In 1965, it was reported as 44.6% from Bengal.19
Population-based surveys (Table 2) are a very few one. In earlier survey, prevalence range of RHD was 1.23/1,00020 to 2.2/1,00021 in rural and urban area of India. In a recent Indian Council of Medical Research (ICMR) survey, prevalence of ARF has been found as low as 0.0007–0.2/1,000 and that of RHD as 0.2–1.1/1,000.22
School survey (Table 3) in Gujarat,23 in 1986, showed prevalence of RHD 2.03/1,000, whereas, in 2006, in Rajasthan24 it was 0.67/1,000. The largest serial school survey was done by ICMR between 1972 and 1975, 1984 and 1987, and 2007 and 2010. Prevalence of RHD in-between 1972 and 1975 in 133,000 was 5.3/1,000, in-between 1984 and 1987 in 53,786 children was 2.9/1,000, and in-between 2007 and 2010 in 176,904 was 0.9/1,000.22 Thus, the prevalence of RHD in school children came down from 5.3/1,000 to 0.9/1,000 from 1970 to 2010.
Many of the school survey done in the first decade on this century included echocardiography to confirm the clinically suspected RHD. Then came up the studies, which surveyed to detect RHD by echocardiography. In consequence, prevalence was shot up. In one of the latest echo Doppler study25 by Nair et al. in 5–15 years-old 2016 schoolchildren in Kerala, using the World Heart Federation (WHF) criteria for RHD, the prevalence of RHD was found as 5.83/1,000.
|
In the latest rheumatic study by Saxena et al.,26 school survey was done in Ballabhgarh, South Gujarat, Manipur, and Goa. The same WHF echocardiographic criteria were followed in 16,294 school-going children between 5 and 15 years of age. They found “clinical” RHD with a prevalence of 0.36/1,000, whereas “echocardiographic” RHD with a prevalence of 7.7/1,000.
Acute Rheumatic Fever and Rheumatic Heart Disease: Really Declining in India?
All the above data indicate a downward trend of both incidence as well as prevalence of ARF and RHD in India. How certain scientifically is this conclusion?
A survey from Orissa showed that hospital admission of ARF/RHD remained same over a 20-years period, 45% of total cardiac cases even during 1991–2000.27 From an institution in Mumbai, autopsy data showed similar incidence of ARF/RHD as on 2002 and 25 years back.28 In a paper from the premier institution such as All India Institute of Medical Sciences (AIIMS), in 2009, the most common cause of heart failure admission was due to RHD.29 With a median incidence of 0.5/1,000, 131,000 children are affected by ARF every year. In consequence, around 44,000 children with RHD are added every year to RHD burden. Considering the lowest and highest prevalence rate of RHD, total cases suffering from RHD in India could be between 0.44 and 3.37 million.306
|
This has nicely been narrated in a review article by Kumar RK et al.,31—“Statistics from one region would most certainly not apply to the country as a whole. Sharp differences are likely to result from extreme variations in geography, living standards, economy, human-development indices, urbanization, and health infrastructure. Given the undeniable relationship between incidence of RF and living standard, it is particularly difficult to make generalizations for ARF and RHD using data collected from various parts of India scattered over the last five decades”.
Global Data
Global incidence and prevalence of ARF and RHD is variable. In industrialized country, it started showing lowering trend since early 60. Incidence of RF is now below 0.1/10,000, 0.7/1,000 in French Polynesia, 1/1,000 in Sudan, 1.5/1,000 in China.32 Prevalence of RHD is 0.2/1,000. Excluding industrialized countries, global burden of RHD is 0.8–5.7/10,000 in schoolchildren.33
Burden
From 1994 World Health Organization (WHO) data, global burden of RHD and ARF was 12 million individuals worldwide; 3 million had heart failure requiring hospitalization. Annual deaths from RHD in year 2000 were 332,000 worldwide.34 Disability-adjusted life years lost to RHD was 6.6 million worldwide. In another series from 1982 through 2002, 15.6 million people had RHD worldwide with 2,282,000 new cases each year and 233,000 resultant deaths each year.35 In a recent observation, there are around 33 million people with RHD globally with nearly 275,000 deaths every year.36
Epidemiological Trend: Is Rheumatic Fever Abating Globally?
Overall trend shows a downward trend of incidence and prevalence of ARF/RHD in developing countries, even after considering the higher detection of silent carditis/RHD by including echocardiogram in diagnostic tool. This trend mostly has been explained as socio-economic changes. However, Kaplan37 was a strong proponent of changing profile of virulence of GAS strain responsible for the variable trend.
The GAS strain, responsible for outbreak of ARF in early to mid-part of last century, was virulent mucoid strain, rich in M protein—same strain was found in the rheumatic outbreak in the United States as discussed below. Those strains are different from the strain now found in tropical country. Penicillin treatment and prophylaxis may have induced a genetic change of GAS strains over decades. There has been also a change in the host genome. Those who were susceptible to ARF epidemic in industrial countries in mid-part of last century have either died or were physically unable to bear offspring. Consequently, genetically most susceptible population may have been 7extinguished. Thus, the factors responsible for abatement of global ARF are:
- Loss of GAS strain virulence
- Change in host's genome
- Less exposure to GAS due to improved environmental factor.
Resurgence of Acute Rheumatic Fever in the United States of America (Fig. 1)
As mentioned earlier, from 1985 to 1992, 250 new cases of ARF were reported in Utah and another 15 cases were seen at Primary Children's Hospital in Salt Lake City between January and November, 1992. This was not an epidemic artifact. During the same period, number of ARF was 5–12 times more than expected in 24 cities in the United States of America.38 The outbreak that occurred in middle-class family with easy access to medical care could not be explained only by socio-economic factors. What found interesting was a more mucoid GAS strain with M-18 type protein associated with ARF and M-1 type associated with toxic-shock syndrome and sepsis. Those two virulent strains were not common in prior decades.
Ethnic Burden
As mentioned earlier, in specific ethnic groups, the disease burden for ARF/RHD is enormous, even rising. In New Zealand, the rate of ARF was almost doubled between 2005 and 2010.39 From 0.19/10,000, it became 0.38/10,000. Mostly, they are occurring in the northern and central North Island. Rate is actually decreasing in New Zealand Europeans, whereas it is 23 times more likely in Maori and 50 times more likely in Pacific peoples than in other ethnic groups.
Prevalence of RHD was mentioned earlier in Samoa as 77.7/1,000, which was based on a school survey on auscultation of murmur by Steer. In subsequent study,40 heart murmur prevalence was 18/1,000 and confirmed RHD on echocardiogram was 3/1,000. Annual incidence of RHD as per registry is 0.66/1,000 and as per echo registry, prevalence is 3/1,000.
PATHOGENESIS OF RHEUMATIC FEVER
Why only a few with GAS pharyngitis will develop ARF? Is it an interaction between rheumatogenicity of the strain, genetic factor of the host, and conductive environment? Pathogenesis lies in the answers. May be the answer is not so simple.
What is a rheumatogenic strain? It must be an M serotype of GAS, which is heavily encapsulated, rich in M protein and is capable of forming large mucoid colonies. Those properties help the specific strains to adhere to host tissue and to fight destruction by host defense system. In most of the RF outbreak, limited number of M proteins was isolated, namely M-5, M-6, and M-18. May be those specific M proteins only have the antigenic mimicry to human tissue protein and, thus, the strains bearing those proteins are the rheumatogenic strains.
However, due to lack of animal model and nearly 130 types of M proteins, no specific rheumatogenic factor, so far, has been identified incontrovertibly. Antigenic mimicry has been questioned on the issue of predominant mitral valve involvement in rheumatic carditis, though all the four valves originate from the same embryonic cell rest. EL Kaplan raised another issue in an editorial,15 “conceptually it has never been explained how five individual humans infected with the same—possibly pathogenetic—strain of group A streptococci respond differently to the antigenic challenge, unless unique host factors are also considered? One of the five might have valvar involvement (carditis), another only arthritis (joints), a third chorea (central nervous system involvement), a fourth erythema marginatum (skin), and the fifth individual does not develop any sequelae? What other interpretation is logical?”8
Looking back in 1924, Home F Swift described the pathological findings in rheumatic carditis,41 “It is a moot point whether the destruction of the endothelium is primary or subsequent to an injury to the underlying tissue. Of this, however, we are certain that characteristic lesions occur in the mural subendocardial region without primary injury to the endothelium and, also, are found in the base of the valve leaflets. It is not difficult to conceive, therefore, of the primary injury of the valves occurring in their substance rather than on their surface; and if this is true it would be better to consider rheumatic disease of these structures as a valvulitis rather than a simple endocarditis”.
