Pediatrics

Rheumatic fever

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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:

  1. 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).

  2. 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:

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

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

  3. 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:

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

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

  3. 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 arthritisof RF include:

  1. Infectious arthritis (septic, Lyme disease, mycobacterial, fungal, viral)

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

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

  4. Other, including gout, cancer, sarcoidosis, mucocutaneous disorders

Entities in the differential diagnosis of chorea:

  1. Atypical seizures

  2. Cerebrovascular accidents

  3. Collagen vascular disease

  4. Drug intoxication

  5. Familial chorea

  6. Chorea related to hormones

  7. Endocrine

  8. Lyme disease

  9. Wilson disease

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

Entities that may mimic the carditis of RF include:

  1. Viral myocarditis

  2. Infective endocarditis

  3. Viral pericarditis

  4. 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:

  1. 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).

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

  3. 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:

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

  2. 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).

  3. 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.

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

  5. 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:

  1. MR or AR color jet >1 cm in length

  2. Color jet evident in at least 2 imaging planes

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

  4. 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:

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

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

  3. Initiate Secondary Prophylaxis (see section for details).

Anti-inflammatory therapy:

  1. 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).

  2. 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:

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

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

  3. 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.

Table I.

Duration of Secondary Prophylaxis
Category Duration
RF with carditis and residual RHD∧ 10 yrs since last episode or until age 40 yrs;, possibly lifelong
RF with carditis, no residual RHD∧ 10 yrs or until age 21 yrs;
RF without carditis 5 yrs or until age 21 yrs;

Of note, patients should continue to receive secondary prophylaxis, even after valve replacement, since recurrence may result in damage to other cardiac valves.

Screening for Rheumatic Heart Disease

Many patients with rheumatic heart disease do not receive secondary prophylaxis for at least 2 reasons:

  1. Patients who would benefit must be identified. Many patients with rheumatic heart disease do not recall having had prior RF and are unaware of their heart disease until they develop symptoms or a murmur is heard.

  2. Once patients who would benefit from prophylaxis have been identified, compliance must be optimized. The World Health Organization and the World Health Federation recommend register-based control programs in populations with a high prevalence of rheumatic heart disease to promote education, training, and early recognition of RF and rheumatic heart disease, and to optimize the delivery of secondary prophylaxis.

The World Health Organization recommends school-based screening inparts of the world where RF is common to identify such patients. Studies suggest that the prevalence of rheumatic heart diseasediagnosed via echocardiography is up to 10 times greater than withauscultation alone. There continues to be some disagreement regardingwhat constitutes subclinical rheumatic heart disease.

Primordial Prevention

The most effective way to decrease the burden of RF and rheumatic heart disease in developing countries may be by reducing exposure to group A strep infections. This is termed by some as "primordial prophylaxis", and can occur in at least 2 ways:

  1. Improvement in socioeconomic conditions has led to a significant decrease in RF and consequent rheumatic heart disease in developed countries. Similar improvements in developing countries may result in similar benefit.

  2. Vaccine against group A strep. There is ongoing work in this area, but at present, no effective vaccine is available for clinical use.

Endocarditis prophylaxis

Although endocarditis continues to be an important complication of rheumatic heart disease, the revised American Heart Association (AHA) Guidelines for endocarditis prophylaxis recommend prophylaxis only for patients at highest risk for adverse outcome from endocarditis. With respect to rheumatic heart disease, this includes patients with a prosthetic valve or with prosthetic material used for valve repair and those who have previously had endocarditis. Such patients who undergo a dental or respiratory tract procedure should receive prophylaxis.

Of particular importance is the recommendation that patients already receiving antibiotics (such as penicillin for secondary prophylaxis) receive an antibiotic from a different class, since such individuals are likely to be colonized with organisms that are relatively resistant to penicillin or amoxicillin. Clindamycin, clarithromycin, or azithromycin should be given for endocarditis prophylaxis in these patients.

What are the adverse effects associated with each treatment option?

