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Seminar

Acute rheumatic fever


Ganesan Karthikeyan, Luiza Guilherme

Acute rheumatic fever is caused by an autoimmune response to throat infection with Streptococcus pyogenes. Cardiac Lancet 2018; 392: 161–74
involvement during acute rheumatic fever can result in rheumatic heart disease, which can cause heart failure and Published Online
premature mortality. Poverty and household overcrowding are associated with an increased prevalence of acute June 29, 2018
http://dx.doi.org/10.1016/
rheumatic fever and rheumatic heart disease, both of which remain a public health problem in many low-income S0140-6736(18)30999-1
countries. Control efforts are hampered by the scarcity of accurate data on disease burden, and effective approaches to
Department of Cardiology,
diagnosis, prevention, and treatment. The diagnosis of acute rheumatic fever is entirely clinical, without any Cardiothoracic Sciences Centre,
laboratory gold standard, and no treatments have been shown to reduce progression to rheumatic heart disease. All India Institute of Medical
Prevention mainly relies on the prompt recognition and treatment of streptococcal pharyngitis, and avoidance of Sciences, New Delhi, India
(Prof G Karthikeyan DM); and
recurrent infection using long-term antibiotics. But evidence for the effectiveness of either approach is not strong.
Heart Institute (InCor),
High-quality research is urgently needed to guide efforts to reduce acute rheumatic fever incidence and prevent University of São Paulo,
progression to rheumatic heart disease. Institute for Investigation in
Immunology, National

Introduction rheumatic fever in large parts of Africa and Asia is Institute of Science and
Technology, São Paulo, Brazil
Acute rheumatic fever results from an autoimmune unknown, because of the absence of regional data (L Guilherme PhD)
response to infection with the group A streptococcus (table 1).6,9 Correspondence to:
(GAS)—Streptococcus pyogenes. The illness is characterised Prof Ganesan Karthikeyan,
by varying degrees of inflammation of the joints and the Trends in incidence of acute rheumatic fever over time Department of Cardiology,
Cardiothoracic Sciences Centre,
heart, typically manifesting as polyarthritis and valvular Few studies have reported acute rheumatic fever
All India Institute of Medical
regurgitation. Less commonly, involvement of the basal incidence over time from the same regions; the available Sciences, New Delhi 110029,
ganglia during the autoimmune process results in chorea. data indicate markedly differing trends, with reductions India
Except for the valve lesions, all other manifestations of in some regions,7,8 no change in others (table 1),11,13,14 and karthik2010@gmail.com
acute rheumatic fever resolve without sequelae. As the possible increases in some others.16 Estimates from
acute illness resolves, valvular lesions usually reduce in the Global Burden of Disease study show a significant
severity, but can persist or progress, leading to chronic reduction in rheumatic heart disease burden over the
rheumatic heart disease. Although acute rheumatic fever past 25 years (1990–2015), which could be due to a decline
itself is rarely life-threatening, rheumatic heart disease in incidence of acute rheumatic fever.17 However,
can cause heart failure, stroke, or death. Acute rheumatic estimates of global rheumatic heart disease burden need
fever and rheumatic heart disease are diseases of poverty, to be interpreted with caution. First, the overall trend
and have largely disappeared from affluent parts of the obscures the large variations observed between regions
world. However, in low-income countries, and among (eg, prevalence decrease in east Asia and no change in
margi­nalised sections of society in high-income countries, sub-Saharan Africa), and even within countries.17,18
acute rheumatic fever and rheumatic heart disease Second, estimates of global burden rely either on
remain an important cause of morbidity and mortality. In
this Seminar we present our understanding of the
epidemiology, pathogenesis, and management of acute Search strategy and selection criteria
rheumatic fever, highlighting knowledge gaps and We searched PubMed up until December, 2017, for
priorities for research. English-language articles using the terms “acute rheumatic
fever”, “rheumatic fever”, “ARF” alone and in combination
Disease burden with other terms including “incidence”, “Streptococcus
Incidence of acute rheumatic fever pyogenes”, “group A Streptococcus”, “GAS”, “pathogenesis”,
The incidence of acute rheumatic fever varies widely, “molecular mimicry”, “genomics”, GWAS”, “proteomics”,
mainly by socioeconomic development.1 Although the “corticosteroids”, “aspirin”, “immunoglobulin”, “rheumatic
disease is no longer a public health problem in high- heart disease”, “RHD”, “primary prevention”, “secondary
income countries, occasional outbreaks do occur,2 and prophylaxis”, “benzathine penicillin”, and “cost-effectiveness”.
the disease continues to persist in some of these We focused on publications in the past 15 years, but did not
countries.3–5 Data from prospective studies suggest that exclude commonly cited and highly regarded older
acute rheumatic fever annual incidence ranges between publications. We also selected relevant publications from the
eight and 51 per 100 000 among children and young reference lists of the retrieved articles and reviews. We chose
people.6 More recent reports from two endemic regions to include more recent publications over older ones that
indicate annual rates that are lower than 20 per 100 000,7,8 illustrated the same point. To provide readers access to more
but incidence remains high in the South Pacific, articles, we have included citations to other comprehensive
and among indigenous people in Australia and reviews on the subject.
New Zealand.9–14 However, the true incidence of acute

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Seminar

Country or territory Population at Annual incidence Comments


risk (age) (per 100 000)
Steer et al (2009)8 Fiji 5–14 years 15·2 Prospective surveillance of hospital admissions for acute rheumatic fever in a tertiary care hospital;
annual incidence rates suggest a decline from the annual rate of 144 per 100 000 estimated in 1965–66
Vinker et al (2010)15 Israel 5–14 years 7·5 Retrospective survey of community clinics and hospital records
Breda et al (2012)4 Italy 2·5–17 years 4·1 Retrospective community-based survey of practitioners and health records
Milne et al (2012)14 New Zealand 5–14 years 17·2 Data obtained from National Medical Statistics; annual incidence rates varied widely by ethnicity—
Maori people 40·2 per 100 000, Pacific islanders 81·2 per 100 000, and others 2·1 per 100 000
Lawrence et al (2013)13 Australia 5–14 years 194 Data obtained from the Northern Territory, Australia, acute rheumatic fever and rheumatic heart
disease register; annual incidence was recorded in Aboriginal children
Kumar et al (2014)7 India 5–14 years 8·7 Prospective, active surveillance of a single district of 1·1 million individuals over 8 years
Beaudoin et al (2015)10 American Samoa <18 years 150 Retrospective review of hospital records at the only hospital in the country
Fauchier et al (2015)12 French South Pacific Island 5–19 years 112 Retrospective review of medical records
Corsenac et al (2016)11 New Caledonia 9–10 years 131 Retrospective review of the acute rheumatic fever and rheumatic heart disease register (we
calculated the crude rate from data in the paper)
Kočevar et al (2017)3 Slovenia 3–14 years 1·25 Retrospective review of hospital records at a single tertiary referral hospital