In a simple way, M protein of rheumatogenic GAS strain has mimicry to human tissue including valve and myocardium (Fig. 2). Molecular mimicry is defined as sharing of epitopes between antigen of the host and streptococcal strain. Autoreactive antibodies, which initiate the autoimmune process, are formed against streptococcal as well as host tissue. Then, a two-staged reaction42 occurs.
In the first stage (Fig. 3), in a genetically predisposed host, endothelium of valve leaflets is inflamed and damaged by that autoantibody of the rheumatogenic strains, which can identify epitopes in laminin of the valvular endothelium as well as myosin. This process leads to upregulation of vascular cell adhesion molecule-I (VCAM-I), which promotes the second stage, CD4+ and CD8+ T-cell infiltration and adhesion. Those M protein specific T cells produce inflammatory cytokines [γ-interferon (IFN)], which lead to destruction, scarring, and neovascularization of the valve tissue.
A new concept43 has been given over the time old concept of autoimmune therapy (Fig. 4). Streptoccal M protein N-terminus domain uses to bind to the CB3 region in the collagen type IV of the subendothelial and perivascular connective tissue matrix. This binding initiates antibody response to collagen, resulting in inflammation. All the organs containing collagen matrix and endothelial cells enveloping them are affected during RF. The characteristic of heart valve is its two layers of endothelial tissue with minimal tissues in between. In consequence heart valves heal with scarring, whereas other organs heal without any residual damage. Thus, this is not a reaction due to failure of immune system and there is no molecular mimicry in the pathogenesis.
CLINICAL CRITERIA
One should not overdiagnose ARF. But, more importantly, not a single patient of RF should be missed. Thus, beyond all the criteria, one should apply his clinical judgment. This is for two reasons. Firstly in 31–78% of cases, depending on economic status, there is no history suggestive of ARF and secondly, in around 16.8% (pooled prevalence) cases, there may be subclinical carditis.
Jones Original Criteria
T Ducket Jones, in 1948, proposed the criteria to diagnose ARF,44 in a very unceremonious way in the journal of American Medical Association only with 11 references! And those criteria became the most quoted criteria in cardiac science. Over next six decades, several modifications by American Heart Association (AHA) and WHO have been done (Box 2 and Table 4). None of those modifications were evidence-based, rather than consensus-based. In his original criteria, Jones kept erythema marginatum in minor criteria, whereas pre-existing ARF/RHD was a major criterion. He did not include evidence of recent streptococcal infection as criteria.
American Heart Association Revision
American Heart Association made the first revision of Jones criteria in 1956, followed by 1965 and 1992.
World Health Organization Revision
Last modification (Box 3) in 2003 by WHO46 did not change much from its preceding AHA update excepting that it included pre-existing ARF/RHD as special consideration instead of minor criteria and scarlet fever as evidence of previous streptococcal infection.
According to these criteria, new onset of ARF may be diagnosed by presence of two major or one major and two minor manifestations along with evidence of preceding streptococcal infection. Recurrent attack of RF in person without preceding ARF/RHD may be diagnosed by presence of similar criteria as above, whereas in presence of past ARF/RHD, recurrence may be established by the presence of two minor manifestations along with evidence of preceding streptococcal infection. Rheumatic chorea or insidious onset carditis does not require any other major manifestation or evidence of preceding streptococcal infection to diagnose ARF.10
|
2012 Australian Guidelines
Subsequently came Australian (Table 5) and New Zealand guidelines, which made some important inclusions. Subclinical carditis, monoarthritis, and polyarthralgia have been included as major criteria. Fever has been defined as temperature >38°C. Increased erythrocyte sedimentation rate (ESR) has been defined as ESR >30–50 mm/h, whereas increased C-reactive protein (CRP) has been defined as CRP >30 mg/L.
High risk: High-risk groups are those living in communities with high rates of ARF (incidence >30/100,000 per year in 5–14 years old) or RHD (all-age prevalence >2/1,000). Aboriginal people and Torres Strait Islanders living in rural or remote settings are known to be at high-risk.11
|
Latest Revision: 2015 American Heart Association Guideline
Last revision by AHA (Box 4) came out in 2015. There are four major revisions:
- The proposed criteria are determined by pretest probability and background disease prevalence in the population to avoid overdiagnosis of ARF in low-risk population and underdiagnosis in high-risk population.
- This was first time, when echocardiographic carditis was included in major criteria.
- Preceding GAS infection is considered as essential criteria.
- “Possible” RF has been introduced. Jones criteria may not be fulfilled in those areas where RF is common, but laboratory facility is not available. A diagnosis of “possible” RF is made and patient is put on secondary prophylaxis. Patient is re-evaluated at 1 year by history, clinical examination, and echocardiography.
To diagnose ARF, there must be two major criteria and one minor criterion or one major and two minor criteria, in the presence of preceding GAS infection.
To diagnose recurrent RF, there must be two major criteria and one minor criterion or one major and two minor criteria or three minor criteria in the presence of preceding GAS infection.
Why so many modifications of Jones criteria?
All the modifications were made to increase the sensitivity and specificity to diagnose ARF.
First modification, in 1956, was to make objective arthritis as major criteria and arthralgia as minor criteria. History of previous ARF/RHD was changed to minor criteria. Thus, in recurrence, documentation of major criteria was made essential. Erythema marginatum was considered as major criteria. Documentation of preceding GAS infection was included in minor criteria.12
In 1965, next revision, evidence of preceding GAS infection was included as essential criteria.
What happened on those modifications? Specificity increased at the cost of sensitivity. At least 25% of ARF diagnosed on 1956 criteria could not be diagnosed on 1965 revision.
In 1984 modification, antecedent GAS infection criteria were no more essential to diagnose RF with late manifestations. Further modification included diagnosis of recurrence, which included findings of pericarditis or obvious change in cardiac findings.
However, pericardial involvement being not common and new changes in cardiac findings being difficult to assess, in 1992 update, past history of ARF/RHD was excluded from criteria. The implication was that Jones criteria would be applicable only for new onset of ARF and not for the diagnosis of recurrence of ARF, as intended by original Jones criteria.
In 2003, in WHO criteria, two minor criteria with evidence of antecedent GAS infection were included as diagnostic criteria for recurrent RF in patients with past history of RHD.
Polyarthralgia and echocardiogram48 have been included as major criteria in high-risk population in preceding and latest 2012 Australian guidelines. In the latest 2015 AHA revision, echocardiography and polyarthralgia were included in major criteria in low-risk population.
RHEUMATIC CARDITIS
Rheumatic carditis is essentially a pancarditis, involving endocardium, myocardium, and pericardium. But to diagnose carditis (Box 5), endocardial involvement, i.e., murmur is essential.
Carditis occurs within 2 weeks of onset of RF in 80% cases. Rule of thumb is severe with the arthritis, lesser the carditis and vice versa. The most common major manifestation during the first episode of ARF is carditis.
Recurrent carditis in presence of pre-existing RHD is difficult to establish. New onset/changing murmur and pericardial rub may be found occasionally. Cardiomegaly may be due to pre-existing cardiac lesion and congestive heart failure (CHF) may be due to progressive deterioration of the pre-existing lesions.
Mitral Valvulitis
Endocarditis or valvulitis is the most important prognostic determinant in rheumatic carditis and murmur is its hallmark. Mitral valve involvement is the most common in rheumatic carditis. There is no known explanation to this fact.
Leaflets, annulus, and chordate are all involved in the process. Mild-to-moderate mitral regurgitation (MR) is common rather than severe MR. If recurrence can be prevented, mild and occasionally moderate MR may be resolved49 over time. Severe MR is responsible for heart failure, progressive, and commonly due to flail leaflet. There may be macroscopic verrucous vegetation on valve apparatus appearing as nodules. Otherwise, leaflets remain remarkably normal in rheumatic valvulitis. Posterior annulus involvement is the most contributory factor to MR. It leads to (posterior) annular dysfunction, lesser movement of posterior mitral leaflet (PML) and anterior mitral leaflet (AML) (pseudo) prolapse. In one series, AML prolapse was found in 90% cases, with average posterior annulus diameter as 37 mm compared with matched control diameter as 23 mm.16 As prolapse is the major mechanism (Box 6), MR murmur in rheumatic carditis may be mid or late systolic, rather than pansystolic.50
Carey Coombs murmur: In the acute stage of acute rheumatic mitral valvulitis there may be a transient and short mid-diastolic murmur. It is presumably due to edema of the leaflets or a functional murmur in presence of severe MR. Dr Carey Coombs, in 1924, described this murmur.
Aortic valvulitis: Aortic annulus is involved by rheumatic process, leading to annular dilatation, dysfunction, and leaflet malcoaptation leading to mild-to-moderate aortic regurgitation (AR). Occasionally, aortic valve may show gross prolapse with severe AR.