For patients receiving aspirin, suggest monitoring salicylate levels.

Adverse reactions related to aspirin include:

  • GI upset (nausea, vomiting, gastritis, GI bleeding, ulcers); should be given with food to decrease GI upset

  • Inhibition of platelet function (bruising, bleeding)

  • Tinnitus (especially with toxicity)

  • Liver toxicity

  • Other: rash, interstitial nephritis, bronchospasm

  • Should not be given to patients recovering from influenza or varicella (due to association with Reye syndrome)

For patients receiving steroids, suggest monitoring BP, growth parameters, glucose, and electrolytes.

Adverse effects associated with steroids include:

  • CV: hypertension, edema

  • GI: nausea, vomiting, ulcer

  • Neuro: headache, mental status changes, other

  • Skin: acne, poor healing; petechiae, bruising

  • Endocrine: Cushing's syndrome, growth suppression; hyperglycemia/diabetes, fluid retention, increased appetite, adrenal suppression

  • Immunosuppression

  • Musculoskeletal: muscle weakness, osteoporosis/fracture

What are the possible outcomes of RF?

With rare exception, all of the manifestations of RF resolve, even without treatment, except for carditis.

Both severity of the initial carditis and recurrent episodes of acute RF and carditis are associated with a higher likelihood of chronic rheumatic heart disease. Unfortunately, some patients with very mild, or even subclinical, cardiac involvement likely progress to chronic rheumatic heart disease. This is supported by the fact that most adults with chronic rheumatic heart disease cannot recall ever having RF. In addition, as many as 20%-44% of patients with "pure" chorea (no clinical carditis) go on to develop chronic rheumatic heart disease. At present, the best way to minimize the risk of progressive rheumatic heart disease is to prevent recurrences via secondary prophylaxis.

Most patients with mild-moderate rheumatic heart disease can be followed without intervention (catheter-based or surgery). However, those who show evidence of severe and/or progressive valvular dysfunction associated with symptoms, ventricular dysfunction, or marked ventricular enlargement may need intervention (catheter-based or surgery).

What causes this disease and how frequent is it?

Epidemiology of RF

RF continues to be a major health problem around the world, especially in developing countries, where it is the most common cause of acquired heart disease in children and young adults.

Worldwide, the estimated incidence is at least 470,000 cases/year.

RF is clearly more common in underdeveloped countries, where crowding, poor hygiene, poor nutrition, and poor access to health care are common. In these settings, there is some evidence that frequent transmission of streptococcal infection results in increased virulence and a higher rate of RF following streptococcal pharyngitis. Moreover, in these settings, a sore throat may be less likely to lead to medical evaluation and treatment. Similarly, mild symptoms of fever, fatigue, joint pain, or a fleeting rash may not result in medical evaluation. Thus, RF is more likely to go undiagnosed in these populations. This precludes initiation of secondary prophylaxis to prevent recurrences.

In parts of the world where RF continues to be a major problem, incidence rates as high as 200-300 per 100,000 per year have been reported. This is in sharp contrast to developed countries, where the incidence is estimated to be 0.5-3.0 per 100,000 population per year.

The initial episode of RF in developing countries occurs at a younger age. Importantly, the natural history of rheumatic carditis and heart disease is one of more rapid evolution and severity, more commonly leading to heart failure with associated increased morbidity and mortality. Worldwide, an estimated 233,000 to 492,000 deaths per year occur due to rheumatic heart disease, with the overwhelming majority (~95%) occurring in developing countries.

Although data suggest that the incidence of strep pharyngitis has remained stable in most countries, with no change in host resistance to strep, there are marked differences in the incidence of RF likely due to other factors. The importance of environmental and socioeconomic factors in the epidemiology and pathogenesis of RF has been recognized for over a half century. Overcrowding, poor nutrition and hygiene, and poor access to healthcare are common in developing countries, and are thought to contribute to the rapid spread of strep with increased virulence. In addition, with poor access to healthcare, pharyngitis is less likely to be recognized and treated, precluding primary prevention of RF.

