Jonathan R. Carapetis
Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A streptococcus. Although many parts of the body may be affected, almost all of the manifestations resolve completely. The exception is cardiac valvular damage (rheumatic heart disease [RHD]), which may persist after the other features have disappeared.
ARF and RHD are diseases of poverty. They were common in all countries until the early twentieth century, when their incidence began to decline in industrialized nations. This decline was largely attributable to improved living conditions—particularly less crowded housing and better hygiene—which resulted in reduced transmission of group A streptococci. The introduction of antibiotics and improved systems of medical care had a supplemental effect. Recurrent outbreaks of ARF began in the 1980s in the Rocky Mountain states of the United States, where elevated rates persist.
The virtual disappearance of ARF and reduction in the incidence of RHD in industrialized countries during the twentieth century unfortunately was not replicated in developing countries, where these diseases continue unabated. RHD is the most common cause of heart disease in children in developing countries and is a major cause of mortality and morbidity in adults as well. It has been estimated that between 15 and 19 million people worldwide are affected by RHD, with approximately one-quarter of a million deaths occurring each year. Some 95% of ARF cases and RHD deaths now occur in developing countries.
Although ARF and RHD are relatively common in all developing countries, they occur at particularly elevated rates in certain regions. These “hot spots” are sub-Saharan Africa, Pacific nations, Australasia, and the Indian subcontinent (Fig. 26-1). Unfortunately, most developing countries do not currently have coordinated, register-based RHD control programs, which are proven to be cost-effective in reducing the burden of RHD. Enhancing awareness of RHD and mobilizing resources for its control in developing countries is an issue requiring international attention.
Prevalence of rheumatic heart disease in children aged 5–14 years. Circles within Australia and New Zealand represent indigenous populations, and also Pacific Islanders in New Zealand. (From JR Carapetis et al: Lancet Infect Dis. Copyright 2005; with permission from Elsevier.)
ARF is mainly a disease of children aged 5–14 years. Initial episodes become less common in older adolescents and young adults and are rare in persons aged >30 years. By contrast, recurrent episodes of ARF remain relatively common in adolescents and young adults. This pattern contrasts with the prevalence of RHD, which peaks between 25 and 40 years. There is no clear gender association for ARF, but RHD more commonly affects females, sometimes up to twice as frequently as males.
Based on currently available evidence, ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci. Although classically, certain M-serotypes (particularly types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29) were associated with ARF, in high-incidence regions, it is now thought that any strain of group A streptococcus has the potential to cause ARF. Potential role of skin infection and of groups C and G streptococci are currently being investigated.
Approximately 3–6% of any population may be susceptible to ARF, and this proportion does not vary dramatically between populations. Findings of familial clustering of cases and concordance in monozygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic. Particular human leukocyte antigen (HLA) class II alleles appear to be strongly associated with susceptibility. Associations have also been described with high levels of circulating mannose-binding lectin and polymorphisms of transforming growth factor β1 gene and immunoglobulin genes. High-level expression of a particular alloantigen present on B cells, D8-17, has been found in patients with a history of ARF in many populations, with intermediate-level expression in first-degree family members, suggesting that this may be a marker of inherited susceptibility.
THE IMMUNE RESPONSE
When a susceptible host encounters a group A streptococcus, an autoimmune reaction results, which leads to damage to human tissues as a result of cross-reactivity between epitopes on the organism and the host (Fig. 26-2). Cross-reactive epitopes are present in the streptococcal M protein and the N-acetylglucosamine of group A streptococcal carbohydrate and are immunologically similar to molecules in human myosin, tropomyosin, keratin, actin, laminin, vimentin, and N-acetylglucosamine. It is currently thought that the initial damage is due to cross-reactive antibodies attaching at the cardiac valve endothelium, allowing the entry of primed CD4+ T cells, leading to subsequent T cell-mediated inflammation.
Pathogenetic pathway for acute rheumatic fever and rheumatic heart disease. (From JR Carapetis et al: Lancet 366:155, 2005. Copyright 2005; with permission from Elsevier.)
There is a latent period of ~3 weeks (1–5 weeks) between the precipitating group A streptococcal infection and the appearance of the clinical features of ARF. The exceptions are chorea and indolent carditis, which may follow prolonged latent periods lasting up to 6 months. Although many patients report a prior sore throat, the preceding group A streptococcal infection is commonly subclinical; in these cases it can only be confirmed using streptococcal antibody testing. The most common clinical presentation of ARF is polyarthritis and fever. Polyarthritis is present in 60–75% of cases and carditis in 50–60%. The prevalence of chorea in ARF varies substantially between populations, ranging from <2% to 30%. Erythema marginatum and subcutaneous nodules are now rare, being found in <5% of cases.
