Rheumatic fever

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Acute Rheumatic Fever? What are the typical findings for this disease?

Acute Rheumatic Fever (RF) occurs as an abnormal immune response to a group A streptococcal infection that most commonly affects the joints, heart, brain, and skin. The most common symptoms of RF are arthritis, symptoms related to carditis, and chorea. These are 3 of the 5 major Jones Criteria, used to diagnose acute RF.

According to the Jones criteria, a patient needs to fulfill:

2 major
or 1 major and 2 minor criteria,

plus

Evidence of a preceding streptococcal infection

The major criteria are:

• Polyarthritis

• Carditis

• Chorea

• Erythema marginatum

• Subcutaneous nodules

The minor criteria are:

• Fever

• Arthralgia (cannot use if polyarthritis is used as major criteria)

• Elevated acute phase reactants (ESR and/or CRP)

• Prolonged PR interval (1st degree AV block on ECG)

Evidence of preceding group A streptococcal infection

• Positive throat culture or rapid strep test

• Elevated or rising streptococcal antibody titer

Diagnosis of Recurrent RF

The World Health Organization guidelines for diagnosis of recurrences recommend:

• A RF recurrence in a patient without rheumatic heart disease requires fulfillment of the Jones criteria (2 major or 1 major with 2 minor criteria, plus evidence of preceding strep infection).

• A RF recurrence in a patient with underlying rheumatic heart disease requires 2 minor criteria PLUS evidence of a preceding strep infection.

Modifications to the Jones Criteria

Diagnostic criteria have been modified in parts of the world where RF and rheumatic heart disease (RHD) continue to be common. The intent of these modifications is to improve the sensitivity of the criteria where there is more of a concern for underdiagnosis.

These modifications include:

• accepting monoarthritis or polyarthralgia as a major criterion, especially in patients who have received anti-inflammatory treatment,

• accepting echocardiographic evidence of cardiac involvement (carditis) as a major criterion in the absence of clinical carditis,

• allow diagnosis of a recurrence of RF based on minor manifestations, especially in patients with existing rheumatic heart disease.

Exceptions to the Jones Diagnostic Criteria

RF may be diagnosed without fulfilling the Jones criteria in 3 settings:

• in patients who present with isolated chorea (longer interval between strep and onset of symptoms).

• in patients who present with indolent or insidious-onset carditis (detected months to years after the acute illness).

• in patients with a prior history of RF or rheumatic heart disease.

Clinical Manifestations of RF

Polyarthritis (40%-70%) is the most common clinical manifestation of RF, followed by carditis (30%-70%) and chorea (10%-30%). Subcutaneous nodules and the rash of erythema marginatum occur in a minority (<2%-3%) of patients, and almost never occur in isolation; both almost always occur with carditis.

The latency period between group A strep pharyngitis and the onset of manifestations ranges from 10 days to 5 weeks (average 18 days) for all of the manifestations except for chorea. Chorea occurs after a longer latency period, ranging from 1-6 months.

Rheumatic Carditis

Carditis occurs in 30%-70% of RF cases and is the manifestation associated with long-term morbidity and mortality. In developing countries, rheumatic carditis is the most common cause of acquired heart disease in children and young adolescents. In the United States and other developed countries, Kawasaki disease is now the most common cause of acquired heart disease.

Although rheumatic carditis has been traditionally described as a pancarditis, the dominant and most important abnormality is valvulitis. Specifically, valvulitis results in mitral and/or aortic regurgitation. The clinical presentation varies widely, from an asymptomatic patient with a murmur of mitral (MR) and/or aortic (AR) regurgitation to a critically ill patient presenting in heart failure. Although the reported severity varies between series, about 25% of patients present with severe carditis and heart failure.

It is important to note that ~80% of patients who develop carditis do so within the first 2 weeks of the RF illness; beyond this time, subsequent development of cardiac involvement with the acute phase is unusual.