In temperate climates, both strep pharyngitis and RF are more common during the winter and spring, but there is no seasonal pattern in the tropics. RF occurs in all geographic latitudes and altitudes.

RF most commonly affects children aged 5-15 years. RF is uncommon before age 5 years, and almost never occurs before age 2 years. It is uncommon in adults. Although chorea is more common in girls, there is no other gender predisposition. There does appear to be a host predisposition to developing RF, and cases can cluster in families.

Only a small proportion of patients with strep pharyngitis develop RF (even during strep epidemics). Certain M types of group A strep are highly rheumatogenic, and their frequency in modern US populations has declined over the past 4 decades. The incidence of recurrent RF in patients with a prior history of RF is as high as 50% following strep pharyngitis.

Studies have revealed both a familial predilection and a higher concordance rate in identical than in fraternal twins.

Higher rates of RF have been reported in certain ethnic groups, including Maoris and Pacific Islanders in New Zealand, Samoans in Samoa and Hawaii, and in the Aboriginal people of Australia. There is growing evidence supporting the importance of a genetically controlled immune response to strep pharyngitis in the pathogenesis of RF. Histocompatibility HLA class 2 alleles are important determinants of the immune response in RF, with several of these HLA class 2 alleles associated with a greater likelihood of developing RF in different countries.

In addition, some studies have reported a much higher degree of expression of a specific B cell alloantigen in patients with RF and controls.

The group A strep infection and organism play an important epidemiologic role. Although most children have at least one episode of pharyngitis per year, with 10%-30% due to group A strep, only ~0.3% (non-epidemic) to 3.0%-5.0% (strep epidemics) of individuals who have not had RF will develop the illness following strep pharyngitis.

There is evidence that the strain and virulence of the strep organism influence the likelihood of strep pharyngitis leading to RF. The M protein is thought to be a virulence factor, with certain M types associated with RF and outbreaks of RF. Other reports have proposed the association between the appearance of heavily encapsulated (so called "mucoid") strains and an increase in the number of RF cases in a community.

What complications might you expect from the disease or treatment of the disease?

With the exception of carditis, the manifestations of acute RF resolve with no residua.

Long-term morbidity and risk for mortality is related to the development of chronic rheumatic heart disease in patients who have had rheumatic carditis. The prognosis and natural history of rheumatic carditis and rheumatic heart disease are influenced by the severity of the initial carditis and recurrences.

Mild carditis without recurrences is much more likely to result in resolution than moderate-severe carditis and/or cases with recurrences. Of patients with acute rheumatic MR, only 30%-40% have clinical evidence (murmur) at follow-up. The majority of improvement occurs in the first 6 months after RF. AR is less likely than MR to resolve on follow-up.

Patients with more severe carditis (heart failure and/or significant cardiomegaly) are much more likely to have persistent rheumatic heart disease. In addition, children presenting with RF before age 5 years tend to have more severe initial cardiac involvement, and more commonly develop chronic rheumatic heart disease.

The mitral valve is the valve most often involved both with acute carditis and chronic rheumatic heart disease:

  • Chronic MR is the most common form of rheumatic heart disease in children and young adults.

  • Chronic rheumatic mitral stenosis often presents 15-40 years after RF illness, in the 3rd-5th decade of life (earlier in developing countries around the world).

    • occurs with leaflet thickening, commissural and leaflet fusion, chordal shortening, impaired mobility (and eventually calcification)

    • some patients with significant mitral stenosis may be treatable by trans-catheter mitral balloon valvotomy.

      • Patients with significant chronic mitral valve disease may require mitral valve repair or replacement.

The aortic valve may be affected both acutely and as a part of chronic rheumatic heart disease:

  • Chronic AR in children and young adults

  • Chronic rheumatic AS

    • occurs with leaflet thickening, fibrosis, commissural fusion, calcification

    • unlike congenital aortic valve stenosis, chronic rheumatic AS is not amenable to transcatheter balloon valvotomy.