This table presents the most recent data on acute rheumatic fever incidence reported in the literature. Data published before 2010 have been reviewed previously.6,9 Note that most data are from retrospective
studies, and there was a single study from Asia and no studies from Africa.

Table 1: Incidence of acute rheumatic fever

Methods to estimate incidence Advantages and disadvantages


the number of school-age children with rheumatic heart
and prevalence of estimation methods disease.9,19–22 However, this formula is likely to
overestimate burden in countries with a young
Continuous and active Ideal metric of ARF incidence; population (most endemic countries), because the all-age
surveillance of the community Acute rheumatic fever estimation is resource-intensive
for cases of ARF and not feasible in low-income burden is extrapolated from the school-age numbers
countries (appendix). A modified formula (also based on data used
for the original derivation),21,22 which uses actual numbers
Echocardiographic screening Subclinical definite Pragmatic surrogate for ARF from census data and a different set of multiplication
of children (5–14 years) using rheumatic heart disease incidence and time-trends; factors could produce more conservative estimates
standardised criteria easily measured, repeatable, (figure 1; appendix).
and less costly

Clinical RHD Subclinical rheumatic heart disease as a surrogate for


Community surveys, and
sequelae
Poor surrogate for ARF acute rheumatic fever incidence
hospital-based registries, incidence, but can mirror
administrative databases, and long-term trends in ARF
Systematic and active surveillance of children and young
vital registration systems incidence* people in the community is needed to establish the true
incidence of acute rheumatic fever. But, active disease-
Figure 1: Estimating the burden of acute rheumatic fever specific surveillance is costly, and is not feasible in low-
The centre of the figure depicts the three principal stages in the progression to RHD. RHD=rheumatic heart disease. income countries. Therefore, other methods might be
*When estimating all-age RHD burden from the prevalence of clinical RHD in school children, we recommend the needed to estimate acute rheumatic fever burden.
following modified formula: total number of people with RHD=(number of people in the 5–14-year age
Subclinical rheumatic heart disease detected by echo­
group × prevalence in the 5–14-year age group) + (number of people over the age of 15 years × [prevalence in the
5–14-year age group × m]), where m ([multiplication factor]=[prevalence in the over 15-year age group/prevalence cardiographic screening23 could represent an intermediate
in the 5–14-year age group]) takes on the values of 1·4 and 3·8 to allow estimation of the upper and lower limits of stage before the development of clinical disease (figure 1;
all-age RHD burden (for derivation see appendix). The population in the different age groups should be obtained panel 1 after the index acute rheumatic fever event.
from local census data. Subclinical RHD should not be used for estimating all-age RHD burden.
Subclinical rheumatic heart disease prevalence correlates
closely with acute rheumatic fever incidence. A study
See Online for appendix modelling17 or on extrapolations from estimates of from Australia showed that the prevalence of echo­
prevalence in school children.19 Either approach has cardiographically confirmed rheumatic heart disease was
potential for error. In the absence of data from all regions higher among indigenous children who are at high risk
of the world,17 modelling-based approaches are of acute rheumatic fever (annual incidence 194 per
susceptible to errors in estimation, simply because of the 100 000),13 than in a low-risk (annual incidence <10 per
influence of model variables that are strongly associated 100 000) population (definite rheumatic heart disease
with disease prevalence. Likewise, extrapolation of prevalence 8·6 per 1000 vs 0 per 1000).24 Similarly, another
school-age burden to estimate all-age rheumatic heart study in a low-risk US paediatric population could not
disease burden is prone to large errors. A widely used identify any cases with definite rheumatic heart disease
formula uses multiplication factors of 5·5 and 7·2 to in the 500 echocardiograms that were screened.25 Definite
derive the lower and upper limits of all-age burden from subclinical rheumatic heart disease prevalence can

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therefore serve as a surrogate measure of acute rheumatic


