CHAPTER 46: ACUTE RHEUMATIC FEVER

Acute rheumatic fever (ARF) is a multisystem autoimmune response to untreated or partially treated group A Streptococcus (GAS) pharyngitis. A single severe episode of ARF or recurrent episodes of ARF can result in permanent heart valve damage known as rheumatic heart disease (RHD). Despite a marked decline in ARF and RHD in the developed world, ARF and RHD persist as major public health problems in developing regions of the world, indicative of inadequate access to health care, poorly functioning health systems, and social inequality.

The incidence of ARF began to decline in developed countries toward the end of the 19th century, and by the second half of the 20th century, ARF had become rare in most affluent populations. This decline is attributed to more hygienic and less crowded living conditions, better nutrition, improved access to medical care, and, to a lesser extent, the advent of antibiotics in the 1950s. The decline in prevalence of RHD in wealthy countries has followed a similar pattern, albeit with a delay compared to ARF incidence, which is explained by the chronic nature of RHD. However, these diseases continue largely unabated in resource-poor countries and in some populations living in relative poverty in industrialized countries.¹

It was previously estimated that approximately 470,000 individuals acquire ARF each year, of whom 97% are in developing countries, where the incidence of ARF exceeds 50 per 100,000 children per year.² The most recent estimates from the Global Burden of Disease study puts the RHD burden at 33 million prevalent cases, causing 275,000 deaths and more than 9 million disability-adjusted life-years lost each year.^3,4 The major burden of ARF and RHD is in sub-Saharan Africa, South Asia, and the Pacific region (Fig. 46–1).

The peak incidence of ARF occurs in those aged 5 to 15 years, with a decline thereafter such that cases are rare in adults aged > 35 years.¹ First attacks are rare in the very young; only 5% of first episodes arise in children aged < 5 years, and the disease is almost unheard of in those younger than aged < 2 years. Recurrent attacks are most frequent in adolescence and young adulthood and are diagnosed infrequently after 45 years of age. By contrast, RHD, which usually represents the accumulated damage from multiple ARF episodes in childhood, is most highly prevalent in the young adult years.⁵

ARF is equally common in males and females, but RHD is more common in females in almost all populations.^5,6 Whether this trend is a result of innate susceptibility, increased exposure to GAS because of greater involvement of women in child rearing, or reduced access to preventive medical care for females is unclear.¹ No association with ethnic origin has been found. There is some evidence that between 3% and 6% of any population is susceptible to ARF.⁷

Epidemiologic and immunologic evidence clearly implicates GAS in the initiation of ARF in a susceptible host.^6,7 Most patients with ARF have elevated titers of antistreptococcal antibodies. Outbreaks of ARF usually follow epidemics of streptococcal pharyngitis. Adequate treatment of streptococcal pharyngitis reduces the incidence of subsequent ARF, and appropriate antimicrobial prophylaxis prevents recurrences after initial attacks. It has generally been considered that certain strains of GAS are more prone to result in ARF, and this “rheumatogenicity” was thought to be a feature of strains belonging to certain M serotypes. More recent studies suggest that rheumatogenicity may not be serotype specific. The long-held opinion that only streptococcal pharyngitis, and not streptococcal skin infections such as impetigo, may be followed by ARF has also been challenged.⁸ Studies in populations where ARF is common find no definite association between GAS sequence type and site of infection or ability to cause disease.^9,10 Thus, the distinction between rheumatogenic and nonrheumatogenic strains, and between those trophic for the skin or throat, is considered by some to become blurred in areas where ARF is common and multiple different GAS strains circulate within small populations.¹

The streptococcal M protein shares an α-helical coiled structure with cardiomyocyte contractile proteins such as myosin, and since antibodies isolated from ARF patients cross-react both with M protein and heart tissue, molecular mimicry and autoimmunity was proposed to be the primary pathogenetic basis of ARF and carditis.⁸ The pathogenesis of RHD is now strongly considered to be an intricate interplay between multiple streptococcal antigens, various cross-reactive antibodies, and multiprong immune targets.

