Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A streptococci. 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 ofheart disease in children in developing countries and is a major cause of mortality and morbidity in adults as well. It was recently 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. 6-1).
Epidemiology
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.
Pathogenesis
Organism Factors
Based on currently available evidence, ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci. 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 are currently being investigated.
FIGURE 6-1
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.
It has been postulated that a series of preceding streptococcal infections is needed to “prime” the immune system prior to the final infection that directly causes disease.
Host Factors
Approximately 3-6% of any population may be susceptible to ARF, and this proportion does not vary dramatically between populations. Findings offamilial clustering ofcases and concordance in monozygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic. Particular 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 ßj 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. 6-2).
Epitopes present in the cell wall, cell membrane, and the A, B, and C repeat regions of the streptococcal M protein are immunologically similar to molecules in human myosin, tropomyosin, keratin, actin, laminin, vimentin, and N-acetylglucosamine. This molecular mimicry is the basis for the autoimmune response that leads to ARF It has been hypothesized that human molecules—particularly epitopes in cardiac myosin—result in T cell sensitization. These T cells are then recalled following subsequent exposure to group A streptococci bearing immunologically similar epitopes.
However, myosin cross-reactivity with M protein does not explain the valvular damage that is the hallmark of rheumatic carditis, given that myosin is not present in valvular tissue. The link may be laminin, another α-helical coiled-coil protein like myosin and M protein, which is found in cardiac endothelium and is recognized by anti-myosin, anti-M protein T cells. Moreover, antibodies to cardiac valve tissue cross-react with the N-acetylglucosamine of group A streptococcal carbohydrate, and there is some evidence that these antibodies may be responsible for valvular damage.
Clinical Features
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.
FIGURE 6-2
Pathogenetic pathway for acute rheumatic fever and rheumatic heart disease.
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. 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. Pericarditis most commonly causes a friction rub or a small effusion on echocardiography and may occasionally cause pleuritic central chest pain. Myocardial involvement is almost never responsible in itself for cardiac failure. 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.
Joint Involvement
To qualify as a major manifestation, joint involvement inARF must be arthritic, i.e., objective evidence ofinflam-mation, 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 monoarthritis 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.
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. 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.
Skin Manifestations
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.
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. 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 antistreptolysin 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 non-group A β-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 6-1). These criteria include a preceding streptococcal type A infection as well as some combination of major and minor manifestations.