fever incidence. The use of subclinical rheumatic heart Panel 1: Nomenclature of cardiac involvement in acute rheumatic fever and rheumatic
disease as an alternative metric to estimate acute heart disease
rheumatic fever incidence has several potential advan­ Subclinical carditis
tages. First, this method is less costly and more feasible Evidence of valvular involvement detected by echocardiography, either during or within
than active surveillance for acute rheumatic fever. Second, 12 weeks of the onset of symptoms of acute rheumatic fever, that is not evident on
the method is repeatable and can yield information on clinical examination.
time trends in acute rheumatic fever incidence. Third,
since a wide variation exists in acute rheumatic fever Subclinical rheumatic heart disease
incidence even within countries, screening can be used to Rheumatic valvular heart disease that is detected on echocardiographic screening of
obtain locally representative data. Finally, this information asymptomatic populations. Lesions are usually trivial or mild and are not detectable on
can be used for targeted implementation of prevention clinical examination. This type of disease is classified as borderline or definite using
programmes. However, the prognosis and treatment of standard criteria.23
patients with subclinical disease is unknown at present,26 Missed clinical rheumatic heart disease
and children identified to have subclinical rheumatic Moderate or severe lesions that are incidentally detected, but are evident on clinical
heart disease could be exposed to anxiety and unnecessary examination. Patients might or might not be symptomatic. The number of these
treatment. More research is needed to validate this patients as a proportion of the overall burden of rheumatic heart disease depends on the
approach. availability and ease of access to health-care facilities, and on the health-seeking
behaviour of the population. These lesions should not be categorised as subclinical
Pathogenesis rheumatic heart disease. The term latent rheumatic heart disease is confusing, and
The pathogenesis of acute rheumatic fever remains should not be used to refer to this condition.
incompletely understood. Evidence supports the view
that acute rheumatic fever is the result of an autoimmune Clinical rheumatic heart disease
response to pharyngeal infection with GAS in genetically Clinically evident rheumatic valvular lesions that come to attention when patients who
predisposed individuals, which is mediated through are often symptomatic seek medical care.
molecular mimicry. About 0·3–3% of people with GAS
pharyngitis develop acute rheumatic fever, depending on
genetic predisposition and the virulence of the infecting blood lymphocytes of patients with acute rheumatic
strain.27 Although some genetic and epidemiological fever, cross-react in vitro with human myosin and
evidence exists for skin infection as the event that valvular endothelium.37 Finally, immunisation with
leads to acute rheumatic fever,28,29 pharyngeal infection is recombinant streptococcal M protein induces autoanti­
considered to be the trigger in most cases. Streptococcal body formation and valvulitis in Lewis rats.38 Structural
antigens activate humoral and cell-mediated immune similarity between the myosin epitopes and heart valve
pathways leading to the production of antibodies against proteins, such as laminin and vimentin, could be the
streptococcal components, which cross-react with human basis of antibody-mediated damage to valve structures.39
proteins. This results in immune-mediated inflammation Although a wide variety of GAS emm types can induce
and injury (figure 2). carditis, a mechanism common to all of them could be
Evidence from numerous small candidate-gene the targeting of epitopes in the S2 subregion of human
studies,1,31 and more recently, two genome-wide asso­ cardiac myosin by autoantibodies.39 Molecular mimicry
ciation studies,32,33 suggests that genetic susceptibility also underlies the cell-mediated immune inflammation
could be conferred by polymorphisms of genes involved that occurs in acute rheumatic fever. T-cell clones derived
both in the innate and adaptive immune pathways from rheumatic lesions react with myosin and valve-
(panel 2). The genetic susceptibility to acute rheumatic derived proteins, and release inflammatory cytokines
fever is heritable, as shown by the higher risk of upon exposure to these antigens in vitro.40
concordance among monozygotic twins than dizygotic Valve damage in acute rheumatic fever occurs as a result
twins (44% vs 12%).34 Inheritance is non-Mendelian and of both humoral and cellular immune responses against
polygenic, with variable and incomplete penetrance.35 valve proteins. Binding of cross-reactive antibodies at the
Ongoing large genome-wide association studies will valve surface induces the upregulation of vascular cell
provide further insights. adhesion molecule 1, which facilitates the adherence and
There are several reasons why molecular mimicry is infiltration of activated CD4 T cells and B lymphocytes.41
believed to be the most likely mechanism underlying the Local tissue damage is mediated predominantly through
development of autoimmunity in acute rheumatic a T helper cell 1 response, leading to production of
fever.1,32,33,36 First, the GAS M protein and the carbohydrate inflammatory cytokines such as interferon γ and tumour
antigen (N-acetyl-beta-D-glucosamine) share antigenic necrosis factor α, with decreased concentrations of
epitopes with human cardiac myosin and laminin on interleukins 4 and 10 (figure 2).42 Local epitope spreading
heart valves. Second, monoclonal antibodies against results in the identification of other self-antigens
these antigens, derived from tonsillar and peripheral (vimentin and collagen), which causes amplification of

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Oropharynx
chorea.43 Accumulation of immune complexes can cause
the transient, migratory joint manifestations associated
Streptococcus pyogenes
with acute rheumatic fever.1
Mechanisms other than molecular mimicry have also
Epithelium been proposed to explain the pathogenesis of acute
rheumatic fever. Streptococcal M protein binding to
basement membrane collagen type 4 epitopes can induce
autoimmunity to collagen, resulting in inflammation and
Peripheral blood scarring of valve leaflets.44 However, antibodies against
Streptococcus
collagen do not induce valvulitis in animal models.
pyogenes Inflammatory Therefore, molecular mimicry is probably essential for
cytokines
induction of autoimmunity and initiation of valve damage
T cell B cell
during acute rheumatic fever, and antibodies against
collagen could contribute to disease progression.

Risk factors and diagnosis


Streptococcus pyogenes Antibodies against Poverty and social disadvantage are among the strongest
Monocyte/macrophage Pathogenic peptides streptococci predisposing factors for developing acute rheumatic
Heart
fever,45 acting possibly through household overcrowding,
Several heart-tissue proteins in the myocardium and valve tissue are recognised
which facilitates easy transmission of GAS.46 Ethnicity
by auto-reactive antibodies and T lymphocytes could be another predisposing factor,45 but the increased
↑IL10 susceptibility in some ethnic groups might be explained
B cell (antibody) ↑TNFα ↓IL4 by the higher prevalence of poverty and overcrowding in
IFNγ, IL17,
Antibodies against IL23 these groups, rather than genetic susceptibility.
myocardium and The incidence of acute rheumatic fever is highest
valve tissue Mononuclear B and T cells
among children aged 10–14 years, followed by those aged
VLA4
5–9 years.7,45,46 Children younger than 5 years rarely
VCAM1
develop acute rheumatic fever,47 and a first episode is rare
beyond age 30 years.45 Recurrences can occur at older ages
but are rare beyond 40 years.13 Males and females are
HLA-DR7 equally likely to have acute rheumatic fever, although
rheumatic heart disease is more common in females.1
Macrophage Intralesional T cell