The antibodies that contribute to rheumatic valvulitis target the N-acetyl-β-D-glucosamine–dominant epitope of the GAS carbohydrate,⁹ but also recognize sequences in α-helical proteins (eg, myosin and tropomyosin).¹⁰ These antibodies are elevated in patients with valvular involvement in ARF, significantly reduce after surgical removal of inflamed valves, and correlate with poor prognosis.¹¹ Cross-reactive M-protein antibodies might recognize the intracellular biomarker antigen cardiac myosin but target the valve surface endothelial antigen laminin, or similar extracellular or basement membrane proteins.¹² The initial antibody-mediated damage to the endocardium leads to expression of vascular cell adhesion protein 1 on the valvular surface, which in turn facilitates the infiltration of T cells into the valve substance, resulting in scarring and neovascularization.¹³ The concept of the target that resides on the cell surface and initiates the disease process in response to or in association with an intracellular biomarker antigen is also demonstrated in the manifestation of ARF Sydenham chorea, wherein the biomarker antigen in the brain is tubulin and the antigen target on the cell surface leads to calcium/calmodulin-dependent kinase II activation and dopamine release.¹¹

Host factors have been considered to be important ever since familial clustering was reported last century. Associations between disease and human leukocyte antigen (HLA) class II alleles have been identified, but the alleles associated with susceptibility or protection differ depending on the population investigated.¹⁴ High concentrations of circulating mannose-binding lectin and polymorphisms of transforming growth factor-β₁ and immunoglobulin genes also are associated with ARF.^15,16,17

Certain B-cell alloantigens are expressed to a greater level in patients with ARF or RHD than controls, with family members having intermediate expression, suggesting that these antigens are markers of inherited susceptibility. The best characterized is D8/17, which is associated with ARF and RHD in several populations worldwide.¹⁸ Further investigation is needed before B-cell alloantigen markers can be used to identify individuals with, or at risk for, ARF or RHD. There is, as yet, no specific investigation that reliably identifies individuals who are at risk of ARF or who will develop chronic rheumatic valvular heart disease.

The histopathologic manifestations of ARF are characterized by connective tissue alterations and are essentially similar in various organs. Collagen is a recognized target for autoantibodies in various autoimmune diseases, and on the basis of histopathologic characteristics, systemic involvement, and complete healing in most tissues, it has been proposed that collagen could be the primary site for inflammation in ARF.¹⁹ It has been demonstrated that streptococcal M proteins form a complex with human collagen type IV in subendothelial basement membranes and might initiate an autoantibody response to the collagen.^20,21,22 This appears somewhat similar to pathogenesis of Goodpasture syndrome and Alport syndrome wherein the autoantibodies are directed at the basement membrane collagen type IV. The autoantigen is the mutated collagen IV (COL4 A3/A4/A5/A6) in Alport syndrome and the altered quaternary structure of the NC1 subunits of the α3 and α5 chains of collagen type IV of the lung and kidney in Goodpasture syndrome.^22,23 In ARF, M protein binds to the collagen IV through an octapeptide motif (Fig. 46–2); mice immunized with the collagen-binding octapeptide produced anticollagen antibodies^20,21,24 that did not cross-react with inducing M proteins, excluding the likelihood of molecular mimicry. Sera from ARF patients demonstrates collagen antibodies as well as increased titers for M proteins.²⁵ In Australia's Northern Territory, where rheumatic fever is endemic, where prevalence of GAS is low and pharyngeal isolation of group G infections is common, the M-like fibrinogen-binding protein of group G streptococci (FOG) has been shown to interact with the collagen family, similar to M protein.^25,26

The long-term clinical consequence of ARF is related to permanent cardiac damage. Although rheumatic carditis involves the pericardium, myocardium, and endocardium, fibrinous pericarditis and interstitial myocardial involvement resolve without residual damage, whereas verrucous valvulitis is associated with permanent damage. Notably, the pathologic changes also indicate that, unlike in the more common lymphocytic form of myocarditis, heart muscle cells are spared in rheumatic carditis (Fig. 46–3).¹⁹

Despite the widespread endothelial activation and the diffuse collagen alterations in ARF, the endothelium has an immense capacity to heal, and the subendothelial damage is limited to a shallow depth, resulting in healing in the other manifestations of ARF. The endothelial cells demonstrate substantial structural and functional variability and may be responsible for the differential response in the valves. Endothelial-cell heterogeneity is best exemplified in the valvular endothelial cells; endothelial cells on the aortic side of the aortic valve have different expression profiles on microarrays from those on the ventricular side. With valvulitis, neoangiogenesis develops within the substance of the valve tissue, which introduces more vascular endothelium and more collagen inflammation, leading to a vicious cycle of valvular damage, healing, and progressive scarring.²⁷

The protean manifestations of this condition were well described in the early part of the last century with a set of diagnostic criteria proposed by Duckett Jones in 1944²⁸ and subsequently modified and updated in 1992 and 2002.^{29,30,31,32,33} These revisions increased specificity but decreased sensitivity, particularly in endemic populations with potential missed diagnoses and failure to provide secondary prophylaxis to deserving patients.³⁴ Local guidelines have been adapted to the Jones criteria to reflect the pattern of disease in high-prevalence regions, local evidence, and current best practice, particularly relating to contemporary echocardiographic techniques.^35,36 The Jones criteria recently underwent an extensive revision.³⁷ This revision has aligned itself with international guidelines by defining high-risk populations, recognizing the variability in disease burden and presentation, categorizing recommendations according to the favored Classification of Recommendations and Level of Evidence categories, and reflecting the era of Doppler echocardiography³⁸ (Table 46–1).