It is also important to note that the severity of the valvular regurgitation and carditis often decreases as the inflammation subsides. Patients with mild involvement may show complete resolution of their cardiac findings. Patients with more severe carditis are more likely to have persistent or evolving rheumatic heart disease.

Rheumatic Mitral Regurgitation

Mitral regurgitation (MR) is the most common cardiac abnormality in patients with acute RF, occurring in ~95% of cases with acute carditis. The mechanism of this MR is a combination of mitral annular dilation and chordal elongation to the anterior leaflet that results in abnormal coaptation (in some cases, prolapse of the tip of the anterior mitral leaflet). Rarely, the chordae may rupture, resulting in a flail leaflet with severe MR.

Most patients have mild MR and do not have cardiac symptoms. However, with acute moderate to severe MR, the LV may have difficulty handling the acute volume overload, leading to elevated left heart and pulmonary venous pressures, and heart failure with pulmonary edema. In this setting, symptoms may include dyspnea, orthopnea, paroxysmal nocturnal dyspnea, cough, and even hemoptysis. Pulmonary venous hypertension may lead to pulmonary hypertension and right heart failure.

On examination, tachycardia out of proportion to age and temperature can be an early sign of carditis. On auscultation, a high-pitched, regurgitant holosystolic murmur of MR is best heard at the apex, radiating to the left axilla. This murmur is best heard at end-expiration with the patient in the left lateral decubitus position. It is important to note that acute severe MR may be present even with a relatively soft murmur. A low-pitched mid-diastolic murmur may be heard at the apex in the setting of significant MR due to increased flow across the mitral valve (Carey Coombs murmur).

Rheumatic Aortic Regurgitation

Aortic regurgitation (AR) occurs in 20%-25% of patients with acute carditis, usually in combination with MR. Isolated AR occurs in ~5% of acute carditis.

Patients with acute mild AR are usually asymptomatic. Moderate to severe acute AR may be poorly tolerated, resulting in heart failure (pulmonary edema and low cardiac output). Heart failure symptoms may be similar to those described above for significant MR. Patients are often tachycardic and tachypneic. Unlike the examination with chronic AR, the pulse pressure may be narrow without increased or bounding pulses. On auscultation, the diastolic decrescendo murmur is softer, shorter, and lower pitched than the murmur heard with chronic AR. Thus, this murmur can be missed, especially if the patient is tachycardic. In some cases, there is a soft, short systolic ejection murmur over the LV outflow tract related to increased flow. A low-pitched, mid-to-late diastolic rumbling murmur may be heard at the apex even though the mitral valve is not stenotic.

It is noteworthy that acute rheumatic AR is less likely than MR to disappear with resolution of acute inflammation.

Rheumatic Pericarditis

Pericarditis occurs in ~5%-10% of acute rheumatic carditis. When it occurs, it is nearly always associated with significant MR and/or AR. In the absence of valvular involvement, pericarditis is unlikely related to RF, and other etiologies should be considered.

Clinically, patients may have positional chest and shoulder pain. On auscultation, a friction rub may be audible, and may obscure murmurs due to valvular dysfunction.

Echocardiography allows detection and semiquantitation of pericardial effusions.

Unlike other types of pericarditis, tamponade, and constrictive pericarditis very rarely occur.

Rheumatic Myocarditis

Rheumatic carditis has long been considered a “‘pancarditis.” However, the important abnormalities are related to valvular dysfunction (specifically, regurgitation) rather than myocarditis and myocardial dysfunction.

Although biopsy and autopsy specimens have shown evidence of myocardial involvement, unlike other forms of myocarditis, myocyte necrosis associated with lymphocyte infiltration does not occur, and troponin I levels are not often elevated. While there may be subtle abnormalities of contractility, left ventricular ejection phase indices (shortening and ejection fraction) are usually normal.

Thus, it is important to note that heart failure does not occur in acute or chronic rheumatic heart disease in the absence of significant valvular dysfunction.