Diagnosis of acute rheumatic fever: the Jones criteria


Heart tissue protein No single laboratory test or clinical feature is diagnostic
Figure 2: From throat infection to valve damage of acute rheumatic fever. Most patients with acute
Streptococcus pyogenes throat infection triggers the innate and adaptive immune rheumatic fever present with a combination of fever,
responses by activating neutrophils, monocytes and macrophages, and B and joint manifestations, and cardiac involvement. A smaller
T lymphocytes. In individuals who are predisposed to autoimmunity,
autoantibodies and autoreactive T-cell clones that can react with self-antigens in
proportion have chorea, and skin manifestations are
the heart (such as myosin, vimentin, and laminin) are produced. A combination infrequent.48 In children, fever and joint symptoms are
of humoral, cell-mediated, and cytokine-mediated injury leads to valve damage. common, can have many causes,49 and are by themselves
The initial step involves endothelial activation by autoantibodies triggering not sufficient to diagnose acute rheumatic fever. Chorea
increased expression of surface VCAM1. This facilitates T-cell infiltration into the
avascular valve matrix, where the cells produce a Th1 response. The resulting
and the skin manifestations are specific to acute
cytokine-mediated immune damage is further amplified by recognition of other rheumatic fever but occur too infrequently to be useful
structural valve proteins such as vimentin and collagen through epitope for diagnosis. The common clinical features of acute
spreading. Additionally, Th17 responses occur with group A streptococcal rheumatic fever are described in panel 3.
infections, and patients with acute rheumatic fever and rheumatic heart disease
have increased numbers of Th17 cells and higher IL17 concentrations,30 but their
The Jones criteria provide a framework for allocating
importance in disease pathogenesis is not known. IFNγ=interferon γ. weights to individual clinical features (ie, major and minor
IL=interleukin. Th=T helper cell. TNFα=tumour necrosis factor α. VCAM1=vascular criteria) to make a syndromic diagnosis.60 With the decline
cell adhesion molecule 1. VLA4=integrin α4β1-very late antigen 4. of acute rheumatic fever in the USA, the original criteria
were revised periodically to improve their specificity
immune damage.41 Inflammation leads to neovascular­ (at the cost of sensitivity).61 Acute rheumatic fever inci­
isation and healing by fibrosis, causing the characteristic dence varies considerably around the world, and clinical
valve lesions of rheumatic heart disease. Likewise, manifestations can vary by acute rheumatic fever
antibodies against GAS N-acetyl-beta-D-glucosamine endemicity.51–54 Therefore, the need for modification of the
cross-react with neuronal cells in the basal ganglia, criteria and their nuanced application to different pop­
causing the release of excess dopamine, which leads to ulations was recognised,62 and the most recent revision of

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the Jones criteria incorporated several modifications.48 The


three major changes in the revision were: risk stratification Panel 2: Mediators of genetic susceptibility to acute rheumatic fever
based on disease endemicity, different implications of joint Several genes confer susceptibility to acute rheumatic fever and rheumatic heart disease,
manifestations for different populations, and acceptance through alleles that code for proteins involved in both the innate and adaptive immune
of echocardiographic evidence of carditis (subclinical response to GAS infection.
carditis) as a major manifestation.48 The revision also • Innate immunity: TLR2, FCN2, MASP2, MBL2, MIF, and FCGR2A
provides guidance on diagnosing recurrent acute • Adaptive immunity: HLA class II alleles and IGHV4-61*02
rheumatic fever (panel 3). • Both innate and adaptive immunity: IL1RA, TNF, TGFB1, IL10, and CTLA4
The 2015 revision adopted a Bayesian approach to
TLR2 and FCN2 are involved in pathogen recognition and elimination of bacteria. MASP2,
diagnosis by categorising patients from regions with an
MBL2, MIF, and FCGR2A are involved in clearing immune complexes. Several HLADR alleles
acute rheumatic fever annual incidence of less than 2 per
are located in the short arm of chromosome 6 in the DRB1 gene, of which HLA-DR7 is the
100 000, or an all-age rheumatic heart disease prevalence
most commonly associated with acute rheumatic fever. GWAS data suggest that variation at
of less than or equal to 1 per 1000, as having a low-risk
the HLA-DQA1 and DQB1 loci could confer increased risk of developing acute rheumatic fever
of disease, and all other patients as having a moderate or
in Indigenous Australians. An allele of the IGH gene segment (IGHV4-61*02) was shown to
high risk.48 Polyarthralgia and aseptic mono­arthritis are
be associated with rheumatic heart disease in another GWAS. The genes that control the
considered to be major manifestations, and mon­o­arth­
production of inflammatory mediators are IL1RA and TNF, and TGFB1 regulates cell
ralgia a minor manifestation of the disease in individuals
proliferation, differentiation, and migration into the tissues. Interleukin 10 induces
who are at moderate or high risk of acute rheumatic fever.
anti-inflammatory cytokines, and CTLA4 interferes with the T-cell immune response.
This classification is based on data indicating that
polyarthralgia and monoarthritis are common mani­ TLR2=toll-like receptor 2. FCN2=ficolin 2. MASP2=mannan-binding lectin serine protease 2. MBL2=mannose-binding lectin.
festations of acute rheumatic fever in endemic regions.51–54 MIF=macrophage inhibitory factor. FCGR2A=Fc fragment of IgG low-affinity IIa receptor. IL1RA=interleukin 1 receptor antagonist.
TNF=tumour necrosis factor α. TGFB1=transforming growth factor β1. CTLA4=cytotoxic T lymphocyte-associated protein 4.
Migratory polyarthritis, the classic description of the type HLA-DR=human leucocyte antigen-antigen D related. GWAS=genome-wide association study. IGH=immunoglobulin heavy chain.
of arthritis in acute rheumatic fever, is observed
infrequently,55 possibly because it is easily masked or
modified by the use of readily available over-the-counter Simplifying the diagnosis of acute rheumatic fever in
anti-inflammatory agents. These changes have improved moderate and high-risk populations
the diagnostic utility of the Jones criteria.55 In endemic regions in low-income countries, less
The decision to include subclinical carditis as a major emphasis should be placed on obtaining evidence of
manifestation is timely, and is supported by good data. preceding streptococcal infection, because bacteriological
Echocardiography identifies patients with cardiac diagnosis is seldom sought, and anti-streptolysin O titres
involvement more reliably than clinical examination alone might not be sufficiently sensitive or specific.66–68
alone. A systematic review showed that echocardiography Similarly, temperature records during fever might not be
performed within 3 months of an episode of acute available, and fever could be masked by the use of over-
rheumatic fever identified subclinical carditis (mitral the-counter antipyretics. Despite these barriers to the
regurgitation as diagnosed by WHO criteria)63 in about strict application of the Jones criteria, correctly identifying
18% of patients.57 About 45% of these patients had patients who will develop chronic rheumatic heart disease
persistent or worsening valve lesions over 2 years, is imperative. Cardiac involvement at baseline, detected by
highlighting the non-trivial nature of subclinical car­ echocardiography, is the best predictor of developing
ditis.57 Echocardiography is also better at establishing the rheumatic heart disease in the future. Because 70–90% of
severity of lesions than clinical examination. Since patients with acute rheumatic fever have echocardio­
severity of the index episode of carditis is one of the best graphic carditis,57 all patients with a high probability of
predictors of rheumatic heart disease on follow-up, acute rheumatic fever based on clinical symptoms
echocardiography could provide better prognostic should under­go echocardiography. Although in developed
information.64 In a retrospective analysis of patients with countries acute rheumatic fever as a cause of joint
acute rheumatic fever followed up for about 9 years, only symptoms is rare both in the community69 and in hospital
4% of patients with a normal echocardiogram progressed settings,70 the small amount of data available from
to rheumatic heart disease, compared with 25% of developing countries indicate a high likelihood of acute
patients who had no clinical carditis.64,65 Likewise, a rheumatic fever among patients presenting with joint
smaller proportion of patients with mild lesions on symptoms. In hospital-based studies, the proportion of
echocardiography progressed than did those who had patients with arthritis who had acute rheumatic fever was
mild clinical carditis. These results highlight the potential 15% in the West Indies and 41% in India.71,72 Therefore, we
for misclassification of moderate carditis as mild, and suggest that all children and adolescents in endemic
mild lesions as normal, by clinical examination.64,65 These regions who have joint manifestations (polyarthritis,
data suggest that for every 1000 patients with acute polyarthralgia, or mono­arthritis), with evidence of elevated
rheumatic fever, echocardiography would identify erythrocyte sedimen­tation rate (ESR) or C-reactive protein,
124 additional patients with subclinical carditis, most of with or without fever, should have echocardiography for
whom would progress to rheumatic heart disease.65 the detection of carditis. Carditis should be diagnosed