Up to 60% of patients with ARF progress to RHD. The endocardium, pericardium, or myocardium may be affected. Valvular damage is the hallmark of rheumatic carditis. The mitral valve is almost always affected, sometimes together with the aortic valve; isolated aortic valve involvement is rare. Early valvular damage leads to regurgitation. Over ensuing years, usually as a result of recurrent episodes, leaflet thickening, scarring, calcification, and valvular stenosis may develop (Fig. 26-3). Videos 26-1 and 26-2 can be accessed at the following link: http://www.mhprofessional.com/mediacenter/. Therefore the characteristic manifestation of carditis in previously unaffected individuals is mitral regurgitation, sometimes accompanied by aortic regurgitation. myocardial inflammation may affect electrical conduction pathways, leading to P-R interval prolongation (first-degree AV block or rarely higher-level block) and softening of the first heart sound.
Transthoracic echocardiographic image from a 5-year-old boy with chronic rheumatic heart disease. This diastolic image demonstrates leaflet thickening, restriction of the anterior mitral valve leaflet tip, and doming of the body of the leaflet toward the interventricular septum. This appearance (marked by the arrowhead) is commonly described as a “hockey stick” or an “elbow” deformity. AV, aortic valve; LA, left atrium; LV, left ventricle; MV, mitral valve; RV, right ventricle. (Courtesy of Dr. Bo Remenyi, Department of Paediatric and Congential Cardiac Services, Starship Children’s Hospital, Auckland, New Zealand.)
To qualify as a major manifestation, joint involvement in ARF must be arthritic, i.e., objective evidence of inflammation, with hot, swollen, red and/or tender joints, and involvement of more than one joint (i.e., polyarthritis). The typical arthritis is migratory, moving from one joint to another over a period of hours. ARF almost always affects the large joints—most commonly the knees, ankles, hips, and elbows—and is asymmetric. The pain is severe and usually disabling until anti-inflammatory medication is commenced.
Less severe joint involvement is also relatively common but qualifies only as a minor manifestation. Arthralgia without objective joint inflammation usually affects large joints in the same migratory pattern as polyarthritis. In some populations, aseptic mono-arthritis may be a presenting feature of ARF. This may occur because of early commencement of anti-inflammatory medication before the typical migratory pattern is established.
The joint manifestations of ARF are highly responsive to salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs). Indeed, joint involvement that persists more than 1 or 2 days after starting salicylates is unlikely to be due to ARF. Conversely, if salicylates are commenced early in the illness, before fever and migratory polyarthritis have become manifest, it may be difficult to make a diagnosis of ARF. For this reason, salicylates and other NSAIDs should be withheld—and pain managed with acetaminophen or codeine—until the diagnosis is confirmed.
Sydenham’s chorea commonly occurs in the absence of other manifestations, follows a prolonged latent period after group A streptococcal infection, and is found mainly in females. The choreiform movements affect particularly the head (causing characteristic darting movements of the tongue) and the upper limbs. They may be generalized or restricted to one side of the body (hemi-chorea). The chorea varies in severity. In mild cases it may be evident only on careful examination, while in the most severe cases the affected individuals are unable to perform activities of daily living and are at risk of injuring themselves. Chorea eventually resolves completely, usually within 6 weeks.
The classic rash of ARF is erythema marginatum, which begins as pink macules that clear centrally, leaving a serpiginous, spreading edge. The rash is evanescent, appearing and disappearing before the examiner’s eyes. It occurs usually on the trunk, sometimes on the limbs, but almost never on the face.
Subcutaneous nodules occur as painless, small (0.5– 2 cm), mobile lumps beneath the skin overlying bony prominences, particularly of the hands, feet, elbows, occiput, and occasionally the vertebrae. They are a delayed manifestation, appearing 2–3 weeks after the onset of disease, last for just a few days up to 3 weeks, and are commonly associated with carditis.
Fever occurs in most cases of ARF, although rarely in cases of pure chorea. Although high-grade fever (≥39°C) is the rule, lower-grade temperature elevations are not uncommon. Elevated acute-phase reactants are also present in most cases. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are often dramatically elevated. Occasionally, the peripheral leukocyte count is mildly elevated.
EVIDENCE OF A PRECEDING GROUP A STREPTOCOCCAL INFECTION
With the exception of chorea and low-grade carditis, both of which may become manifest many months later, evidence of a preceding group A streptococcal infection is essential in making the diagnosis of ARF. As most cases do not have a positive throat swab culture or rapid antigen test, serologic evidence is usually needed. The most common serologic tests are the anti-streptolysin O (ASO) and anti-DNase B (ADB) titers. Where possible, age-specific reference ranges should be determined in a local population of healthy people without a recent group A streptococcal infection.