Polyarthritis

Migratory polyarthritis is the most common major manifestation of RF, affecting 40%-70% of cases. Although it is the most common manifestation, it is the least specific and is, therefore, the most common feature associated with misdiagnosis. Typically, the arthritis migrates from large joint to large joint. Joints most commonly affected are the knees, ankles, elbows, and wrists. The joints are red, swollen, and very tender. It is important to note that the presentation and evolution of joint involvement and symptoms may be affected by the administration of anti-inflammatory medications such as aspirin or nonsteroidal anti-inflammatory agents.

In some parts of the world, monoarthritis or polyarthralgia appears to be a common mode of presentation.

Even without treatment, the arthritis of RF resolves within 3-4 weeks in most cases and is almost always not associated with residual abnormalities. See below for response to treatment. Although arthritis and carditis may occur together, the severity of joint and heart involvement tend to be inversely related.

Poststreptococcal Reactive Arthritis

Some patients develop arthritis after strep pharyngitis that differs from the typical polyarthritis of RF. This has been termed poststreptococcal reactive arthritis, which typically occurs after a shorter latent period (7-10 days compared with 10 days to 5 weeks for RF), tends to be non-migratory and more additive and persistent, may involve small joints or the axial skeleton, and does not respond as well to anti-inflammatory medications as the arthritis of RF. These patients do not meet the Jones Criteria.

The important consideration is whether these patients are at risk for rheumatic heart disease (and, therefore, in need of secondary prophylaxis). A very small number of patients with poststreptococcal reactive arthritis have been found to have evidence of cardiac involvement, but the vast majority do not. Some experts recommend that patients with this entity receive secondary prophylaxis for up to one-two years after onset, but this is controversial. Patients with evidence of valvular heart disease should be treated as having had RF and should receive secondary prophylaxis.

Chorea

The chorea of RF, also called Sydenham chorea, occurs in 10%-30% of cases of RF. In younger children, boys and girls are equally affected, but after age 10 years, females are more often affected, and chorea occurs uncommonly in postpubertal males.

It is important to note that the latency between strep pharyngitis and the onset of chorea is longer than for other manifestations of RF, and ranges from 1-6 months. Thus, chorea and arthritis are uncommon in the same patient. In addition, acute phase reactants are often normal, and anti-streptococcal antibodies may not be elevated.

The clinical manifestations of Sydenham chorea occur due to neuropathologic changes in the basal ganglia, cerebral cortex, and the cerebellum, and are characterized by involuntary, purposeless movements, muscular incoordination and/or weakness, and emotional lability. Descriptions have included facial grimaces, tongue movements (“bag of worms”), fidgetiness, halting and explosive speech, ” pronator sign,” ” milkmaid’s grip,” ” spooning,” and clumsiness. School performance may be affected due to irritability, decreased attention span, and decreased ability to cooperate. It is noteworthy that sensory deficits do not occur. Manifestations are usually bilateral, but in some patients, hemichorea is seen. Symptoms decrease with rest and sedation, and increase with effort or excitement. Median duration is 15 weeks; 75% of patients show resolution by 6 months, and, rarely, duration has been reported out to 2-3 years. Recurrent episodes of chorea are not uncommon.

Although neuroimaging and EEG abnormalities have been reported, these studies should not be performed routinely; rather, they should be reserved for atypical cases.

For consideration of pediatric autoimmune neuropsychiatric disorders associated with strep infections (PANDAS), see section on conditions sharing symptoms.

Erythema Marginatum

The rash of erythema marginatum is one of the major diagnostic criteria. It is relatively uncommon, occurring in <1% of RF cases. It is described as a bright pink macular rash with serpiginous borders with central clearing. The rash is painless, not pruritic, blanches on pressure, and, rarely, if ever, appears on the face. It is most common on the trunk and proximal extremities. The rash is often evanescent, with lesions that may change in appearance rapidly. Sometimes a hot bath or shower may bring out or accentuate the rash. Thus, this rash may be easily missed. It is usually seen early in the course of RF, but persistence or recurrence for months to years has been described.