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Panel 3: Common clinical features of acute rheumatic fever


The clinical features of acute rheumatic fever are accompanied regions of the myocardium are involved, which might not cause
by evidence of inflammation in the form of elevated C-reactive systolic dysfunction.56 Endocardial involvement in the form of
protein (CRP; >3 mg/dL) and erythrocyte sedimentation rate valvulitis presents as regurgitation of the mitral valve and, less
(ESR; >60 mm in the first hour in low-risk populations, and commonly, of the aortic valve. Clinical manifestations can include
>30 mm in high-risk populations). A prolonged PR interval palpitations, dyspnoea, and heart failure (when regurgitation is
(after adjustment for age) is considered a minor manifestation severe due to leaflet prolapse or chordal rupture). The holosystolic
(in the absence of carditis), along with raised ESR and CRP, fever, murmur of mitral regurgitation and, uncommonly, the
and monoarthralgia (polyarthralgia in low-risk populations). mid-diastolic Carey Coombs murmur can be audible. Carditis is
A first or recurrent episode of acute rheumatic fever can be diagnosed clinically in 50–70% of cases. Subclinical carditis is
diagnosed in the presence of two major and one minor criteria, diagnosed in an additional 12–21% of cases.57 Carditis, either
or one major and two minor criteria. A recurrent episode can clinical or subclinical, is now considered a major manifestation.
also be diagnosed if three minor criteria are present.48
Chorea
Fever Chorea involves involuntary, purposeless movements of the
Seen in more than 90% of patients; a low temperature cutoff extremities and trunk. Chorea usually follows the index episode of
of 38°C has been suggested for diagnosing fever in endemic acute rheumatic fever by 1–3 months, and can occur as an isolated
regions. In low-resource settings, a clear history of fever can be manifestation.58 Seen in 10–30% of cases of acute rheumatic
more important than the temperature at the time of fever, chorea is considered a major manifestation for diagnosis.
examination. Evidence of preceding streptococcal infection can be absent
because of the long delay to manifestation. Cardiac involvement
Joint manifestations
is common in patients with chorea. Up to 90% of patients have
Seen in more than 75% of patients; the classic description is that
carditis when subclinical involvement is also considered.59 When
of a migratory polyarthritis involving the large joints (knees,
chorea is the only manifestation, other causes such as drug
ankles, elbows, and wrists) that responds well to salicylates. Axial
toxicity and Wilson’s disease should be ruled out.
and small joint involvement is rare. Usually these joint
manifestations are self-limiting and subside with or without Skin manifestations
treatment by 4 weeks.50 Polyarthralgia and aseptic monoarthritis Erythema marginatum is a non-pruritic pink maculopapular rash
are commonly seen in endemic regions51–55 and are considered that blanches on pressure, and occurs mainly on the trunk and
major manifestations for diagnosis in moderate-to-high risk proximal extremities. The rash is transient and difficult to identify
populations in the 2015 Jones criteria.48 Monoarthralgia is in patients with dark skin. Subcutaneous nodules seen in acute
considered a minor manifestation.48 rheumatic fever are small, painless, and palpated over the bony
prominences on the extensor surfaces of the limbs, and along the
Carditis
spinous processes of the vertebrae. Skin manifestations are
Classically described as a pan-carditis—ie, carditis is associated
uncommon (0–10%), but are specific for acute rheumatic fever
with involvement of the pericardium, myocardium, and
and are considered major manifestations for diagnosis.
endocardium. Pericarditis resolves without sequelae. Only some

using the modified World Heart Federation criteria chorea,5,59,74 and will improve sensitivity in moderate and
suggested by Gewitz and colleagues.48 The presence of high-risk populations.
carditis should be sufficient to make a diagnosis of acute
rheumatic fever (figure 3). A normal echocardiogram Treatment of acute rheumatic fever
documented during the index illness rules out carditis. If The treatment of acute rheumatic fever has three
facilities for echocardiography are not available locally (as primary goals: elimination of the inciting GAS infection;
can often be the case), patients should be referred to an supportive treatment for arthritis, carditis, and chorea;
equipped centre for evaluation within 12 weeks of the and treatment directed at reducing progression to
onset of symptoms.57,64 This flexibility in the timing to chronic rheumatic heart disease. However, many of the
obtain an echocardiogram can ensure feasibility in most treatments that are in use are not based on strong
situations. Patients who have a normal echo­cardiogram evidence.
can be further assessed for acute rheumatic fever (without
carditis) based on the 2015 Jones criteria. The implications Treatment of the GAS infection
of incorrect diagnosis in the absence of carditis are small, The goal of treatment with penicillin in acute rheumatic
because cardiac involvement is unlikely during re­ cur­ fever is to eradicate GAS infection. Eradication is
rences because of its mimetic nature.73 The suggested achieved with either a single dose of intramuscular
approach is very similar to that used for the diagnosis benzathine benzylpenicillin, or a 10-day course of oral
of acute rheumatic fever in patients presenting with phenoxymethylpenicillin. Although resistance of GAS

