Chapter 352: Acute Rheumatic Fever

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 major 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.

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, with particularly high rates in sub-Saharan Africa, Pacific nations, Australasia, and South and Central Asia. The pathogenetic pathway from exposure to group A streptococcus followed by pharyngeal infection and subsequent development of ARF, ARF recurrences, and development of RHD and its complications is associated with a range of risk factors and, therefore, potential interventions at each point (Fig. 352-1). In affluent countries, many of these risk factors are well controlled, and where needed, interventions are in place. Unfortunately, the greatest burden of disease is found in developing countries, most of which do not have the resources, capacity, and/or interest to tackle this multifaceted disease. In particular, almost none of the developing countries has a coordinated, register-based RHD control program, which is proven to be cost-effective in reducing the burden of RHD. Enhancing awareness of RHD and mobilizing resources for its control in developing countries are issues requiring international attention.

ARF is mainly a disease of children age 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.

ORGANISM FACTORS

Based on currently available evidence, ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci (Chap. 143). 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. The potential role of skin infection and of groups C and G streptococci is currently being investigated.

HOST FACTORS

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 mono-zygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic, with 44% concordance in mono-zygotic twins compared to 12% in dizygotic twins, and heritability more recently estimated at 60%. Most evidence for host factors focuses on immunologic determinants. Some human leukocyte antigen (HLA) class II alleles, particularly HLA-DR7 and HLA-DR4, appear to be associated with susceptibility, whereas other class II alleles have been associated with protection (HLA-DR5, HLA-DR6, HLA-DR51, HLA-DR52, and HLA-DQ). Associations have also been described with polymorphisms at the tumor necrosis factor α locus (TNF-α-308 and TNF-α-238), high levels of circulating mannose-binding lectin, and Toll-like receptors.

THE IMMUNE RESPONSE

The most widely accepted theory of rheumatic fever pathogenesis is based on the concept of molecular mimicry, whereby an immune response targeted at streptococcal antigens (mainly thought to be on the M protein and the N-acetylglucosamine of group A streptococcal carbohydrate) also recognizes human tissues. In this model, cross-reactive antibodies bind to endothelial cells on the heart valve, leading to activation of the adhesion molecule VCAM-1, with resulting recruitment of activated lymphocytes and lysis of endothelial cells in the presence of complement. The latter leads to release of peptides including laminin, keratin, and tropomyosin, which, in turn, activates cross-reactive T cells that invade the heart, amplifying the damage and causing epitope spreading. An alternative hypothesis proposes that the initial damage is due to streptococcal invasion of epithelial surfaces, with binding of M protein to type IV collagen allowing it to become immunogenic, but not through the mechanism of molecular mimicry.

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 features are polyarthritis (present in 60–75% of cases) and carditis (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.

HEART INVOLVEMENT

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. Damage to the pulmonary or tricuspid valves is usually secondary to increased pulmonary pressures resulting from left-sided valvular disease. 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. 352-2). See Videos 352-1 and 352-2. 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 atrioventricular block or rarely higher level block) and softening of the first heart sound.

People with RHD are often asymptomatic for many years before their valvular disease progresses to cause cardiac failure. Moreover, particularly in resource-poor settings, the diagnosis of ARF is often not made, so children, adolescents, and young adults may have RHD but not know it. These cases can be diagnosed using echocardiography; auscultation is poorly sensitive and specific for RHD diagnosis in asymptomatic patients. Echocardiographic screening of school-aged children in populations with high rates of RHD is becoming more widespread and has been facilitated by improving technologies in portable echocardiography and the availability of consensus guidelines for the diagnosis of RHD on echocardiography (Table 352-1). Although a diagnosis of definite RHD on screening echocardiography should lead to commencement of secondary prophylaxis, the clinical significance of borderline RHD has yet to be determined.

JOINT INVOLVEMENT

The most common form of joint involvement in ARF is arthritis, i.e., objective evidence of inflammation, with hot, swollen, red, and/or tender joints, and involvement of more than one joint (i.e., polyarthritis). Polyarthritis is typically 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 and has been recognized as a potential major manifestation in high-risk populations in the most recent revision of the Jones criteria. Arthralgia without objective joint inflammation usually affects large joints in the same migratory pattern as polyarthritis. In some populations, aseptic monoarthritis may be a presenting feature of ARF, which may, in turn, result from 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 for more than 1 or 2 days after starting salicylates is unlikely to be due to ARF.

CHOREA

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 (Chap. 428). They may be generalized or restricted to one side of the body (hemi-chorea). In mild cases, chorea may be evident only on careful examination, whereas in the most severe cases, the affected individuals are unable to perform activities of daily living. There is often associated emotional lability or obsessive-compulsive traits, which may last longer than the choreiform movements (which usually resolve within 6 weeks but sometimes may take up to 6 months).

SKIN MANIFESTATIONS

The classic rash of ARF is erythema marginatum (Chap. 16), 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.

OTHER FEATURES

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.

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. Because 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.

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. The most recent revision of the Jones criteria (Table 352-2) require the clinician to determine if the patient is from a setting or population known to experience low rates of ARF. For this group, there is a set of “low-risk” criteria; for all others, there is a set of more sensitive criteria.

TREATMENT

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.

PRIMARY PREVENTION

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 above for treatment of ARF) will prevent almost all cases of ARF that would otherwise have developed. In settings where ARF and RHD are common but microbiologic diagnosis of group A streptococcal pharyngitis is not available, such as in resource-poor countries, primary care guidelines often recommend that all patients with sore throat be treated with penicillin or, alternatively, that a clinical algorithm be used to identify patients with a higher likelihood of group A streptococcal pharyngitis. Although imperfect, such approaches recognize the importance of ARF prevention at the expense of overtreating many cases of sore throat that are not caused by group A streptococcus.

SECONDARY PREVENTION

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 an every-4-week dosing schedule can be achieved, more frequent dosing is rarely needed. Oral penicillin V (250 mg) can be given twice daily instead but is 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 352-4). 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 to institute strategies to improve adherence.