Of importance, erythema marginatum is usually associated with carditis and almost never occurs as the sole major manifestation.

Subcutaneous Nodules

This is one of the major diagnostic criteria. It is uncommon, reported in <2% of RF cases. Subcutaneous nodules are usually 0.5-2.0 cm in diameter, round, firm, freely movable, nontender, and without evidence of inflammation. They tend to occur in crops over the extensor surfaces of joints or over the bony prominences of elbows, wrists, knees, ankles, scalp, and spinous processes over the back. Subcutaneous nodules are not evanescent, usually persisting for a few days up to 1-2 weeks. Because they are small and may not be associated with symptoms, they may be easily missed. Subcutaneous nodules almost always occur with carditis, and almost never as the sole major manifestation.

Other Clinical Manifestations

Manifestations not included in the diagnostic criteria include epistaxis and abdominal pain, each of which occur in ~5% of cases, and may occur before major manifestations. Both were minor manifestations in the original Jones criteria, but were subsequently removed for lack of specificity. Other nonspecific features include anorexia, malaise, fatigue, and a family history of RF or rheumatic heart disease.

What other disease/condition shares some of these symptoms?

Diseases that mimic the arthritis of RF include:

• Infectious arthritis (septic, Lyme disease, mycobacterial, fungal, viral)

• Post-infectious or reactive arthritis (enteric infection or inflammatory bowel disease; urogenital infection)

• Connective tissue/rheumatologic disease (rheumatoid arthritis, systemic vasculitis, SLE)

• Other, including gout, cancer, sarcoidosis, mucocutaneous disorders

Entities in the differential diagnosis of chorea:

• Atypical seizures

• Cerebrovascular accidents

• Collagen vascular disease

• Drug intoxication

• Familial chorea

• Chorea related to hormones

• Endocrine

• Lyme disease

• Wilson disease

• Possibly PANDAS (pediatric autoimmune neuropsychiatric disorders associated with strep infections)

Entities that may mimic the carditis of RF include:

• Viral myocarditis

• Infective endocarditis

• Viral pericarditis

• Newly diagnosed congenital heart disease (congenital mitral and/or aortic regurgitation), uncommon

What caused RF to develop at this time?

Current understanding of pathogenesis

Although our understanding of the pathogenesis of RF is incomplete, current evidence suggests an important inter-relationship between group A streptococci, the environment, and a susceptible host (see section on Epidemiology). Our current understanding of pathogenesis includes the following:

• Group A strep pharyngitis in a susceptible individual leads to strep breakdown products, including antigens that are cross-reactive with heart and other tissue antigens (termed, molecular mimicry).

• Immune response results in cross-reactive antibodies, cellular immune responses, and cytokine production.

• Antibodies bind endothelium of cardiac valves and other host tissues, resulting in injury, infiltration of inflammatory cells, and possibly upregulation of vascular cell adhesion molecule 1 (VCAM-1), which further promotes infiltration of T cells and macrophages, leading to further inflammation and damage.

For patients who develop rheumatic carditis and subsequent rheumatic heart disease, the following is postulated:

• Injury to the valve endothelium may expose structures and antigens (including vimentin and laminin).

• Inflammation of valve tissue may lead to neovascularization and further recruitment of T cells, leading to changes seen with chronic rheumatic heart disease (including granulomatous inflammation and Aschoff bodies).

• Activated B cells and macrophages express increased amounts of HLA class II molecules (on their surfaces), and may play a central role in presenting antigen to T cells, which are increasingly recognized as important effectors in the pathogenesis of chronic rheumatic heart disease.

• Infiltrating T cells are cross-reactive with strep M protein and cardiac proteins (myosin and laminin).

• Inflammatory cytokines seem to be important in the development of chronic rheumatic valvular disease.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Acute phase reactants, including C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR), should be drawn. CRP and/or ESR are almost invariably highly elevated in patients with acute rheumatic arthritis and/or carditis. In the presence of frank congestive failure, the ESR may be virtually normal.