Frequency of different valve involvement is different in different series (Table 6).
Pal Wood52 provided a pathophysiological postulation for this order of frequency of valve involvement. Mitral valve is subject to the highest pressure, a systolic pressure of around 120 mm Hg. Aortic valve withstands aortic diastolic pressure, which is around 80 mm Hg. Tricuspid valve is exposed to right ventricular systolic pressure, which is around 15–20 mm Hg, whereas pulmonary valve is subject to pulmonary diastolic pressure of around 8–10 mm Hg. This explains rheumatic aortic valve involvement without mitral valve involvement is uncommon, whereas isolated tricuspid valve involvement without mitral or aortic valve involvement is not reported.
|
Incidence of clinical cardiac involvement in ARF has been reported in 50–70% in various studies.53 In prospective studies, incidence has been reported as high as 50%.54 In the resurgence of ARF in the United States in ’80s, the Utah series showed clinical carditis in 72% of children, whereas echocardiographic carditis was found in 91% of cases.55
- Subclinical carditis: When clinical examination is normal but echocardiogram is abnormal.
- Indolent carditis: It is a common entity in developing country. Patient presents with persistent features of heart failure, murmur, and cardiomegaly. There is no other manifestation of ARF.
- Smoldering carditis: Chronic subclinical rheumatic activity which may be responsible for very early stenotic lesions in developing country.
- Heart failure in first attack: 5–10% cases.
Myocarditis
Incidence of myocarditis is difficult to decide in ARF. Time-old concept that myocardial involvement (Box 7) being responsible for heart failure and significant cardiomegaly has not been established. Rather, it has been shown in several studies56–58 that myocardial involvement is unlikely to cause heart failure.
Pericarditis
Pericarditis in rheumatic carditis may be detected clinically in 6–25% cases. It never happens without valvulitis. Its association indicates severe carditis. It may be transient and missed easily. Pericardial fluid may be hemorrhagic. Spontaneous remission is the norms. Tamponade or constriction is rare.14
RHEUMATIC ARTHRITIS
Rheumatic arthritis (Table 7) occurs in around 35–66% of patients with first episode of ARF. This is the most common, earliest, and sometimes the only major manifestation of RF. More the age, more common and severe is the arthritis, whereas lesser the age, more common is carditis.
Classically, arthritis is migratory, involving most commonly knee and ankle joints, whereas axial joints are rarely affected. Involved joints show all the features of inflammation such as redness, swelling, and tenderness. Excruciating tenderness is essentially the hallmark of rheumatic arthritis. Another characteristic feature is arthritis being exquisitely responsive to nonsteroidal anti-inflammatory drugs (NSAIDs), more specifically to aspirin. Inflammation of an affected joint is usually resolved within 2 weeks and arthritis as a major manifestation is resolved without any residual by 1 month, even without treatment.
|
Jaccoud's Arthritis
Jaccoud,60 in 1869, first described residual deformities following rheumatic arthritis. Subsequently, Bywaters61 described the following criteria for Jaccoud's arthritis.
- History of severe RF with repeated and prolonged attack.
- Recovery delayed and associated with stiffness in metacarpophalangeal joints, which later results in the appearance of joint deformity.
- Deformity appears to be due to periarticular fascial and tendon fibrosis rather than to synovitis.
- The deformity consists of flexon at the metacarpophalangeal joints with some associated periarticular soft tissue swelling and ulnar deviation most marked in the fifth finger.
- Associated hyperextension at the proximal interphalangeal joints.
- Joint disease is usually inactive with little or no symptoms and good functional capacity.
- Radiologically, the earliest bone changes are erosion of the metacarpal head on the palmar and radial part of their circumference in an anteroposterior projection producing a hoof-like erosion.
Monoarthritis
Monoarthritis is not very uncommon in high-risk group. Septic arthritis must be excluded in this sort of presentation. In an Australian national study, monoarthritis was found in 19% of high-risk children and account for 24% of all joint manifestation 15with ARF in 2 years prospective study. Monoarthritis has been included in major criteria in high-risk children in Australian guideline62 and in moderate-to-high-risk population in 2015 AHA guideline. Its incidence is more frequent when NSAID has been started earlier in the disease process.
Polyarthralgia
Polyarthralgia more specifically migratory polyarthralgia is not uncommonly seen as the major joint manifestation in ARF, particularly in developing country. Thus, it has been included in major criteria in high-risk patient in Australian, New Zealand, and latest AHA guideline. Polyarthralgia is more common in ARF recurrence.
There is an inverse relation between severity of arthritis and carditis. In one study, severe carditis was found in 10% cases with classical arthritis, 33% cases with arthralgia, and 50% without any joint involvement.63
Poststreptococcal Reactive Arthritis
Arthritis may be a reactive phenomenon following streptococcal pharyngitis, called “poststreptococcal reactive arthritis (PSRA)”. Potential relationship of PSRA to ARF remains unresolved (Table 8). Features of PSRA include the development of arthritis 3–14 days after streptococcal pharyngitis; fever and a scarlatiniform rash are often present during the acute phase of pharyngitis but are absent by the time arthritis appears. Typically, these patients have prolonged symptoms and protracted arthritis, without any other major manifestation for ARF. Extra-articular manifestations such as tenosynovitis and renal abnormalities are more common.
|
Some of these patients fulfill the Jones criteria and should be diagnosed as having ARF. For those who do not fulfill the Jones criteria, the diagnosis of PSRA should be made only after other rheumatologic diagnoses [e.g., Lyme arthritis and rheumatoid arthritis (RA)] have been carefully excluded.
Close follow up, because some of those patients may develop RHD.64 Penicillin prophylaxis is recommended by AHA for 1 year and then discontinued, if found no carditis. If found any carditis, prophylaxis should be continued as ARF with carditis.65
CHOREA (CHOREA MINOR OR SAINT VITUS’ DANCE)
Chorea, popularly called Sydenham's chorea, is a late neurological manifestation of ARF. It is an uncommon major manifestation, more common in female and rare beyond the age of 21 years, reported in a wider range from 5 to 36% cases.66 Manifestation is in the form of sudden, pseudopurposive, repetitive involuntary movements along with muscular weakness, and emotional disturbances. Latent period between GAS infection and chorea is around 1–7 months. Thus, it is not associated with concomitant arthritis. Associated carditis or its sequel may be the only evidence in favor of RF.
Median duration of its natural course is around 4 months, ranging from 1 week to 2 years. Convulsive disorders, behavioral problems, learning disorders, and psychotic problems are the long-term sequel of rheumatic chorea. Recurrence, even on penicillin prophylaxis, has been reported.
Chorea is often preceded and followed by behavioral abnormalities, simulating obsessive-compulsive disorder (OCD). Recently, a strong association between D8/17B cell marker, preceding streptococcal infection and children suffering from OCD has been found.67 The theory has been proposed that GAS induces antibrain antibody, which functionally disrupts the basal ganglia pathways, leads to chorea and abnormal behavioral disorder.16
SUBCUTANEOUS NODULE
Reported incidence is variable (0–10%); may be up to 20% cases.55 They are painless, firm, and freely mobile, 0.5–1.5 cm. Site of occurrence is over bony prominence and extensor tendon, such as elbow (the most common), wrist, ankles, Achilles tendon, occiput, and spinal process of vertebrae. They appear in corpses, average 2–3 in number, and persist average for 2 weeks. They are usually associated with severe carditis and appear when carditis has already set in. Similar nodules also appear in RA and systemic lupus erythematosus (SLE). However, in ARF, nodules are smaller and shorter-lived than in RA. In both situations, they appear on elbow, but in ARF they are on olecranon, whereas in RA, they are 3–4 cm distal to it.
ERYTHEMA MARGINATUM (ERYTHEMA ANULARE)
Erythema marginatum is the uncommon major manifestation of ARF, particularly in dark-skinned persons. Incidence may be 4–15% in various series. As the rash may appear in early part of the disease and is evanescent in nature, it may be missed. A hot bath or shower may make them prominent. They appear on trunk and proximal limbs, uncommon on distal limbs, and never on face. Lesions are pink or red, nonpruritic, not raised from skin, and blanching in nature. They extend centrifugally with central clearing. Lesions may appear late in the disease process, during convalescence, even months after remission. They are usually associated with carditis.
MINOR MANIFESTATIONS
Fever
Fever is the most consistent minor manifestation of ARF. Australian and New Zealand guideline, fever has been defined at or >38°C. In 2015 AHA guideline, fever should be ≥38°C in moderate—and high-risk population and ≥38.5°C in low-risk population. Temperature uses to persist 1–2 weeks and not more than a month.