OTHER POST-STREPTOCOCCAL SYNDROMES THAT MAY BE CONFUSED WITH RHEUMATIC FEVER
Post-streptococcal reactive arthritis (PSRA) is differentiated from ARF on the basis of: (1) small-joint involvement that is often symmetric; (2) a short latent period following streptococcal infection (usually <1 week); (3) occasional causation by nongroup A (μ-hemolytic streptococcal infection; (4) slower responsiveness to salicylates; and (5) the absence of other features of ARF, particularly carditis.
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) is a term that links a range of tic disorders and obsessive-compulsive symptoms with group A streptococcal infections. People with PANDAS are said not to be at risk of carditis, unlike patients with Sydenham’s chorea. The diagnoses of PANDAS and PSRA should rarely be made in populations with a high incidence of ARF.
CONFIRMING THE DIAGNOSIS
Because there is no definitive test, the diagnosis of ARF relies on the presence of a combination of typical clinical features together with evidence of the precipitating group A streptococcal infection, and the exclusion of other diagnoses. This uncertainty led Dr. T. Duckett Jones in 1944 to develop a set of criteria (subsequently known as the Jones criteria) to aid in the diagnosis. An expert panel convened by the World Health Organization (WHO) clarified the use of the Jones criteria in ARF recurrences (Table 26-1). Because each revision of the Jones criteria since 1944 has reduced sensitivity and increased specificity, in response to the decline in incidence of ARF in high-income countries, there is now concern that they may be too insensitive for countries where ARF incidence remains high. As a result, some countries (e.g., Australia and New Zealand) have developed their own, more sensitive, diagnostic criteria for ARF in their populations (links available at the RHDnet website www.worldheart.org/rhd).
2002–2003 WORLD HEALTH ORGANIZATION CRITERIA FOR THE DIAGNOSIS OF RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE (BASED ON THE 1992 REVISED JONES CRITERIA)
TREATMENT Acute Rheumatic Fever
Patients with possible ARF should be followed closely to ensure that the diagnosis is confirmed, treatment of heart failure and other symptoms is undertaken, and preventive measures including commencement of secondary prophylaxis, inclusion on an ARF registry, and health education are commenced. Echocardiography should be performed on all possible cases to aid in making the diagnosis and to determine the severity at baseline of any carditis. Other tests that should be performed are listed in Table 26-2.
RECOMMENDED TESTS IN CASES OF POSSIBLE ACUTE RHEUMATIC FEVER
There is no treatment for ARF that has been proven to alter the likelihood of developing, or the severity of, RHD. With the exception of treatment of heart failure, which may be lifesaving in cases of severe carditis, the treatment of ARF is symptomatic.
ANTIBIOTICS All patients with ARF should receive antibiotics sufficient to treat the precipitating group A streptococcal infection. Penicillin is the drug of choice and can be given orally (as phenoxymethyl penicillin, 500 mg [250 mg for children ≤27 kg] PO twice daily, or amoxicillin 50 mg/kg [max 1 g] daily, for 10 days] or as a single dose of 1.2 million units (600,000 units for children ≤27 kg) IM benzathine penicillin G.
SALICYLATES AND NSAIDS These may be used for the treatment of arthritis, arthralgia, and fever, once the diagnosis is confirmed. They are of no proven value in the treatment of carditis or chorea. Aspirin is the drug of choice. An initial dose of 80–100 mg/kg per day in children (4–8 g/d in adults) in 4–5 divided doses is often needed for the first few days up to 2 weeks. A lower dose should be used if symptoms of salicylate toxicity emerge, such as nausea, vomiting, or tinnitus. When the acute symptoms are substantially resolved, the dose can be reduced to 60–70 mg/kg per day for a further 2–4 weeks. Fever, joint manifestations, and elevated acute-phase reactants sometimes recur up to 3 weeks after the medication is discontinued. This does not indicate a recurrence and can be managed by recommencing salicylates for a brief period. Although less well studied, naproxen at a dose of 10–20 mg/kg per day has been reported to lead to good symptomatic response.