The disease usually has an acute febrile onset and presents with variable combinations of major and minor manifestations. The diagnosis of ARF is made when the patient develops two major manifestations, or one major manifestation and at least two minor manifestations; in addition, evidence of preceding infection with GAS must be demonstrated using streptococcal serology. The exceptions are patients who present with chorea or indolent carditis, because these manifestations may only become apparent months after the inciting streptococcal infection so that additional manifestations may not be present and streptococcal serology testing may be normal.³⁹

Carditis

Carditis is the single most important component of the disease in determining prognosis. The carditis of ARF occurs in > 50% of patients and is characterised predominantly by valvulitis of the mitral valve (mitral regurgitation) and, less frequently, the aortic valve (aortic regurgitation).^40,41,42 Pathologically, ARF produces a pancarditis, with involvement of the pericardium, myocardium, and endocardium. Clinical manifestations may vary widely and range from subclinical to life-threatening heart failure. Pericarditis may manifest with typical pericardial pain and a friction rub. Auscultation may reveal new murmurs or changing murmurs. Stenotic lesions are uncommon in the early stages of the disease, but a transient apical mid-diastolic murmur (Carey-Coombs) may occur in association with the murmur of mitral regurgitation. This murmur occurs in patients with mitral valvulitis due to ARF. It is a short, mid-diastolic rumble best heard at the apex, which disappears as the valvulitis improves. It can be distinguished from the diastolic murmur of mitral stenosis by the absence of an opening snap before the murmur. The murmur is caused by increased blood flow across a thickened mitral valve.⁴³

Atrioventricular conduction delay, resulting in a prolonged PR interval, is an important and helpful diagnostic clue. Recent data strongly substantiates the importance of subclinical carditis based on Doppler echocardiography.^{42,44,45,46,47} Hence, echocardiographic evaluation for all patients with suspicion of ARF is recommended in the 2015 Jones criteria, and both clinical and subclinical carditis fulfil a major criterion, even in the absence of classical auscultatory findings.⁴⁸ Subclinical carditis of the mitral or aortic valves requires all four criteria to be met in order to fulfil the major criterion. Additional morphologic features may also be present.

Arthritis and Arthralgia

The conventional description is of a polyarthritis affecting large joints, with the lower limb joints involved first, and involvement of each joint overlapping giving the impression that the process “flits.” The arthritis of ARF responds promptly to anti-inflammatories, and thus, the classical presentation may be uncommon where medication with nonsteroidal anti-inflammatory drugs before the diagnosis is considered or confirmed.

The differential diagnosis of polyarticular arthritis in children and adolescents is wide (Table 46–2).⁴⁹ Monoarticular arthritis is increasingly recognized to be important in populations where ARF is common. The arthritis of ARF presents a difficult diagnostic challenge, especially in the patient presenting with an initial monoarthritis.⁵⁰ The arthritis of ARF is highly responsive to anti-inflammatory drugs (both aspirin and nonsteroidal anti-inflammatory drugs), and if the patient does not respond within 48 to 72 hours, alternate diagnoses should be considered. Poststreptococcal reactive arthritis is diagnosed in patients who have an arthritis that is not typical of ARF but who recently had streptococcal infection. This condition is said to occur after a shorter latent period than ARF, responds less well to anti-inflammatories, and may be associated with renal manifestations, and evidence of carditis is usually not seen. The distinction between post-streptococcal reactive arthritis and ARF is unclear, and many would recommend that a diagnosis of post-streptococcal reactive arthritis not be made in populations in which ARF is common.⁴⁹ Even if the diagnosis is considered, it is appropriate to offer a period of secondary penicillin prophylaxis, as for episodes of ARF in such populations.

Chorea

Sydenham chorea may be associated with other manifestations of ARF but may also be the sole expression of the disease. It is a neurologic disorder characterized by involuntary, purposeless, rapid, and abrupt movements associated with muscular weakness and emotional lability. Chorea occurs in up to 30% of cases of ARF. The abnormal movements disappear during sleep.