Epistaxis
Epistaxis is reported less and less in number. In and old series, its incidence was reported as high as 48%.55 Epistaxis was thought to be related to severe carditis. It may be a simple effect of high-dose aspirin.
Abdominal Pain
Abdominal pain may be the presenting feature in some children. As it may happen before other manifestation of ARF, pain abdomen may mimic mesenteric vasculitis or acute appendicitis.
Acute Phase Reactants
Acute phase reactants, including ESR (≥60 mm in the 1st hour) and CRP (≥30 mg/L), are the two most important markers to assess disease activity. They decide how long patient should be on rest and anti-inflammatory treatment should be continued.
EVIDENCE OF RECENT STREPTOCOCCAL PHARYNGITIS
In initial guidelines, evidence of recent streptococcal infection was an essential criterion. Subsequently, it is considered as supporting evidence, because ARF may have a late presentation with chorea or smoldering carditis, which can be diagnosed as ARF without evidence of recent streptococcal infection. In 2015 AHA guideline, it was again fixed as essential criteria.
As per AHA 2015 guideline preceding GAS infection is evidenced by any one of the following:
- Throat swab culture, positive only in 11% of patients at diagnosis of ARF.
- Rising titer of antistreptococcal antibody, either antistreptolysin O (ASO) or antideoxyribonuclease B (anti-DNase B).
- Positive rapid group A streptococcal carbohydrate antigen test
Isolation of Group A Streptococci: Throat Culture
- Throat culture should be done in all suspected patients of ARF before starting antibiotics.
- Swab should be taken vigorously from tonsillar and pharyngeal area and culture should be looked at least for 48 hours.
- When properly done, a single culture on a blood agar plate has a 90–95% sensitivity to detect GAS pharyngitis.68
Detection of Streptococcal Antigen
- Rapid antigen detection test (RADT) kit can be used to detect carbohydrate cell-wall antigen to GAS from throat swab materials.
- A positive test bears a high specificity, nearing 85–100%, but a low sensitivity, nearing 31–95%.
- Thus, a positive test ensures the presence of GAS, but a negative test needs a confirmation by doing a throat culture, specifically in children. In adult, a negative RADT can exclude the presence of GAS.
- However, a positive RADT does not differentiate carrier state from infection.
Detection of Streptococcal Antibody69
Antistreptolysin-O antibody test and anti-DNase B test are commonly recommended. Antihyarulonidase test is no more done. Streptozyme test, a slide agglutination test for the detection of antibodies to several streptococcal antigens, is not standardized and is not recommended.
Upper limit of normal value (Table 9) defined as level not >20% of the population is variable, depending upon age and population in a region. In endemic area, ASO level may be up to 250 Todd units and in nonendemic area, level can be even 50 Todd units.
A single increased level of their titer indicates antecedent streptococcal infection. However, a rising titer at 3–4 weeks is more convincing. ASO begins to rise 1 week and peaks 3–6 weeks, remains detectable at a plateau level up to 3–6 months after infection, becomes undetectable in the next 6–12 months, whereas anti-DNAse begins to rise at 1–2 weeks and peak 6–8 weeks after GAS infection. This antibody titer remains high for 2–3 months and start declining up to 5–6 months. Anti-DNase level is not affected by liver disease or bacterial contamination, unlikely of ASO titer. It is falsely elevated in hemorrhagic pancreatitis. Some detectable ASO titer may be found in healthy population from previous minor GABHS infection.
|
Antibiotics or steroids may affect this level.70 Most patient with chorea and 20% patients with 1st episode of ARF may have low titer of anti-streptococcal antibody. ASO level is determined first and, if found normal, anti-DNase level is tested. When combined, specificity is raised to 90%69 and sensitivity is near 100%.
Other Evidences
During active stage, patients with ARF express abnormal level of D8/17+ B cells, almost in all cases. This monoclonal antibody test can be used for diagnosis of ARF in doubtful case.71
ROLE OF ECHOCARDIOGRAPHY IN RHEUMATIC FEVER
Vide Chapter 50.
NATURAL HISTORY AND PROGNOSIS OF RHEUMATIC CARDITIS
First Episode
Active rheumatic process uses to persist around 6–8 weeks. The activity is decided by the symptoms of manifestations and acute phase reactants. No more mentioned, still useful is the pulse rate of the patient. There is a disproportionate tachycardia during disease activity. Few manifestations may manifest, even after cessation of rheumatic activity. They are rheumatic chorea and erythema marginatum and obviously carditis, indolent, or smoldering.
Severity of valvulitis on first episode determines the prognosis of that single episode. Mild-to-moderate MR can be resolved over time. Moderate-to-severe MR progressively deteriorates. Aortic valve lesion on presentation is usually mild-to-moderate. What cannot be predicted on first attack is the stenotic lesion. As a late squeal, its development appears inevitable in susceptible population. Mitral stenosis (MS) to develop after the initial episode takes 1–2 years to two decades. In developing country, MS develops quickly. There are several theories. One is subclinical recurrence. Another is smoldering carditis.18
But the most reasonable is Selzar and Cohn theory,72 in which they stated: “Considering an alternate explanation for progression of MS beyond its early stages, the most attractive hypothesis is to abandon the postulate of continuing rheumatic activity and to accept a theory that the initial rheumatic valvulitis and its early scarring consequences produce changes upon the valve that are capable later of perpetuating themselves in a nonspecific manner. ...One should thus visualize the rheumatic process as one responsible for the early changes upon the leaflets leading eventually to their fusion. Such fusion, producing the commissural type of MS, may cause only minimal trauma or none at all, because the normal atrioventricular filing pathway may not be affected. In such cases, mild MS may persist for life. Slight alteration of flow pattern producing minimal trauma to the valve may be analogous to a bicuspid aortic valve, i.e., produce progressive valve changes over a period of many decades. More severe involvement of the commissures and the involvement of the cusps and chordae by the early rheumatic process would alter flow patterns through the mitral orifice to a degree that progressive valvular deformity would ensue earlier in life”.
Recurrence
Recurrence is probably most important prognostic factor. It increases cardiovascular mortality and residual heart disease. Recurrence is the responsible factor for the aggressive nature of the disease in tropics. RF recurrence rate can be divided in two components: The rate of GAS infection per patient-year and the rate of rheumatic recurrence per streptococcal infection, the primary and secondary attack rate respectively. In a sporadic GAS pharyngitis, primary attack rate is 0.3%, whereas in epidemic GAS pharyngitis, primary attack rate is 3%. In patients with recent history of ARF, GAS pharyngitis may cause secondary attack rate as high as 65%.73 Secondary attack rate (Table 10) uses to come down from 23 to 11% between 1st and 5th year after the last attack.74
Among all patients with GAS infection with a previous history of ARF, recurrence rate is 16.5%.75
Chance of recurrence is high in the 1st year of the first attack and then decreases over years. This is explained by the fact that as children grow older, they are less prone to GAS infection. Another reason is that there is a reducing tendency of GAS infection to elicit ARF. In the 1st year, the secondary attack rate is 50%, whereas after 5 years of first attack, attack rate is only 10%. The risk becomes minimum after the age of 35–40 years of age.
|
To enumerate factors responsible for recurrence of RF:75
- Symptomatic GAS infection
- Young age
- Short interval since preceding rheumatic attack
- Number of previous attacks
- Existing RHD
- Prophylaxis by oral penicillin only
In contrast to popular belief, following factors are not responsible for recurrence:75
- High ASO titer
- Overcrowding, family welfare status
- Rheumatic fever in sibling
- Ethnic group
As mentioned earlier, recurrence can be diagnosed by WHO criteria: Two minor criteria with evidence of antecedent GAS infection with a history of RHD. As per AHA 2015 guideline, recurrent ARF requires two major, one major and two minor or three minor criteria, along with evidence of preceding GAS infection. Recurrent carditis upon existing RHD may be difficult to diagnose. In a known patient of RHD, new onset heart failure, appearance of new or changing murmur or pericardial rub are suggestive.
Related Terminology
Recurrence: A new episode of ARF following another GABHS infection; occurring after 8 weeks following stopping treatment.19
Rebound: Manifestations of ARF occurring within 4–6 weeks of stopping treatment or while tapering drugs.
Relapse: Worsening of ARF while under treatment and often with carditis.
UK/US Cooperative Trial70
This very old trial is excellent for information on follow-up and prognosis. This was a 10-year follow-up study of ARF. In the study, 94% of patients who had not any carditis at presentation did not show cardiac disease at 10 years of follow-up. Those who had grade 1 apical systolic murmur at presentation, only 30% showed significant valvular lesions at the end of 10 years, whereas those who presented with grade 2–3 apical systolic murmur, only 36% showed valvular lesions. In cases with pre-existing heart disease, the prognosis was poor. 60% of those initially without CHF and 89% of those with CHF were with significant valvular lesions at 10 years.