A throat culture should be performed, but recovery of strep from the pharynx of a patient with RF is relatively uncommon. Also, a positive culture may only reflect the “carrier state” and may not be the strain of group A strep that triggered acute RF.

In addition, blood should be tested for anti-streptococcal antibody titers. Elevated or rising titers are evidence of a preceding streptococcal infection. When a single antibody titer is measured, 80%-85% of patients with RF will have an elevated titer. When two different tests are measured, over 90% of patients with RF have elevation of at least one titer. The ASO titer is sometimes/often measured first, and if it is not elevated, the anti-DNase B titer can be measured. ASO titers rise in about 1 week and peak ~3-6 weeks following strep infection. Anti-DNase B titers rise 1-2 weeks and peak 6-8 weeks following infection.

If infective endocarditis is being considered in the differential diagnosis, blood cultures should be obtained. These are negative in RF cases.

An electrocardiogram should be performed to search for 1st degree AV block or, less commonly, more advanced heart block.

Would imaging studies be helpful? If so, which ones?

Echocardiography should be performed on all patients with suspected RF with carditis to search for evidence of cardiac involvement. In particular, evidence of rheumatic carditis includes pathologic mitral and/or aortic regurgitation. Trivial or very mild mitral regurgitation may be detected by echocardiography in normals. This “‘physiologic” mitral regurgitation must be differentiated from “pathologic” mitral regurgitation. Even small amounts of aortic regurgitation are very uncommon in children, but occur in adults. The most widely accepted echo criteria to differentiate “physiologic” from “pathologic” mitral or aortic regurgitation are:

• MR or AR color jet >1 cm in length

• Color jet evident in at least 2 imaging planes

• Color jet with evidence of aliasing and peak velocity >2.5 m/s

• Doppler signal is holosystolic for MR and holodiastolic for AR

In some cases, there may be an associated pericardial effusion, but an isolated pericardial effusion in the absence of valvular regurgitation is unlikely to be due to RF. Mitral and/or aortic stenosis do not occur with the first episode of RF, but rather, represent chronic rheumatic heart disease that takes years to evolve. Either may be present in a patient with a recurrence of RF. Of particular importance, ventricular dysfunction does not occur with acute rheumatic carditis. The hallmark abnormality is valvular dysfunction, not myocardial dysfunction.

A chest x-ray should be performed if there is evidence of rheumatic carditis and/or increased work of breathing. An enlarged cardiac silhouette may be seen with significant valvular dysfunction or in the presence of a significant pericardial effusion. With significant carditis, there may be evidence of pulmonary venous congestion/pulmonary edema, or even evidence of right heart failure.

If you are able to confirm that the patient has rheumatic fever, what treatment should be initiated?

Treatment of Rheumatic Fever and Carditis

Medical management of RF and carditis has not changed substantially over the past ~50 years. The treatment is largely supportive, aimed at reducing inflammation and directed at preventing recurrences.

Although in the past, many patients with RF have been hospitalized for evaluation, diagnosis, and initiation of treatment, some patients can be evaluated and managed as outpatients with close follow-up, although there is older evidence that failure to hospitalize for acute RF is correlated with poor adherence to regimens to prevent recurrences.

Management of RF should include:

• Restricted activity. Some recommend bed/chair rest for up to 4-6 weeks for carditis.

• Antibiotic treatment to eradicate pharyngeal streptococci (whether or not throat culture is positive); see Primary Prophylaxis for details.

• Initiate Secondary Prophylaxis (see section for details).

Anti-inflammatory therapy:

• Mild to moderate carditis: Aspirin: 50-70 mg/kg/day in 3-4 divided doses for children; max 4-8 grams/day in adolescents and adults (target salicylate levels 20-30 mg/dL).

• Severe carditis (defined as cardiomegaly on x-ray and/or some degree of congestive failure):

• Steroids (prednisone 2 mg/kg/day or equivalent) for approximately 2 weeks, then taper over 4-6 weeks.

• Consider starting aspirin one week prior to stopping steroids to prevent rebound; duration may be guided by acute phase reactants (ESR, CRP).