Mild chorea may best be demonstrated by asking the patient to squeeze the examiner’s hand. This results in repetitive irregular squeezes labeled as the milking sign. Emotional lability manifests in personality changes, with inappropriate behavior, restlessness, and outbursts of anger or crying.⁵¹

Erythema Marginatum

Erythema marginatum is a nonitchy, evanescent rash that is pink or slightly red and that affects the trunk predominantly. The rash extends centrifugally, and the skin in the center returns toward normal. The rash may be fleeting and disappear within hours. It may be brought out by a warm bath or shower. It is reported to be found in only 4% to 15% of cases and may be difficult to detect in dark-skinned patients.

Subcutaneous Nodules

These nodules generally appear later in the course of the disease after several weeks of illness and are seen most commonly in patients with carditis. They are firm and painless; the overlying skin is not inflamed and may vary in size from a few millimeters to several centimeters. They are most commonly located over bony surfaces or tendons such as elbows, wrists, knees, occiput, and spinous processes of the vertebrae. These occur in less than 10% of cases of ARF.

There is no definitive laboratory test for ARF, with the diagnosis based on a combination of clinical manifestations and laboratory evidence of previous streptococcal infection. Evidence of preceding streptococcal infection may be demonstrated by increased or rising antistreptolysin O titer, other streptococcal antibodies, a positive throat swab culture, or rapid antigen test for group A β-hemolytic streptococci. The revised Jones critieria³⁷ present two distinct decision paths depending on the risk category (high and moderate risk vs low risk) of the population (see Table 46–1). The changes to the major and minor criteria represent a significant attempt at weighing sensitivity versus specificity in its diagnostic acumen in both low- and moderate-/high-risk populations.

The three key changes are the risk stratification, adaptation of both major (carditis and arthritis/arthralgia) and minor (arthralgia, fever, and erythrocyte sedimentation rate [ESR] cutoffs) criteria, and the definition of recurrent ARF episodes.

Risk Stratification

Recent data have emphasized the disproportionate burden, pattern, and presentation of ARF and RHD.^52,53,54 The 2015 iteration of the Jones criteria defines low risk as coming from a population with an ARF incidence of < 2 per 100,000 per year for school-aged children or an all-age RHD prevalence of < 1 per 1000 population per year, with those not clearly coming from a low-risk population considered to be a moderate to high risk with the modified major and minor criteria applying (Class IIa, Level of Evidence C). This has important practical implications for clinicians working in countries with mixed risk populations.^55,56

Changes in Major and Minor Criteria

Carditis

Subclinical carditis or clinically silent but echocardiographically evident valvulitis has long been recognized as a manifestation of ARF with a weighted pooled prevalence of 16.8%.^57,58,59,60 As a result, the comprehensive evaluation of all cases of confirmed and suspected ARF includes echocardiography with Doppler, regardless of the findings on auscultation (Class I, Level of Evidence B).

Arthritis

In moderate-/high-risk populations, monoarthritis in addition to the more classic polyarthritis has been demonstrated to be an important clinical manifestation of ARF.^61,62 Previously reflected in the Australian and New Zealand guidelines,^63,64 the consideration of monoarthritis as part of the ARF spectrum is now included, although limited to moderate-to-high risk populations (Class I, Level of Evidence C). Monoarthralgia is now also included as a minor criterion in moderate-/high-risk populations, although this will only apply when arthritis (monoarthritis/polyarthritis and/or polyarthralgia) has not been used as a major criterion.

Fever and Erythrocyte Sedimentation Rate

Finally, revised cutoffs have been introduced for three of the minor criteria in order to improve sensitivity in the higher risk populations. The cutoff for fever has been lowered to 38.0°C (compared to 38.5°C in low-risk patients), and the ESR has been lowered to > 30 mm/h (compared to 60 mm/h in moderate-/high-risk patients).

Definition of Rheumatic Fever Recurrences

Prior to the 2015 iteration, there were no specific diagnostic criteria for ARF recurrences. The new criteria now state that with a reliable past history of ARF or RHD and in the face of documented GAS infection, two major, or one major and two minor, or three minor manifestations may be sufficient for a presumptive diagnosis of an ARF recurrence (Class IIb, Level of Evidence C).

The current guidelines seek to increase sensitivity in populations that have a high incidence of ARF and maintain high specificity in low-risk populations. They rely on considerable diagnostic and echocardiographic acumen complemented by laboratory testing to confirm and monitor disease activity. Table 46–2 presents the differential diagnoses for polyarthritis and carditis in children and adolescents. The Doppler findings in rheumatic valvulitis are presented in Table 46–3. Laboratory investigations, other than those to confirm GAS exposure and ESR and C-reactive protein, are otherwise nonspecific. Modest normochromic normocytic anemia of chronic inflammation is frequent.