Disadvantaged Population
Prognosis is poor in certain population, who are very susceptible to ARF, as mentioned earlier. In a 13 years follow-up study in the indigenous Australian and Northern Territory, after the first RF diagnosis, 61% developed RHD within 10 years. After RHD diagnosis, 27% developed heart failure within 5 years. The relative survival rate was 88.4% with standardized mortality ratio 1.56.76
MANAGEMENT OF RHEUMATIC FEVER
Hospital Admission
All patients with RF preferably should be admitted in the hospital for diagnosis, management, and counseling for secondary prophylaxis plan.
Rest
Duration of ARF is around 10–12 weeks. Bed-chair rest is advised in the initial phase. Patient without carditis may be allowed to be ambulatory,2 once symptoms of arthritis get subsided and acute phase reactants are returning to normal. For patients with carditis, minimum 4-week rest77 is advised. For patients with heart failure, rest is advised for a longer period. Duration of rest and ambulation should be decided by physician as individual case basis.
Eradication of Group A Streptococci (Vide Primary Prevention)
Before starting antibiotic therapy, two throat swab cultures should be sent. But full course of therapy has to be given to everyone, once diagnosis of ARF is done irrespective of culture report. Antibiotic treatment reduces the infectivity and chance of relapse. However, it does not alter the disease course.
Anti-inflammatory
Aspirin (salicylates) is the first line of therapy. It is given in the dose of 100 mg/kg/day in 3–4 divided doses and can be increased to 125 mg/kg in children or 6–8 g/day in adult.78 Blood level of salicylate may be determined for a safer therapeutic window. Optimum level is 20–30 mg/dL. After 2 weeks, doses may be reduced to 60–70 mg/kg and be continued for 3–6 weeks.77
Nonsteroidal anti-inflammatory drug is not evidence-based. However, in aspirin-intolerant patient, naproxen in the dose of 10–20 mg/kg/day can be used.79
Steroid can be used when patient is unresponsive to aspirin or deteriorating on aspirin or is developing heart failure.2 Steroid may help to reduce pericarditis and toxic state faster. Apical systolic murmur may disappear earlier. Steroids neither have any mortality benefit nor any effect on course of the disease, but it may be life-saving in carditis with heart failure.80 Meta-analysis of several small studies, however, did not show any difference in the risk of cardiac disease at the end of 1 year.81 There had been no study in postecho era with modern corticosteroids.82 Prednisolone is used in the dose of 1–2 mg/kg/day. Dose tapering is started after 2 weeks, 20–25% each week and continued another 2 weeks.65–77 In the last week, aspirin is started in its full therapeutic dose to prevent rebound.2
Methylprednisolone has been used as pulse therapy in severe rheumatic carditis in the dose of 1 g/day, three consecutive days in the 1st and 2nd weeks, 2 days in the 3rd week and 1 day in the 4th week.83 However, pulse therapy did not show any better result than prednisolone therapy.8420
Duration of therapy is not well-defined. To prevent rebound, prolonged anti-inflammatory has been suggested even up to 3 months.14 Duration should be guided by disappearance of symptoms and signs and acute phase reactants, rather than any fixed duration. Acute phase reactants may be checked in every week.14 In occasional cases, rheumatic activity may linger for a longer time, even 6 months. In those cases, anti-inflammatory drugs will have to be continued for longer time.
Rebound78 is not uncommon when therapy is stopped prematurely. Rebound may occur 2–3 weeks after completion of therapy. Remission occurs without further treatment, excepting occasional cases, which needs reinstitution of therapy.
How to Monitor Disease Activity?
Acute phase reactants can be used for monitoring disease activity and duration of therapy. Leukocytosis and prolonged PR interval have lesser role. ESR and CRP are the main determinants. ESR may be falsely low and high in heart failure and anemia respectively. Both ESR and CRP may be found normal, even if disease is active, such as in chorea and smoldering carditis.
Induction of subcutaneous nodule by injecting autologous blood or concentrated leukocytes on olecranon process of the patient along with frictional pressure upon it has been described without much validation.
Rheumatic carditis with heart failure not responding to medical management should be treated surgically. Hospital mortality in various study varied from 3.2 to 2.6%. 5-year mortality was around 15%. When valve repair was done in relatively early part of carditis, reoperation was very high and was in 27% cases. Thus, event-free survival at 5 years was 73%. Surgeon should check the valve during operation. If macroscopic inflammation can be seen, valve replacement, rather repair is a better choice to prevent continuation of rheumatic activity and reoperation.
PREVENTION
Prevention (Fig. 5) should play the most important role in RF.
Primordial Prevention
Primordial prevention targets to prevent GAS infection in population, thus, related to the socio-economic and health vision of the society and of the country. It involves creating an environment that will prevent the occurrence of GAS infection. This is difficult to achieve in the developing country. Other measures include:
- Mass chemoprophylaxis that involves huge economic burden, wastage, and relative ineffectiveness.
- To identify susceptible host and to treat them by chemoprophylaxis.
- Vaccine
Primary Prevention
Primary prevention targets treating GAS infection in a susceptible host to prevent occurrence of ARF.
To identify Group A Streptococci Pharyngitis
Around 15 million acute pharyngitis per year in the United States of America, 20–30% in children, and 5–15% in adult of sore throat visits are from GAS pharyngitis.87 Mostly, etiology is viral (Table 11). There are scoring systems for diagnosing GAS etiology. But bacterial confirmation is always needful.21
|
|
When score is ≤2, only symptomatic treatment is given and when score is ≥3, antibiotic treatment is given.
Guideline does not follow scoring system (Table 12) for decision to treat. Rather, scoring is done to decide pretest probability of GAS etiology. If it is low, further test is not done and antibiotic treatment is withheld. If the probability is high, throat culture is done. As mentioned earlier, RADT can be done. In children, a negative RADT must be cross-checked by throat culture. In adult, however, a negative RADT is enough documentation against GAS etiology. GAS antibody test is not recommended to establish the bacteriological etiology.
Treatment65
Rheumatic fever may be prevented (Table 13), even when treatment is delayed for 9 days89 from onset of symptoms. Thus, treatment can be started after culture report being available. RADT can help starting treatment and to make patient ambulant earlier. Patient becomes noncontagious within 24 hours of antibiotic treatment.90
Penicillin is the drug of choice because it is cheap, easily available and resistance to GAS has never been reported. Oral penicillin V (phenoxymethyl penicillin) or G can be used. Penicillin V is preferred because it is more resistant to gastric acid,65 thus absorption is better. It is given in the dose of 40 mg/kg/day (maximum up to 750 mg in <27 kg child) in three divided doses. Average dose is 250 mg two times a day.91 Therapy should be continued for 10 days. Both of them are available in:
|
- Tablet 250 mg (400,000 units)
- Tablet 500 mg (800,000 units)
Alternately, oral amoxicillin can be used (in the dose of 50 mg/kg, maximum to 1,000 mg) for 10 days.
When noncompliance is an issue or patient is in high-risk to develop RHD, single intramuscular benzathine penicillin can be used.
In patients allergic to penicillin, narrow spectrum cephalosporin can be used for 10 days. Clindamycin (GAS resistance around 1%) and macrolides (including erythromycin, clarithromycin, and azithromycin; GAS resistance around 5–8%) are reasonable alternates.
Routine post-therapy throat culture is not needful. Only when patient remains symptomatic, or recurrence of symptom or patient is of high risk for RHD, it may be done. In those patients, if culture is positive, re-treatment is indicated. Narrow spectrum cephalosporin, clindamycin, or penicillin plus rifampicin can be used in penicillin failure cases.65
SECONDARY PREVENTION (TABLE 14)
Recurrence of ARF is the most important prognostic factor and its prevention is the best way to prevent RHD burden.
|
Drug of Choice
Intramuscular long-acting penicillin is the drug of choice. Preferred molecule is the benzathine salt of penicillin G (benzylpenicillin), combined with procaine salt of penicillin G to reduce pain at injection site. Penicillin G benzathine is prepared by combination of dibenzylethylenediamine with two molecules of penicillin G. Penicillin G procaine is an equimolar salt of procaine and penicillin G. Procaine is a local anesthetic agent, thus reducing pain. Penicillin G benzathine and penicillin G procaine have a low solubility and they are slowly released from intramuscular sites. They are then hydrolyzed to penicillin G. Both hydrolysis and slow absorption result in blood serum level much lower but more prolonged.