• Consider salt and fluid restriction, diuretics, afterload reduction as temporizing measures.

• Some older literature suggests a role for digoxin, but this may relate to the prior belief that myocardial dysfunction played an important role. At present, the role for digoxin is unclear.

• Surgery to restore valve competence in severe, intractable heart failure. Note that such surgery may be life-saving since the abnormality is valvular dysfunction, not myocardial dysfunction.

Treatment of Rheumatic Fever without Carditis

Management of RF without carditis should include:

• Restricted activity. Duration should be guided by symptoms (joint and/or neurologic symptoms).

• Antibiotic treatment to eradicate pharyngeal streptococci (whether or not throat culture is positive); see Primary Prophylaxis section for details.

• Initiate secondary prophylaxis (see section for details).

The arthritis of RF is typically very responsive to aspirin within 24-48 hours. In fact, lack of response should prompt serious consideration of other etiologies. Nonsteroidal anti-inflammatory agents are a reasonable alternative to aspirin for patients with polyarthritis but have not been evaluated for carditis. The duration of anti-inflammatory treatment should be guided by response to therapy but should continue for 4-6 weeks. A small subset of patients may relapse 1-2 times after a 6-week course of anti-rheumatic treatment.

In most cases, the chorea of RF does not require specific pharmacologic treatment. In cases with severe symptoms, treatment options include phenobarbital, haloperidol, valproic acid, or corticosteroids.

Primary Prophylaxis

Appropriate treatment of streptococcal pharyngitis markedly decreases the risk of developing RF. Such treatment must be started within the first 9 days following onset of pharyngitis symptoms. Even with a negative throat culture, all patients diagnosed with acute RF should be treated to eradicate group A strep from the pharynx and prevent repetitive antigenic stimulation.

A single IM injection of long-acting benzathine penicillin is most effective, but oral penicillin or amoxicillin can be given as an alternative, requiring the full 10-day course of treatment. Patients allergic to penicillin should receive 10 days of a narrow-spectrum cephalosporin (unless they are anaphylactically sensitive to penicillin) or clindamycin or clarithromycin, or 5 days of azithromycin (12 mg/kg/d).

Penicillin-resistant strains of group A strep have never been reported. Follow-up cultures are not necessary.

Although other antibiotics for the treatment of strep pharyngitis have been suggested, penicillin remains the treatment of choice. Amoxillin is often given for taste issues.

Of note, administration of antibiotics during an episode of RF does not alter the course or severity of carditis.

No studies have shown tonsillectomy to be effective in reducing the incidence of RF.

Secondary Prophylaxis

As there is no specific treatment for rheumatic carditis, preventing RF recurrences is the most effective means of decreasing the likelihood and severity of chronic RHD.

It is well known that all patients who have had RF are at increased risk for recurrences. This risk is as high as 40%-60% with each strep throat for patients with cardiac involvement. The risk of recurrence is greatest in the first five years following an episode of RF but persists for many years.

Recurrences often result in more severe rheumatic valvular dysfunction and a greater likelihood of significant chronic rheumatic heart disease.

It is recommended that allpatients who have had RF should receive secondary prophylaxis to prevent recurrences.

The most effective regimen is benzathine penicillin. In most areas, this can be given every 4 weeks. However, there is evidence that penicillin levels fall between 3 and 4 weeks following these injections. In areas where RF is highly endemic or in cases with a documented RF recurrence on every-4-weeks prophylaxis, every-3-weeks injections may be preferable. Oral penicillin is a reasonable alternative in parts of the world where RF is less common and in low-risk cases. For patients allergic to penicillin, sulfadiazine is recommended.

The recommended duration of secondary prophylaxis is influenced by the presence of acute or chronic rheumatic cardiac involvement, and by the time since the last RF episode (Table I). Patients who have had carditis are at the highest risk for cardiac involvement with recurrences. Therefore, the recommended duration of secondary prophylaxis is longer for this group.