      • Patients with significant chronic aortic valve disease may require aortic valve repair or replacement.

The right heart is uncommonly involved:

  • Tricuspid and/or pulmonary valve involvement may occur related to pulmonary hypertension occurring secondary to left heart disease

  • Chronic rheumatic changes are uncommon, but affect the tricuspid valve more often than the pulmonary valve.

    • Tricuspid stenosis/regurgitation due to leaflet thickening, fusion of leaflets, commissures, and chordae, chordal shortening, decreased leaflet excursion

    • Pulmonary valve may show evidence of rheumatic involvement after the Ross procedure for rheumatic aortic valve disease, resulting in neo-aortic regurgitation

What is the evidence?

"World Health Organ Tech Rep Ser". vol. 923. 2004. pp. 1-122.

(Comprehensive review of RF and rheumatic heart disease from the World Health Organization, including review of global importance of RF, etiology and pathogenesis, diagnosis, role of echocardiography, sequelae, and treatment.)

Gerber, MA, Baltimore, RS, Eaton, CB. " Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics". Circulation. vol. 119. 2009. pp. 1541-1551.

(This report presents new recommendations for the treatment of group A strep pharyngitis as well as for secondary prophylaxis for rheumatic fever.)

Bryant, PA, Robins-Browne, R, Carapetis, JR, Curtis, N. "Some of the people, some of the time: susceptibility to acute rheumatic fever". Circulation. vol. 119. 2009. pp. 742-753.

(Review presenting current understanding regarding host susceptibility to acute rheumatic fever.)

Steer, AC, Carapetis, JR. "Prevention and treatment of rheumatic heart disease in the developing world". Nat Rev Cardiol.. vol. 6. 2009. pp. 689-698.

(Review discussing primary prophylaxis, secondary prophylaxis including screening, and primordial prophylaxis [improvement in socioeconomic conditions, vaccine development] in changing the burden of rheumatic heart disease, especially in the developing world.)

"Jones Criteria,1992 update". JAMA. vol. 268. 1992. pp. 2069-2073.

(Guidelines present most recent update to the Jones Criteria, used in the diagnosis of RF. Includes discussion of major and minor manifestations, supporting evidence of antecedent strep infection, and exceptions to the Jones criteria [when diagnosis can be made without strict adherence to the criteria])

Pinals, RS. "Polyarthritis and fever". N Engl J Med. vol. 330. 1994. pp. 769-774.

(Excellent review of the differential diagnosis of polyarthritis and fever.)

Guilherme, L, Kalil, J. "Rheumatic fever and rheumatic heart disease: cellular mechanisms leading autoimmune reactivity and disease". J Clin Immunol. vol. 30. 2010. pp. 17-23.

(Excellent review of our current understanding of pathogenesis, including genetic susceptibility, molecular mimicry, role of T cells, and role of cytokines).

Steer, AC, Carapetis, JR. "Acute rheumatic fever and rheumatic heart disease in indigenous populations". Pediatr Clin N Am. vol. 56. 2009. pp. 1401-1419.

(Excellent review of rheumatic fever and rheumatic heart disease. Includes discussion of epidemiology in indigenous populations, diagnosis [Jones criteria and modifications to Jones criteria], clinical manifestations, management, prevention, and screening.)

Lee, JL, Naguwa, SM, Cheema, GS, Gershwin, ME. "Acute rheumatic fever and its consequences: a persistent threat to developing nations in the 21st century". Autoimmun Rev. vol. 9. 2009. pp. 117-123.

(Nice review of epidemiology, pathogenesis, clinical presentation and diagnosis, prevention, and treatment.)

Cilliers, AM. "Rheumatic fever and its management". BMJ. vol. 333. 2006. pp. 1153-1156.

(Nice overview of rheumatic fever, including discussion of epidemiology, pathogenesis, diagnosis, prevention, and treatment.)

Walsh, WF. " Medical management of chronic rheumatic heart disease". Heart Lung Circ.. vol. 19. 2010. pp. 289-294.