Interval
Interval of benzathine penicillin, 2 weeks versus 3 weeks versus 4 weeks, is debated. A nicely methodological review, known as Cochrane review92 explored nine studies, mostly methodologically poor and suggested a 2-weekly or 3-weekly penicillin regime. They argued that a 2- or 3-weekly regimen maintains blood penicillin level above minimum inhibitory concentration (0.02 mcg/mL) better than a 4-weekly regime. Others favor a 4-weekly regime. They93 showed a better adherence with 4-weekly regime, thus the same recurrence rate between this regime and 2- or 3-weekly regimes. Guidelines, including AHA,65 Australian95 and New Zealand94 guidelines suggest a 3-weekly regime for high-risk group (moderate or severe carditis or history of valve surgery or a breakthrough on 4-week regime), otherwise a 4-weekly regime. Indian Pediatric guideline suggests a 2-weekly and 3-weekly regime.96
Doses
All guidelines suggest 1.2 million-unit doses of benzathine penicillin for adult patient. For children, opinion differs as mentioned on the Table 14. One pharmacokinetic study97 suggested that 0.6-million-unit dose in <27 kg was insufficient to maintain optimum blood level of penicillin.23
Duration
There are consensus guidelines regarding the duration of prophylaxis. But physician should consider several factors in an indexed case. Those who have higher risk of recurrence (Box 8 and Table 15) should be considered for a longer prophylaxis.
Rheumatic fever is uncommon between 25–40 years of age and rare after 40 years of age. In high-risk Northern Territory Aboriginal patients, ARF beyond 40 years of age was 1%.98 Chance of recurrence becomes uncommon after 5 years from last episode. All those factors should be considered before deciding the duration of secondary prophylaxis.
World Health Organization ARF and RHD technical report46 suggests: Duration should be 5 years after last attack or until 18 years of age (whichever is longer) in patients without carditis; duration should be 10 years after last attack, if carditis is present or at least 25 years of age (whichever is longer). It should be lifelong, if severe valvular disease or after valve surgery.
New Zealand guideline94 suggests: Minimum 10 years after the last episode of ARF with no or mild carditis; duration should be minimum of 10 years after last attack or until the age of 30 years whichever is longer, if moderate carditis is present. If severe carditis is present, prophylaxis as above and then specialist review for consideration of lifelong prophylaxis.
|
Australian guideline95 suggests: Minimum 10 years after the episode of ARF or 21 years, whichever is longer. Same duration is applicable, if there is a mild regurgitant lesion without any cardiomegaly on echocardiogram. In moderate carditis, prophylaxis should be continued till 35 years of age. In severe carditis, it should be continued till 40 years of age or lifelong.
Penicillin Allergy
In view of benefit far outweighing risk, penicillin should be continued in most of the patients. Allergic reaction, anaphylaxis and fatality are uncommon, in the tune of 3.2% and 0.2% and 0.05%, respectively.99 Skin test does not always ensure safety (Box 9).
Oral Penicillin
Adherence is the most important problem. Chance of recurrence is also high. Molecules and dosage have been described in primary prevention.
Sulfonamide100
Sulfadiazine and other sulfonamides can be used in penicillin allergic patients. It is not effective in eradicating GAS, but can prevent recurrence. It is given in the dose of 1 g (>27 kg) and 500 mg (below 27 kg) daily.
Macrolides
Macrolides can be used in penicillin and sulfadiazine allergic patient.
Prophylaxis in Pregnancy
Penicillin prophylaxis must be continued in pregnancy. It has no documented ill effects on pregnancy. In penicillin allergic patients, erythromycin can be used.95 However, no controlled trial has been done.
Prophylaxis after Valve Replacement
Remaining native valve tissue of the replaced prosthetic valve and other native valve may be affected by recurrent carditis. Intramuscular bleeding in anticoagulated patients on intramuscular penicillin is not common.95 Thus, penicillin prophylaxis should be continued after valve replacement surgery.101
Prophylaxis Failure
In the above-mentioned Cochrane review,92 in four studies, 561 received intramuscular penicillin and 537 received oral penicillin. There were seven recurrences of ARF in the former group and 89 recurrences of ARF in the later group.
In Irvington House study,102,103 recurrence of RF on intramuscular penicillin, oral penicillin, and sulfadiazine had been shown as 0.4, 5.5, and 2.8 per 100 patient-years, respectively. In that way, sulfonamides offer better prophylaxis than oral penicillin.104
CONCLUSION
May be, incidence and prevalence of ARF/RHD are declining in developing country too. It may resurge again with the appearance of more virulent strain. Jones criteria are still useful. So far, secondary prevention with benzathine penicillin is the best way among the preventive measures. However, best ways to prevent ARF/RHD in future are primordial prevention and rheumatic vaccine. Over last five decade, trials so far have been failed to isolated M protein based vaccine.
In the latest WHO statement in 71st World Health Assembly, published in April 2018, epidemiological data has been updated. As per this data, some 30 million people are currently thought to be affected by RHD globally. About of 305,000 deaths and 11.5 million disability-adjusted life years loss due to RHD happened in 2015. The most important statement made by WHO 2018 was:
Also came out the REMEDY study,105 in which between 2010 and 2012, 3,343 patients from 25 centers in 14 low- and middle-income countries were studied for 2 years to assess mortality, CHF, stroke, recurrent ARF, and infective endocarditis. Mortality rate was 116.3/1,000 patients-years in the 1st year and 65.4/1,000 patients-years in the 2nd year. Median age at death was 28.7 years. Predictors of death were severe valve disease, CHF, New York Heart Association (NYHA) III/IV, atrial fibrillation, and older age.
Ramakrishnan S et al. can be quoted from their elegant review,28—“RHD is not gone, but forgotten. The decline in the incidence of RF/RHD in the developed world has unfortunately resulted in a parallel decline in the research interest in the disease. The developed world has forgotten RHD with a waning of the disease burden among <20% of the world's population living in the high-income countries. Similarly, a reduction in the RHD burden among the 20% privileged population in India should not make us lose focus from this enigmatic illness”.
Statistical data in relation to ARF/RHD are summarised in the Table 16.
When did ARF occur first on this earth? Was it present at the time of Hippocrates? Described106 in Hippocratic Corpus (*) as,—“An ulcerated throat with fever is serious; but if some other symptom also supervene that has been already classed as bad, forecast that the patient is in danger. Angina is very serious and rapidly fatal, when no lesion is to be seen in either throat or neck and moreover it causes very great pain and orthopnea……”. The enigma is unending.25
|
REFERENCES
- Kaplan E. Recent epidemiology of Group A streptococcal infections in North America and abroad: an overview. Pediatrics. 1996;97(6):S945–8.
- World Health Organization. (1988). Rheumatic fever and rheumatic heart disease: Report of a WHO Study Group. Geneva, World Health Organization, 1988 (Technical Report Series, No. 764). [online] Available from https://apps.who.int/iris/handle/10665/40051 [Last accessed May, 2020].
- Kumar RK, Rammohan R, Kaplan E, Narula J. Epidemiology of streptococcal pharyngitis, rheumatic fever and rheumatic heart disease. In: Kumar RK, Rammohan R, Kaplan E, Narula J (eds). Rheumatic fever. Washington, DC: American Registry of Pathology Publisher; 1999. pp. 41–78.
- McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis. 2004;4(4):240–5.
- Bryant PA, Robins-Browne R, Carapetis JR, Curtis N. Some of the people, some of the time susceptibility to acute rheumatic fever. Circulation. 2009;119:742–53.
- Davies A, Lazarov E. Heredity, infection and chemoprophylaxis in rheumatic carditis: an epidemiologic study of a communal settlement. J Hygiene. 1960;58:263–9.
- Engel ME, Stander R, Vogel J, Adeyemo AA, Mayosi BM. Genetic susceptibility to acute rheumatic fever: a systemic review and meta-analysis of twin studies. PLos One. 2011;16:e25326.
- Adams J, Carlin J, Nolan T, Shann F. Rheumatic heart disease in school children in Samoa. Arch Dis Child. 1999;81(4):372.
- Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis. 2004;4(4):240–5.
- Kaplan EL. The group A streptococcal upper respiratory tract carrier state: an enigma. J Pediatr. 1980;97(3):337–45.
- Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Diseases Society of America. Clin Infect Dis. 2002;35:113–25.
- Martin JM, Green M, Barbadora KA, Wald ER. Group A streptococci among school-aged children: clinical characteristics and the carrier state. Pediatrics. 2004;114:1212–9.
- Committee on Infectious Diseases, American Academy of Pediatrics. Group A streptococcal infections. In: Pickering LK, Baker CJ, Long SS, McMillan JA (eds). 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, Il: American Academy of Pediatrics; 2006. pp. 610–20.
- Krishnakumar R, Tandon R. Rheumatic fever and Rheumatic heart disease: The last 50 years. Indian J Med Res. 2013;137:643–58.