CONGESTIVE HEART FAILURE Glucocorticoids The use of glucocorticoids in ARF remains controversial. Two meta-analyses have failed to demonstrate a benefit of glucocorticoids compared to placebo or salicylates in improving the short- or longer-term outcome of carditis. However, the studies included in these meta-analyses all took place >40 years ago and did not use medications in common usage today. Many clinicians treat cases of severe carditis (causing heart failure) with glucocorticoids in the belief that they may reduce the acute inflammation and result in more rapid resolution of failure. However, the potential benefits of this treatment should be balanced against the possible adverse effects, including gastrointestinal bleeding and fluid retention. If used, prednisone or prednisolone are recommended at doses of 1–2 mg/kg per day (maximum, 80 mg). Glucocorticoids are often only required for a few days or up to a maximum of 3 weeks.
MANAGEMENT OF HEART FAILURE See Chap. 17.
BED REST Traditional recommendations for long-term bed rest, once the cornerstone of management, are no longer widely practiced. Instead, bed rest should be prescribed as needed while arthritis and arthralgia are present, and for patients with heart failure. Once symptoms are well controlled, gradual mobilization can commence as tolerated.
CHOREA Medications to control the abnormal movements do not alter the duration or outcome of chorea. Milder cases can usually be managed by providing a calm environment. In patients with severe chorea, carbamazepine or sodium valproate are preferred to haloperidol. A response may not be seen for 1–2 weeks, and a successful response may only be to reduce rather than resolve the abnormal movements. Medication should be continued for 1–2 weeks after symptoms subside.
INTRAVENOUS IMMUNOGLOBULIN (IVIg) Small studies have suggested that IVIg may lead to more rapid resolution of chorea but has shown no benefit on the short- or long-term outcome of carditis in ARF without chorea. In the absence of better data, IVIg is not recommended except in cases of severe chorea refractory to other treatments.
Untreated, ARF lasts on average 12 weeks. With treatment, patients are usually discharged from hospital within 1–2 weeks. Inflammatory markers should be monitored every 1–2 weeks until they have normalized (usually within 4–6 weeks), and an echocardiogram should be performed after 1 month to determine if there has been progression of carditis. Cases with more severe carditis need close clinical and echocardiographic monitoring in the longer term.
Once the acute episode has resolved, the priority in management is to ensure long-term clinical follow-up and adherence to a regimen of secondary prophylaxis. Patients should be entered onto the local ARF registry (if present) and contact made with primary care practitioners to ensure a plan for follow-up and administration of secondary prophylaxis before the patient is discharged. Patients and their families should also be educated about their disease, emphasizing the importance of adherence to secondary prophylaxis. If carditis is present, they should also be informed of the need for antibiotic prophylaxis against endocarditis for dental and surgical procedures.
Ideally, primary prevention would entail elimination of the major risk factors for streptococcal infection, particularly overcrowded housing. This is difficult to achieve in most places where ARF is common.
Therefore, the mainstay of primary prevention for ARF remains primary prophylaxis (i.e., the timely and complete treatment of group A streptococcal sore throat with antibiotics). If commenced within 9 days of sore throat onset, a course of penicillin (as outlined earlier for treatment of ARF) will prevent almost all cases of ARF that would otherwise have developed. This important strategy relies on individuals presenting for medical care when they have a sore throat, the availability of trained health and microbiology staff along with the materials and infrastructure to take throat swabs, and a reliable supply of penicillin. Unfortunately, many of these elements are not available in developing countries.
The mainstay of controlling ARF and RHD is secondary prevention. Because patients with ARF are at dramatically higher risk than the general population of developing a further episode of ARF after a group A streptococcal infection, they should receive long-term penicillin prophylaxis to prevent recurrences. The best antibiotic for secondary prophylaxis is benzathine penicillin G (1.2 million units, or 600,000 units if ≤27 kg) delivered every 4 weeks. It can be given every 3 weeks, or even every 2 weeks, to persons considered to be at particularly high risk, although in settings where good compliance with 4-weekly dosing can be achieved, more frequent dosing is rarely needed. Oral penicillin V (250 mg) can be given twice daily instead but is somewhat less effective than benzathine penicillin G. Penicillin-allergic patients can receive erythromycin (250 mg) twice daily.
The duration of secondary prophylaxis is determined by many factors, in particular the duration since the last episode of ARF (recurrences become less likely with increasing time), age (recurrences are less likely with increasing age), and the severity of RHD (if severe, it may be prudent to avoid even a very small risk of recurrence because of the potentially serious consequences) (Table 26-3). Secondary prophylaxis is best delivered as part of a coordinated RHD control program, based around a registry of patients. Registries improve the ability to follow patients and identify those who default from prophylaxis and institute strategies to improve adherence.
AMERICAN HEART ASSOCIATION RECOMMENDATIONS FOR DURATION OF SECONDARY PROPHYLAXISa