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strains to penicillin has not been reported, tolerance


is well recognised,75 but its clinical significance is Joint manifestations and elevated
CRP and ESR, with or without fever
unknown. Oral amoxicillin (35–40 mg/kg per day
for 10 days),76,77 oral cephalosporins,78 and high-dose
azithromycin,79 all result in higher cure rates than oral Echocardiography within 12 weeks
penicillin. But resistance to macrolide antibiotics is
common, and treatment failures have been reported.80–82
The antibiotic regimen with the lowest likelihood of
treatment failure should be chosen while also taking Pathological mitral or aortic No cardiac involvement on
regurgitation, with or without echocardiogram performed within
into account availability and cost constraints. In practice, morphological changes suggestive 12 weeks of the index illness
a single dose of benzathine benzylpenicillin is often of acute carditis
used, because it is cheap, eliminates the potential for
non-compliance associated with oral agents, and serves
Diagnose acute rheumatic fever Diagnose ARF if 2015 Jones criteria
as an introduction to secondary prophylaxis. In patients fulfilled
who have known minor hypersensitivity to penicillin,
cephalosporins could be the best option. Patients with a Figure 3: A simplified algorithm for the diagnosis of a first episode of acute
history of angio-oedema, hypotension, or anaphylaxis rheumatic fever in moderate and high-risk populations
CRP=C-reactive protein. ESR=erythrocyte sedimentation rate. ARF=acute
following penicillin administration should receive
rheumatic fever.
macrolide antibiotics.
reverse once inflammation subsides, aggressive vasodilator
Symptomatic and supportive care therapy might be useful in the acute phase of the illness.
Arthralgia and arthritis Rarely, chordal rupture and severe mitral valve prolapse
Joint manifestations respond within 1–3 days to treatment can cause fulminant mitral regurgitation, requiring urgent
with high-dose aspirin (80–100 mg/kg per day in three or surgery.88 The cause of heart failure in patients with acute
four divided doses).83 Treatment is usually required for rheumatic fever has been attributed solely to the rapid
1–4 weeks, but can be given for up to 12 weeks. Aspirin onset of valvular regurgitation.87 Left ventricular dys­
commonly causes gastrointestinal side-effects, and function is thought not to occur in rheumatic carditis,
proton pump in­hibitors are often co-prescribed. Tinnitus because myocardial involvement is patchy and does not
can occur with aspirin, but subsides after cessation of fulfil the criteria for diagnosis of myocarditis,56 and
treatment.84 Data on the efficacy of non-steroidal anti- echocardiographic indices of ventricular function are
inflammatory drugs (NSAIDs) other than aspirin in the normal in patients with heart failure.87 However, data
treatment of acute rheumatic fever are scarce. In a small, showing elevated cardiac troponin concentrations during
open-label, randomised controlled trial (RCT), naproxen carditis suggest that myocardial injury can occur.89
(15–20 mg/kg/day in two divided doses) showed com­ Furthermore, cardiac MRI in some patients with carditis
parable symptom relief to aspirin.85 Other NSAIDs such shows features suggestive of myocarditis.90 If ventricular
as ibuprofen could plausibly also be effective, but this dysfunction is documented, patients should receive
assumption is based on anecdotal data. Steroid therapy guideline-based therapy for heart failure.91
results in a more rapid fall in ESR than treatment with
aspirin, but can be associated with a greater likelihood of Chorea
rebound ESR increase on cessation of therapy than Chorea generally develops weeks to months after the GAS
aspirin.84,86 Fever is rarely high grade and responds well to infection, and therefore patients can present without the
either paracetamol or aspirin. other features of acute rheumatic fever. Spontaneous
resolution occurs in most patients between 1 and
Carditis 6 months.92 Numerous reports of symptomatic improve­
Most patients with carditis during an acute episode of ment with dopamine antagonists, such as haloperidol,
acute rheumatic fever have mild or moderate mitral pimozide, and chlorpromazine, have been published, but
regurgitation.64,87 These patients are usually treated with controlled trials have not been done with any of these
angiotensin-converting enzyme inhibitors, although these agents.93 Moreover, these agents, especially haloperidol, are
drugs have not been studied in acute rheumatic fever. associated with extrapyramidal side-effects that limit
Diuretics are used for symptom relief. About 10–30% of patients’ daily activities. The antiepileptic drugs car­
patients have severe mitral regur­gitation,64,87 and 10% have bamazepine and sodium valproate provide symptomatic
heart failure.84 Patients with severe mitral regurgitation relief with fewer side-effects, and might be preferable over
who have pulmonary oedema often benefit from intra­ dopamine antagonists.93,94 Oral prednisolone (2 mg/kg per
venous vasodilators such as sodium nitroprusside, day for 4 weeks) reduced the intensity of chorea and the
although there are no data in patients with acute rheumatic time to complete remission in a randomised trial.95
fever. Nevertheless, since the annular and ventricular However, clinically significant side-effects (such as weight
dilatation causing severe mitral regurgitation87 are likely to gain) occurred with steroid treatment. Low-quality evidence

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Panel 4: Acute rheumatic fever: critical research needs