- Kaplan EL. Pathogenesis of acute rheumatic fever and rheumatic heart disease: evasive after half a century of clinical, epidemiological, and laboratory investigation. Heart. 2005;91:3–4.
- Marcus RH, Sareli P, Pocock WA, Meyer TE, Magalhaes MP, Grieve T, et al. Functional anatomy of severe mitral regurgitation in active rheumatic carditis. Am J Cardiol. 1989;63:577–84.
- Basu UP. Preliminary observation on acquired diseases of the heart and aorta as met with in Bengal. Indian Med Gaz. 1925;60:307–10.
- Kutumbiah P. Rheumatism in childhood and adolescence. Part 1. Indian J pediatr. 1941;8:65–86.
- Banerjea JC. Incidence of rheumatic heart disease in India. Indian heart J. 1965;17:201–3.
- Berry JN. Prevalence survey of chronic rheumatic heart disease and rheumatic fever in Northern India. Br Heart J. 1972;34:134–49.
- Roy SB. Prevalence of rheumatic fever and rheumatic heart disease in Ballabhgarh. Annual report, Indian council of medical research 1968-1969, p. 52.
- Shah B, Sharma M, Kumar R, Brahmadathan KN, Abraham VJ, Tandon R. Rheumatic heart disease: Progress and challenge in India. Indian J pediatr. 2013;80(suppl 1):77–86.
- Patel DC, Patel NI, Patel JD, Patel SD. Rheumatic fever and RHD in school children of Anand. J Assoc Phys India. 1986;34:837–9.
- Periwal KL, Gupta BK, Panwar RB, Khatri PC, Raja S, Gupta R. Prevalence of rheumatic heart disease in school children in Bikaner: an echocardiographic study. J Assoc Phys India. 2006;54:279–82.
- Nair B, Viswanathan S, Koshy AG, Gupta PN, Nair N, Thakkar A. Rheumatic heart disease in Kerala: a vanishing entity? An echo Doppler study in 5–15-years-old school children. Int J Rheumatol. 2015.
- Saxena A, Desai A, Narvencar AD, Ramakrishnan S, Thangjam RS, Kulkarni S, et al. Echocardiographic prevalence of rheumatic heart disease in Indian school children using World Heart Federation criteria—a multisite extension of Rheumatic study (e-RHEUMATIC study). Int J Cardiol. 2017;249:438–42.
- Mishra TK, Routray SN, Behera M, Pattniak UK, Satpathy C. Has the prevalence of rheumatic fever/rheumatic heart disease really changed? A hospital-based study. Indian Heart J. 2003;55:152–7.
- Deshpande J, Vaideeswar P, Amonkar G, Vasandani S. Rheumatic Heart disease in the past decade: an autopsy analysis. Indian Heart J. 2002;54:676–80.
- Seth S, Ramakrishnan S, Roy A, Bhargava B, Bahl VK, Poole-Wilson PA. Epidemiology of heart failure in India. Eur Heart Fail Suppl. 2009;8:1117.
- Ramakrishnan S, Kothari SS, Juneja R, Bhargava B, Saxena A, Bahl VK. Prevalence of rheumatic heart disease: has it declined in India? National Med J India. 2009;22:72–4.
- Kumar RK, Paul M, Francis FT. RHD in India: are we ready to shift from secondary prophylaxis to vaccinating high-risk children? Cure Sci. 2009;97:397–404.
- World Health Organization. (1994). Joint WHO/ISFC meeting on RF/RHD control with emphasis on primary prevention, Geneva, 7–9 September 1994. Geneva, World Health Organization, 1994 (WHO Document WHO/CVD 94.1). [online] Available from https://apps.who.int/iris/handle/10665/60727?locale-attribute=pt&show=full [Last accessed May, 2020].
- World Health Organization. Health system: improving performance. In: World Health Organization (Ed). The World Health Report 2001. Geneva: World Health Organization; 2001. pp. 144–55.
- Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5:685–94.
- Naghavi M, Wang HD, Lozano R, Davis A, Liang X, Zhou M, et al. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–71.
- Kaplan EL. T. Duckett Jones Memorial Lecture. Global assessment of rheumatic fever and rheumatic heart disease at the close of the century. Influences and dynamics of populations and pathogens: A failure to realize prevention? Circulation. 1993;88:1964–72.
- Johnson DR, Stevens DL, Kaplan EL. Epidemiologic analysis of group A streptococcal serotype associated with severe systemic infection, rheumatic fever, or uncomplicated pharyngitis. J Infect Dis. 1992;166:374–82.
- Hale M, Sharpe N. Persistent rheumatic fever in New Zealand—a shameful indicator of child health. N Z Med J. 2011;124(1329):6–8.
- Viali S. Rheumatic fever and Rheumatic heart disease in Samoa. Pacific public health. 2006;13(2):31–8.
- Swift HF. The pathogenesis of rheumatic fever. J Exp Med. 1924;39:497–508.
- Guiherme L, Jorgr K, Cunningham M. Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity. 2006;39(1):31–9.
- Tandon R, Sharma M, Chandrasekhar Y, Kotb M, Yacoub MH, Narula J. Revisiting the pathogenesis of rheumatic fever and carditis. Nat Rev Cardiol. 2013;10:171–7.
- Jones TD. Diagnosis of rheumatic fever. J Am Med assoc. 1944;126:481–4.
- Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA. 1992;268:2069–73.
- World Health Organization. Rheumatic fever and rheumatic heart disease: report of a WHO Expert Consultation Geneva. Geneva: World Health Organization; 2004.
- Gewitz MH, Baltimore RS, Tani LY, Sable CA, Shulman TS, Carapetis J, et al. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131:1806–18.
- Narula J, Chandrasekhar Y, Rahimtoola S. Diagnosis of Active Rheumatic carditis. The Echoes of changes. Circulation. 1999;100:1576–81.
- Stollerman GH. Rheumatic carditis. Lancet. 1995;346:390–91.
- Steinfield L, Dimich I, Rappaport H, Baron M. Late systolic murmur of rheumatic mitral insufficiency. Am J Cardiol. 1975;35:397.
- Chopra P, Tandon HD. Pathology of chronic rheumatic heart disease with particular reference to tricuspid valve involvement. Acta Cardiol. 1977;32:423–34.
- Wood P. Chronic rheumatic heart disease. In: Wood P (ed). Disease of the Heart and circulation, 3rd edition. Philadelphia: JB Lippincott; 1968. pp. 690–9.
- Feinstein AR, Spagnuolo M. The clinical pattern of acute rheumatic fever, a reappraisal. Medicine (Baltimore). 1962;41:279–305.
- Kothari SS, Chandrashekhar Y, Tandon RK. Rheumatic carditis. In: Narula J, Virmani R, Reddy KS, Tandon R (eds). Rheumatic Fever. Washington, DC: American Registry of Pathology Publication; 1999. pp. 257–70.
- Veasy LG, Wiedmeier SE, Orsmond GS, Ruttenberg HD, Boucek MM, Roth SJ, et al. Resurgence of acute rheumatic fever in the intermountain area of the United states. N Engl J Med. 1987;316:421–7.
- Essop MR, Wisenbaugh T, Sarel P. Evidence against a myocardial factor as the cause of left ventricular dilatation in active rheumatic carditis. J Am Coll Cardiol. 1993;22:826–9.
- Gupta M, Lent RW, Kaplan EL, Zabriskie JB. Serum cardiac troponin I in acute rheumatic fever. Am J Cardiol. 2002;89:779–82.
- Edwards BS, Edwards JE. Congestive heart failure in rheumatic carditis: valvular or myocardial origin? J Am Coll Cardiol. 1993;22:830–1.
- Tandon R. Rheumatic fever pathogenesis: Approach in research needs change. Annal Pediatr Cardiol. 2012;5:169–78.
- Jaccoud S. Leçons de clinique médicale faites a l'Hôpital de la Charité, 2nd edition. Paris, Adrien Delahaye. 1869.
- Bywaters EGL. The relation between heart and joint disease including ‘rheumatoid heart disease’ and chronic post-rheumatic arthritis. Br Heart J. 1950;12:101–32.
- Carapetis J, Brown A, Wilson NJ, Edwards KN. An Australian guideline for rheumatic fever and rheumatic heart disease: An abridged outline. Med J Aus. 2007;186(11):581–6.
- Feinstein AR, Spagnuolo M, Wood HF, Taranta A, Tursky E, Kleinberg E. Rheumatic fever in children and adolescents. A long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae. VI. Clinical features of streptococcal infection and rheumatic recurrences. Ann Intern Med. 1964;60(Suppl 5):68–86.
- Crea MA, Mortimer EA Jr. The nature of scarlatinal arthritis. Pediatrics. 1959;23:879–84.