(Nice review of management of chronic rheumatic heart disease, including endocarditis prophylaxis and pregnancy with rheumatic heart disease.)

Tani, LY, Allen, H, Driscoll, D, Shaddy, R, Feltes, T. "Moss and Adams' Heart Disease in Infants, Children, and Adolescents". Lippincott Williams & Wilkins. 2008. pp. 1256-1280.

(Comprehensive review of rheumatic fever and rheumatic heart disease, including discussion on epidemiology and pathogenesis [scope of problem, environment, host, organism], clinical manifestations and diagnosis, testing, chronic rheumatic heart disease, and treatment [of rheumatic fever, rheumatic heart disease, prophylaxis]).

Singhi, AK, Bobhate, P, Kappanayil, M. "Acute rheumatic fever: subcutaneous nodules and carditis". Circulation. vol. 121. 2010. pp. 946-947.

(Beautiful photos of subcutaneous nodules.)

Oosterveer, DM, Overweg-Plandsoen, WC, Roos, RA. "Sydenham's chorea: a practical overview of the current literature". Pediatr Neurol. vol. 43. 2010. pp. 1-6.

(Nice review of chorea, including clinical characteristics, diagnosis, pathogenesis, and treatment options for severe cases.)

Tubridy-Clark, M, Carapetis, JR. "Subclinical carditis in rheumatic fever: a systematic review". Int J Cardiol. vol. 119. 2007. pp. 54-58.

(Excellent review of important topic, including discussion of the fact that subclinical carditis is common, may persist or deteriorate, and management and follow-up.)

Lennon, D. "Acute rheumatic fever in children: recognition and treatment". Paediatr Drugs. vol. 6. 2004. pp. 363-373.

(Excellent overview of clinical manifestations, diagnosis, and treatment.)

Binotto, M, Guilherme, L, Tanaka, A. "Rheumatic fever". Images Paediatr Cardiol.. vol. 4. 2002. pp. 12-31.

(Nice pictures of carditis [pathology and echocardiography], subcutaneous nodules, erythema marginatum.)

Carapetis, JR, Brown, A, Wilson, NJ. " An Australian guideline for rheumatic fever and rheumatic heart disease: an abridged outline". Med J Aust. vol. 186. 2007. pp. 581-586.

(Discussion of diagnosis and treatment of both rheumatic fever and rheumatic heart disease, including stratification of diagnosis and management by risk. Includes discussion of modifications to Jones criteria for diagnosis in high-risk groups and recommended treatment and follow-up.)

Gewitz, MH. "Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association". Circulation. vol. 131. 2015. pp. 1806-1818.

Ongoing controversies regarding etiology, diagnosis, treatment

Despite evidence for strep pharyngitis, but not skin infections, as the initial event that can lead to RF, recent epidemiologic evidence suggests that skin strains may play a role in some populations. Specifically, in the Aboriginal population of Australia where RF continues to be endemic, strep impetigo is common and strep pharyngitis is not. Some have speculated that such strep skin infections may result in immune priming; others have postulated movement of strains from the skin to the pharynx. The role of strep skin infections in the pathogenesis of RF remains unclear.

Despite increasing support for the use of echocardiography for the diagnosis of RF, and to identify patients with previously undiagnosed rheumatic heart disease, this remains an area of controversy. As previously stated, the concern is related to creating "iatrogenic" disease by diagnosing rheumatic carditis in the absence of clinical findings, since some normal individuals have very small amounts of "physiologic", Doppler-detected regurgitation. Overall, however, there is increasing acceptance of the use of subclinical carditis in the diagnosis of RF and of subclinical rheumatic heart disease in screening programs to identify patients who would benefit from secondary prophylaxis.

Despite fairly broad acceptance of the use of aspirin and steroids in the treatment of acute rheumatic carditis, there is little evidence that either alters the natural history of rheumatic heart disease. While there is evidence for improvement in valvular function as the acute inflammation subsides, there is no clear-cut evidence that steroids or aspirin affect long-term outcome.

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