Although several questions relating to acute rheumatic fever Randomised trials of anti-inflammatory therapy in acute
remain unanswered and merit focused research, there are only a rheumatic fever
small number of dedicated acute rheumatic fever and rheumatic No treatment is known to reduce or delay progression to
heart disease researchers, and the funding available for acute rheumatic heart disease. International randomised trials are
rheumatic fever research is small compared with other neglected needed to rigorously assess the efficacy of immunosuppressive
diseases.100,101 Therefore, consolidating international research regimens in reducing disease progression in patients with acute
efforts might be wise, as is prioritising the research agenda to rheumatic fever.
focus on key areas. Efforts in this direction include the Addis
Genomics and proteomics to unravel susceptibility and
Ababa Communiqué,102 and the recent resolution on rheumatic
pathogenesis
heart disease passed at the 71st World Health Assembly.
Contemporary genomic and proteomic approaches could help
Obtain locally relevant data on the burden and time trends unravel new pathophysiological pathways of immune damage
of acute rheumatic fever and disease progression in acute rheumatic fever, some of
Collecting these data might require the use of surrogate which might be amenable to therapeutic intervention. Several
measures, such as subclinical rheumatic heart disease in genome-wide association studies are underway, two of which
vulnerable populations. This approach will help with efficient have already reported their primary results.32,33 Early plasma and
resource allocation, and focus preventive efforts to communities tissue proteomic data provide support for current hypotheses
with the greatest need. Interventions such as school-based of acute rheumatic fever pathogenesis.105,106
sore-throat screening and treatment programmes, which have
Vaccine development
been shown to work in wealthy countries,103,104 could be too
This approach potentially offers the most efficient method to
resource intensive for low-income countries to implement as fully
reduce disease burden. Although a large proportion of the
fledged national programmes, but could be feasible in selected
funding for acute rheumatic fever and rheumatic heart disease
communities at high risk of acute rheumatic fever.
research goes to vaccine development,101 the quantum of
Randomised trials of secondary prophylaxis to prevent acute funding available is only a fraction of that available for other
rheumatic fever recurrence vaccines in development, and a viable vaccine is still several
Rigorous evaluation of secondary antibiotic prophylaxis in stages away from clinical use. Aiming for a vaccine that
subclinical rheumatic heart disease, using contemporary prevents sore throat and invasive group A streptococcus
research methods and assessment tools, will provide much infection could avoid the market failure that has been
needed evidence for the use of secondary prophylaxis in general. associated with the development of a dedicated vaccine for
One trial (NCT03346525) is underway, and more are needed to acute rheumatic fever prevention.
assess the efficacy of prophylaxis.

from two small random­ised trials (with a total of 14 children the different agents that were used (oral prednisone,
treated) suggests that intravenous immunoglobulin can corticotropin, hydrocortisone, and intravenous immuno­
result in faster recovery than symptomatic treatment globulin).97 Moreover, echo­ cardiography was used for
alone.96 Small case series have also reported the successful diagnosing carditis and assessing outcomes in only one of
use of plasmapheresis.93 Given its self-limited course the studies.98 Therefore, although the available evidence
however, mild isolated chorea often does not need does not support the use of anti-inflammatory therapy in
treatment. Carbamazepine or sodium valproate could be acute rheumatic fever with carditis, adequately powered
the best choices when drug therapy is needed. RCTs of anti-inflammatory therapy are clearly needed.
Such studies should evaluate contemporary immuno­
Reducing progression to rheumatic heart disease suppressive regimens, such as pulse methylprednisolone,99
Anti-inflammatory therapy for acute rheumatic fever has and use echocardiography for diagnosing carditis and
long been considered to have the greatest potential for assessing progression (panel 4).
reducing the risk of progression to rheumatic heart disease.
Eight RCTs (n=996) have compared various steroid Prevention of acute rheumatic fever
preparations with aspirin, placebo, or no treatment.97 The decline in mortality due to acute rheumatic fever and
Overall, steroid therapy did not result in lower rates of valve rheumatic heart disease in developed countries preceded
disease at 1 year (relative risk 0·87, 95% CI 0·66–1·15). The the discovery of penicillin by a few decades, and is
results were similar in the subgroup of patients with severe attributable mainly to the improved living conditions that
carditis.97 However, these results cannot be considered followed economic prosperity.107,108 Rising incomes
conclusive because of serious limitations of the data. The plausibly lead to better housing and reduced household
risk of bias was high, and there was significant heterogeneity overcrowding.46 Primordial prevention measures such as
between studies, which could only partly be explained by improved housing are likely to yield the greatest reduction