- Gerber MA, Baltimore RS, Eaton CB, Gewitz M, Rowley AH, Shulman ST, 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: Endorsed by the American Academy of Pediatrics Circulation. 2009;119:1541–51.
- Swedo SE, Leonard HL, Mittleman BB, Allen AJ, Rapoport JL, Dow SP, et al. Children with PANDAS (pediatric autoimmune neuropsychiatric disorders associated with strep infections) are identified by a marker associated with rheumatic fever. Am J Psychiatry. 1997;154:110–2.
- Gerber MA. Diagnosis of pharyngitis: methodology of throat cultures. In: Shulman ST (ed). Pharyngitis: management in an era of declining rheumatic fever. New York: Praeger; 1984. pp. 61–72.
- Wannamaker LW, Ayoub EM. Antibody titers in acute rheumatic fever. Circulation. 1960;21:598–614.
- United Kingdom and United States Joint Report on Rheumatic Heart Disease. The natural history of rheumatic fever and rheumatic heart disease. Ten-year report of a cooperative clinical trial of ACTH, cortisone, and aspirin. Circulation. 1965;32:457–76.
- Patarroyo ME, Winchester RJ, Vejerano A, Gibosky A, Chalem F, Zabriskie JB, et al. Association of a B cell alloantigen with susceptibility to rheumatic fever. Nature. 1979;278:173–4.
- Selzar A, Cohn KE. Natural history of mitral stenosis: a review. Circulation. 1972;45:878–90.
- Taranta A. A long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae: V. Relation of the rheumatic fever recurrence rate per streptococcal infection to the titres of streptoccal antibodies. Ann Intern Med. 1964;60(Suppl 5):58–67.
- Taranta A, Kleinberg E, Feinstein A. A long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae: IV. Relation of the rheumatic fever recurrence rate per streptococcal infection to pre-existing clinical features of the patients. Ann Intern Med. 1964;60(Suppl 5):47.
- Spagnuolo M, Pasternack B, Taranta A. Risk of rheumatic fever recurrence after streptococcal infections. N Engl J Med. 1971;285:641–7.
- Lawrence JG, Carapetis JR, Griffiths K, Edwards K, Condon JR. Acute rheumatic fever and rheumatic heart disease: Incidence and progression in the Northern Territory of Australia, 1997 to 2010. Circulation. 2013;128:492–501.
- Silva NA, Pereira BA. Acute rheumatic fever: still a challenge. Rheum Dis Clin North Am. 1997;23(3):545–68.
- Thatai D, Turi ZG. Current guidelines for the treatment of patients with rheumatic fever. Drugs. 1999;57(4):545–55.
- Uziel Y, Hashkes PJ, Kassem E, Padeh S, Goldman R, Wolach B. The use of naproxen in the treatment of children with rheumatic fever. J Pediatr. 2000;137:269–71.
- Markowitz M, Kuttner AG. Treatment of acute rheumatic fever. Am J Dis Child. 1962;104:137–44.
- Amigo MC, Martinez-Levin M, Reyes PA. Acute rheumatic fever. Rheum Clin North Am. 1993;19:333–50.
- Cillers AM. Rheumatic fever and its management. BMJ. 2006;333:1153–6.
- Cilliers AM, Manyemba J, Saloojee H. Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database Syst Rev. 2003;(2):CD003176.
- Camara EJ, Braga JC, Alves-Silva LS, Camara GF, da Silva Lopes AA. Comparison of an intravenous pulse of methylprednisolone versus oral corticosteroid in severe acute rheumatic carditis: a randomized clinical trial. Cardiol Young. 2002;12(2):119–24.
- Duran CM, Gometza B, de Vol EB. Valve repair in rheumatic mitral disease. Circulation. 1991;84(5 Suppl.):III125–32.
- Skoularigis J, Sinovich V, Joubert G, Sareli P. Evaluation of the long-term results of mitral valve repair in 254 young patients with rheumatic mitral regurgitation. Circulation. 1994;90(5 Pt 2):II167–74.
- Bisno AL. Acute pharyngitis: etiology and diagnosis. Pediatrics. 1996;97:949–54.
- Joachim L, Campos D, Smeesters PR. Pragmatic Scoring System for Pharyngitis in Low-Resource Settings. Pediatrics. 2010;126(3):e608–14.
- Gordis L. The virtual disappearance of rheumatic fever in the United States: lessons in the rise and fall of disease. Circulation. 1985;72(6):1155–62.
- Snellman LW, Stang HJ, Stang JM, Johnson DR, Kaplan EL. Duration of positive throat cultures for group A streptococci after initiation of antibiotic therapy. Pediatrics. 1993;91:1166–70.
- Gerber MA, Spadaccini LJ, Wright LL, Deutsch L, Kaplan EL. Twice-daily penicillin in the treatment of streptococcal pharyngitis. Am J Dis Child. 1985;139:1145–8.
- Manyemba J, Mayosi BM. Intermuscular Penicillin is more effective than oral penicillin in secondary prevention of rheumatic fever—a systemic review. S Afr Med J. 2003;93:212–8.
- Carapetis JR, McDonald M, Wilson NJ. Acute rheumatic fever. Lancet. 2005;366(9480):155–68.
- National Heart Foundation of New Zealand and the Cardiac Society of Australia and New Zealand. New Zealand Guidelines for Rheumatic Fever: 1. Diagnosis, Management and Secondary Prevention. 2006. [online] Available from https://www.heartfoundation.org.nz/shop/marketing/non-stock-resources/diagnosis-management-rheumatic-fever-guideline.pdf [Last accessed May, 2020].
- National Heart Foundation of Australia (RF/RHD guideline development working group) and the Cardiac Society of Australia and New Zealand. Diagnosis and management of acute rheumatic fever and rheumatic heart disease in Australia—an evidence-based review. 2006.
- Consensus guidelines on Pediatric Acute Rheumatic fever and Rheumatic Heart Disease. Working group on Pediatric Acute Rheumatic Fever and Cardiology chapter of Indian Academy of Pediatrics. Indian Pediatr. 2008;45:556–73.
- Meira ZM, Mota Cde C, Tonelli E, Nunan EA, Mitre AM, Moreira NS. Evaluation of secondary prophylactic schemes, based on benzathine penicillin G, for rheumatic fever in children. J Pediatr. 1993;123(1):156–8.
- Australian Government: AIHW. Cardiovascular disease: Australian facts 2011. Cardiovascular disease series. 2011, Canberra: Australian Institute of Health and Welfare. [online] Available from https://www.aihw.gov.au/getmedia/13cd081b-8123-4660-ad68-3d780c12ffeb/12116-20111005.pdf.aspx [Last accessed May, 2020].
- International Rheumatic Fever Study Group. Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever. Lancet. 1991;337(8753):1308–10.
- World Health Organization. (1999). WHO model prescribing information: Drugs used in the treatment of streptococcal pharyngitis and prevention of rheumatic fever. Geneva: World Health Organization; 1999 (WHO/EDM/PAR/99.1). [online] Available from https://apps.who.int/iris/handle/10665/65864?show=full [Last accessed May, 2020].31
- Hodes RM. Recurrence of rheumatic fever after valve replacement. Cardiology. 1989;76:465–8.
- Wood HF, Simpson R, Feinsrein AR, Taranta A, Stollerman GH. Rheumatic Fever in Children and Adolescents: A Long-term Epidemiologic Study of Subsequent Prophylaxis, Streptococcal Infections, and Clinical Sequelae: I. Description of the Investigative Techniques and of the Population Studied. Ann Intern Med. 1964;60(suppl 5):6–17.
- Wood HF, Feinsrein AR, Taranta A, Epstein JA, Simpson R. Rheumatic Fever in Children and Adolescents: A Long-term Epidemiologic Study of Subsequent Prophylaxis, Streptococcal Infections, and Clinical Sequelae: III. Comparative effectiveness of three prophylaxis regimens in preventing streptococcal infection and rheumatic recurrence. Ann Intern Med. 1964;60(suppl 5):31–46.
- Kuttner AG, Reyersbach G. The prevention of streptococcal upper respiratory infection and rheumatic recurrence by the prophylactic use of sulfonamide. J Clin Invest. 1943;22:77–85.
- Zühlke L, Engel ME, Karthikeyan G, Rangarajan S, Mackie P, Cupido B, et al. Characteristics, complications and gaps in evidence-based interventions in rheumatic heart disease: the global rheumatic heart disease registry (the REMEDY study). Eur Heart J. 2015;36:1115–22.
- Jones WHS. Hippocrates with an English translation, Vol. 2, 1st edition. In: Capps E, Page TE, Rouse WHD (Eds). Vol II, Case XXIII. Cambridge: Harvard University Press; 1923. pp. 47–9.