The electrocardiogram may be unhelpful apart from reflecting sinus tachycardia. Prolongation of the PR interval serves as a useful minor criterion and may be particularly helpful in recurrences where previous electrocardiograms are available.

Management of the Acute Episode

The aims of treatment of ARF are to suppress the inflammatory response so as to minimize cardiac damage, to provide symptomatic relief, and to eradicate pharyngeal streptococcal infection.⁵¹ Patients are usually hospitalized, and the long-standing recommendation of bedrest or chair rest is appropriate if heart failure is present. Ambulation is usually started once fever has subsided and joint pain and heart failure are controlled.

Although evidence of active infection is unusual during the acute phase, it is recommended that patients receive a single dose of benzathine penicillin or a 10-day course of penicillin V (or erythromycin if penicillin allergic) to curtail exposure to streptococcal antigens. After completion of the course, secondary prophylaxis should be commenced. This recommendation is based on observational and longitudinal data.⁵

Anti-inflammatory agents, including salicylates and corticosteroids in appropriate dose, provide dramatic improvement in symptoms such as arthritis and fever soon after starting treatment. Doses of aspirin of 80 to 100 mg/kg/d in children and 4 to 8 g/d in adults may be needed initially. The usual dose of prednisone or prednisolone is 1 to 2 mg/kg/d. There is no good evidence that steroids are superior to aspirin in terms of altering the natural history of the disease. Some believe that they do result in more rapid resolution of carditis and can be lifesaving, but this is unproven.^49,65

Patients with severe heart failure require usual antifailure treatment. When carditis complicated by marked valvular regurgitation causes severe hemodynamic compromise, valve surgery is life-saving and should not be delayed by trials of anti-inflammatory medication. Valve repair rather than replacement is the preferred option for RHD surgery, considering the concerns regarding adherence to anticoagulation.⁶⁶ However, repair should be performed by a surgeon experienced in rheumatic valvular surgery.^67,68

Primary prevention refers to antibiotic treatment of GAS pharyngitis to prevent subsequent attacks of ARF. A single intramuscular injection of 600,000 or 1.2 million units of benzathine penicillin (depending on weight) or 10-day course of penicillin V is advised (Table 46–4). Efforts at primary prevention are confounded by the fact that many patients who develop ARF are not aware of preceding sore throat, there are no simple specific clinical signs diagnostic of streptococcal pharyngitis, and throat swabs and cultures are expensive. In an individual patient, antibiotic treatment for streptococcal sore throat is effective in reducing the occurrence of subsequent attacks of ARF by 70% to 80%.⁶⁹ While it is important in populations with a high incidence of ARF to promote presentation to primary health care with sore throat and proper diagnosis and management by the health system,⁷⁰ there is no definitive proof that this approach is effective in reducing overall ARF incidence in the population.^71,72

Secondary prevention, the long-term administration of antibiotics to prevent recurrences, is of proven benefit and is cost-effective.⁷³ Benzathine penicillin 600,000 or 1.2 million units intramuscularly every 4 weeks is the standard recommendation.^50,74 An injection once every 2 or 3 weeks is more effective but may be more difficult to implement.⁷³ Oral penicillin V 250 mg orally twice daily is preferred by some practitioners, particularly in very thin patients who are on warfarin anticoagulation after valve replacement surgery, when deep intramuscular injections may be undesirable.⁷⁵ However, no studies have compared oral penicillin V with intramuscular benzathine penicillin in the prevention of rheumatic fever.

Prophylaxis is usually advised until age 21 years or for at least 10 years after the last attack of ARF, whichever is longer, with longer durations for individuals who have persistent and significant valvular damage. Duration of secondary prophylaxis should be individualized, taking into account factors influencing risk of recurrence. Prophylaxis until age 35 to 40 years, or sometimes for life, is recommended for patients with severe valve disease or after valve replacement surgery.

Cardiac involvement remains the most serious manifestation of ARF with severe life-threatening heart failure in the acute stages due to the acute valvulitis.^76,77 Inadequate coverage with antibiotic prophylaxis to prevent future attacks of ARF puts patients at risk for repeated episodes of ARF, scarring of the heart valves, chronic valvular heart disease, heart failure, and death, usually before middle age. The revised Jones criteria provide an important opportunity to improve the diagnostic accuracy of ARF, particular in moderate-/high-risk populations. These, together with increased awareness and global advocacy, will improve case detection, foster research, and accurately determine the global burden of ARF and RHD.

We would like to thank Dr. Bongani M. Mayosi, who contributed to the previous version of this chapter in the 13th edition.