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in acute rheumatic fever incidence. Prevention and as army barracks).123 The magnitude of effect of any
treatment of GAS infection (primary prevention), and antibiotic therapy compared with a placebo in preven­ting
prevention of recurrent GAS infections with long-term acute rheumatic fever is large (RR 0·32, 95% CI
antibiotics (secondary prevention) are other approaches 0·21–0·48), with most of the studies using intramuscular
to reduce acute rheumatic fever and rheumatic heart penicillin (RR 0·20, 0·11–0·36).123 Model-based analyses
disease burden. Although we discuss these individually, also suggest that, in endemic areas, treating all patients
we emphasise that countries that have managed to re­­duce presenting to a clinic with a sore throat, even without
disease burden have done so by implementing compre­ bacteriological confirmation of GAS infection, might be
hensive control programmes, which included both cost-effective.124
primary and secondary prophylaxis, complemented by However, implementation of primary prevention in the
education of people and health-care workers in the wider population presents numerous challenges.111 Poor
community.109–111 health-seeking behaviour, low awareness among patients
and caregivers about the importance of prompt treatment,
Primary prevention: GAS vaccine and lack of resources for bacteriological confirmation of
Prevention of GAS infection using a vaccine could be the GAS infection are some of these challenges. Additionally,
most efficient method for preventing acute rheumatic many sore throats that lead to acute rheumatic fever can
fever. The GAS M protein, encoded by the emm gene, is remain asymptomatic.5 One approach to implementation
the primary target for vaccine development. The main of primary prevention in the community is a school-based
challenges to the development of a viable vaccine sore-throat identification and treatment programme. In a
candidate are the diversity of the emm types and the cluster-randomised trial, such a programme was asso­
wide variation in their global distribution.112 Researchers ciated with a (non-statistically significant) 28% reduction
have adopted two strategies to overcome these chall­­enges. in the number of acute rheumatic fever cases when
First, recombinant vaccines based on multivalent compared with usual care.125 Analysis of pooled data from
polypeptides, comprising the most common rheuma­ all the available randomised and before–after studies
togenic M protein epitopes, have been developed. A indicated a nearly 60% reduction in the number of acute
30-valent vaccine shows promising efficacy in preclinical rheumatic fever cases.103 In a subsequent national school-
testing,113 and a 26-valent vaccine has already completed based sore-throat screening and treatment programme in
early clinical evaluation.114 Despite the small number of New Zealand, a statistically significant 26% decline in
emm types covered by these vaccines, cross-opsonisation notifications of first acute rheumatic fever episodes was
has recently been shown between several emm types reported among children aged 5–12 years in all the
(so-called emm clusters), raising the possibility that these ten District Health Boards covered by the programme.126
might be more broadly protective than previously However, the decline in the number of acute rheumatic
believed.115,116 The second approach is to target the con­ fever cases cannot be definitively attributed to the
served regions of the M protein on the C terminal, programme, because a significant reduction in the
exemplified by two candidate vaccines.117 One is based on number of cases was also observed among older children
a minimal B-cell epitope on the conserved region of the who were not covered by school-based screening.126
M protein known as J8, and has been shown to induce Moreover, the programme was cost-effective only in a
protective antibodies in mouse models.118,119 A C-repeat region where both the incidence of acute rheumatic fever
epitope-based vaccine has been shown to induce high and programme effectiveness were high (annual
titres of opsonic, neutralising, and protective antibodies, incidence of acute rheumatic fever was 87 per 100 000,
and will also shortly enter clinical trials.120,121 Despite and reduction by 30%).126 Therefore, despite the potential
substantial advances in knowledge and technology, for benefit, the practicability and cost-effectiveness of
progress in vaccine development has been slow. A shift in such resource-intensive efforts in low-income countries
strategy, towards a vaccine to prevent GAS pharyngitis is debatable. Integrating primary prevention into the
and invasive infections (which might have greater global existing health-care infrastructure could be more feasible
utility than a vaccine solely for preventing acute rheumatic and less expensive.
fever), has been advocated to avoid the potential for
market failure.122 Whether this strategy will accelerate Secondary antibiotic prophylaxis
vaccine development remains to be seen. Disease progression after the index acute rheumatic fever
episode is believed to be due to incremental valve damage
Primary prevention: treatment of GAS pharyngitis sustained during recurrences of acute rheumatic fever.
Primary antibiotic prophylaxis aims to eradicate the GAS Long-term antibiotic prophylaxis, usually with benzathine
infection before it can trigger the immune response benzylpenicillin, is widely advocated to prevent GAS
leading to acute rheumatic fever. Moderate quality infections that could lead to recurrences.63,127 Although this
evidence exists for the concept from several randomised approach has a strong biological plausi­bility, good evidence
and quasi-randomised hospital-based studies, which were of efficacy and effectiveness is lacking. The efficacy of
done with patients drawn from closed communities (such routine secondary prophylaxis in preventing disease

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pro­gression has primarily been assumed from compa­ biological plausibility of the value of secondary prophylax­
risons between acute rheumatic fever recurrence and is, and data showing near-zero acute rheumatic fever
disease progression rates in the pre-penicillin era128 with recurrence rates beyond this period.7,13 Contrary to
those from several decades later in the penicillin era.1,129–131 guidelines (which tailor duration on the basis of disease
Such comparisons ignore the temporal decline in acute severity),63,127 the duration of prophylaxis should be the
rheumatic fever rates during this period. A systematic same for all patients with carditis detected during the first
review of penicillin prophylaxis in rheumatic heart acute rheumatic fever episode, with the recognition that
disease132 identified only three randomised or quasi- patients with milder disease could potentially derive the
randomised trials (n=1301) of poor methodological quality greatest benefit from preventing recurrent acute rheumatic
comparing antibiotic therapy with a control.133–135 Of these fever. In patients with clinically significant disease, the ma­
trials, the only study that showed a reduction in acute nagement of valve disease and heart failure, which have
rheumatic fever recurrences lost over a quarter of patients major prognostic implications, should be prioritised.141
during follow-up.135 The best support for secondary Patients who are allergic to penicillin should receive oral
prophylaxis comes from studies comparing intra­ erythromycin (250 mg, twice per day). Less frequent
muscular benzathine benzylpenicillin with oral penicillin dosing regimens of macrolides should not be used.146
preparations. Although these studies were also of
poor method­ ological quality, they showed large re­ duc­ Conclusion
tions (87–96%) in the risk of recurrent acute rheumatic For a disease that has afflicted humans for over a century,
fever.136–139 Despite reducing acute rheumatic fever re­ our understanding of acute rheumatic fever remains
currence, no randomised trial evidence supports secondary incomplete. Accurate data on disease burden from
prophylaxis to prevent disease progression. endemic countries are scarce, and there are gaps in our
Despite the scarcity of data on efficacy, long-term understanding of disease pathogenesis. Treatments for
benzathine benzylpenicillin is widely used in practice. the disease are all based on low-quality evidence.
However, the delivery of benzathine benzylpenicillin to Nevertheless, the global burden of acute rheumatic fever
the community has numerous challenges. Poor patient and rheumatic heart disease has decreased over the past
adherence because of low awareness, the pain of intra­ few decades, probably more as a result of socioeconomic
muscular injections, inconsistent availability and quality development than control efforts. Further acceleration of
of benzathine benzylpenicillin, and the fear of anaphylaxis this decline will require concerted, international effort
all contribute to poor compliance.140 Perhaps owing partly (panel 4) to bridge the gaps in knowledge.
to suboptimal delivery, observational studies have not Contributors
shown the effectiveness of benzathine benzylpenicillin in GK wrote the first draft of all sections, and all subsequent revisions.
preventing recurrences or disease progression. Penicillin LG contributed to the sections on pathogenesis and vaccine development
prophylaxis did not independently predict acute rheumatic Declaration of interests
fever recurrence or disease progression in the Northern GK is a member of the rheumatic heart disease expert panel of the Global
Burden of Disease study group, and is chair of the Global Advisory Board
Territory of Australia.13 In a 2-year prospective study of of Rheumatic Heart Disease, Evidence, Advocacy, Communication, Hope.
patients with established valve disease, measures of the LG holds a patent for a group A streptococcal vaccine that is due to enter
severity of valve disease, and not secondary prophylaxis, clinical trials.
were associated with clinical outcomes.141 A similar References
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