Acute Rheumatic Fever and Rheumatic Heart Disease

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49 Acute Rheumatic Fever and Rheumatic Heart Disease

Acute rheumatic fever (ARF) is postulated to be caused by a delayed systemic autoimmune reaction to group A β-hemolytic streptococcal (GAS) pharyngitis. It is a self-limited disease that may involve the heart, skin, brain, joints, and serosal surfaces (Figure 49-1). It is a disease of clinical interest primarily because of its propensity to create heart disease. Rheumatic carditis and valvulitis may be self-limited or may lead to progressive valve deformity.

Figure 49-1 Cardiac manifestations of acute rheumatic fever.

Since the 1980s, the incidence of ARF has declined in most developed countries to the point where many physicians have little or no practical experience with diagnosis and management of the disease. Credit has been given to improved sanitation and widespread use of antibiotic therapy for GAS pharyngitis. Recently, however, several sporadic outbreaks have been reported in several regions of the United States, which have generally been attributed to new virulent strains of GAS.

In the United States, the incidence of ARF after untreated streptococcal pharyngitis is 0.5% to 3% with a peak frequency in children age 6 to 20 years. The disease is virtually unheard of in children younger than 2 years old and in adults older than 30 years old. The mean age of the first attack of ARF is 8 years. Internationally, however, rheumatic heart disease accounts for 25% to 50% of all cardiac admissions with most major outbreaks occurring in poverty-stricken, overcrowded areas with limited access to antibiotics.

Etiology And Pathogenesis

The exact cause of ARF and rheumatic heart disease (RHD) is unknown. ARF tends to occur after streptococcal pharyngitis rather than cellulitis. The familial tendency toward ARF is well documented. The HLA-DR2 and DR4 antigens have been linked to an increased incidence of ARF.

The virulence of GAS is related to the bacterial M protein, which structurally resembles human myosin. It is presumed that GAS adheres to the pharyngeal mucosa of the patient and activates antigens and superantigens, which triggers an immune response. In genetically susceptible individuals, antibodies against myosin are produced, which can lead to carditis. Repeated untreated infections with GAS may reactivate antibody production and lead to an autoimmune response that lasts several weeks and eventually damages heart valves (Figure 49-2).

Figure 49-2 Manifestations of acute rheumatic carditis.

Clinical Presentation

The diagnosis of ARF is challenging for several reasons. Pharyngitis is a common complaint in the pediatric population. About 70% of older children and young adults with ARF will recollect an antecedent pharyngitis, but only 20% of young children will. There is an average latent period from the onset of streptococcal pharyngitis to ARF of 18 days (range, 1-5 weeks), which can make recollection during the history challenging. Thus, GAS is rarely isolated from the oropharynx in patients with ARF. Typically, the first manifestation is a painful migratory polyarthritis, but 10% of rheumatic patients will present with pure chorea and no other manifestations of rheumatic fever.

More than 60 years ago, T. Duckett Jones published guidelines for diagnosis of ARF that have been slightly revised by the World Health Organization (Box 49-1 and Figure 49-3). To make a primary diagnosis of ARF, two major or one major and two minor criteria plus evidence of a preceding GAS infection are needed. The exception is rheumatic chorea. Sydenham’s chorea (St. Vitus dance) in isolation is considered diagnostic, and no other criteria or evidence of GAS infection are required to make the diagnosis.

Box 49-1 2002 to 2003 World Health Organization Revision of Jones Criteria for the Diagnosis of Rheumatic Fever

Major Criteria

1. Carditis: Murmur, irregular heartbeat, congestive heart failure. Murmur of mitral regurgitation is typically blowing, high frequency, and audible at the apex, and it transmits to the axilla. There may be a mid-diastolic rumble (Carey-Coombs murmur) that does not signify mitral stenosis. Heart rate irregularity can be noted with variable 2 : 1 block. A friction rub indicates pericarditis. CHF is rare, but patients may be very ill with dyspnea, vomiting, hepatomegaly, and tachycardia (see Figure 49-2).

2. Polyarthritis: Most commonly involved are hips, knees, ankles, shoulders, elbows, and wrists. It typically occurs in a migratory pattern and responds promptly to nonsteroidal antiinflammatory drugs or salicylates.

3. Erythema marginatum: Rapidly enlarging macules in ring or crescent shapes with clear centers. It is a rare manifestation but when present is very specific for ARF.

4. Subcutaneous nodules: Small, firm, nontender nodules over tendons and bony prominences that look similar to rheumatoid nodules. They are a rare manifestation.

5. Sydenham’s chorea: Involuntary choreoathetoid movements of the tongue, face, and upper extremities that are exacerbated by stress. It can occur as the sole manifestation of ARF. It is more common in girls than boys and is rare in adults.

Minor Criteria

1. Fever: Usually a low-grade fever, rarely higher than 103°F

2. Polyarthralgia

3. Laboratory evidence of elevated acute phase reactants: ESR, leukocyte count, or CRP

4. Prolonged PR interval on ECG)

Evidence of Preceding GAS Infection

1. Positive throat culture

2. Rapid antigen test for GAS

3. Recent scarlet fever

4. Elevated or rising ASO, anti-DNAse B, or other streptococcal antibody titer

anti-DNAse B, anti-deoxyribonuclease B; ARF, acute rheumatic fever; ASO, antistreptolysin O; CHF, congestive heart failure; CRP, C-reactive protein; ECG, electrocardiography; ESR, erythrocyte sedimentation rate; GAS, group A streptococcus.

Figure 49-3 Noncardiac manifestations of acute rheumatic fever.

Acute carditis is usually clinically manifest by sinus tachycardia without diurnal variation and new onset of a heart murmur of mitral regurgitation with or without aortic regurgitation. With a single attack of ARF, the mitral regurgitation often resolves over months to years, but aortic regurgitation is more likely to persist. In severe cases, signs of heart failure or a friction rub from pericarditis may also be present.

Chronic RHD results when a single or multiple attacks of ARF deform and fuse valve cusps, commissures, or chordae. Stenosis or insufficiency of the valve, and often both, occur. Isolated mitral valve involvement occurs in 60% to 70%, mitral and aortic involvement in 20%, and isolated aortic involvement is rare. The tricuspid valve is involved in 5% to 10% but occurs with mitral or aortic disease. Pulmonary valve involvement is rare.

A history of ARF is obtained in only 60% of patients with RHD. Whereas chronic mitral regurgitation is the most common form of RHD in children and young adults (Figure 49-4), mitral stenosis is more common in older adults. Aortic regurgitation, although less common than mitral regurgitation with ARF, is more likely to persist (see Figure 49-4). Patients with mitral or aortic valve disease may present with an isolated heart murmur or palpitations caused by atrial arrhythmias. They can present with fatigue, decreased exercise tolerance, dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea, which can represent low cardiac output or pulmonary hypertension. However, the onset of symptoms can often be so insidious that patients adapt and are unaware of their significant functional limitations.

Figure 49-4 Rheumatic heart disease: clinical presentation.

The differential diagnosis of ARF is depicted in Box 49-2.

Diagnostic Evaluation

Laboratory Studies

With a few exceptions, diagnosis of ARF requires evidence of preceding GAS infection. Throat culture or rapid antigen tests should be performed, although they have a low yield and do not differentiate between acute infection and a chronic carrier state. Rising titers of antistreptococcal antibodies are more useful in confirming recent GAS infection. The most commonly used antibody test is the antistreptolysin (ASO) titer, which begins to increase approximately 1 week and peaks 3 to 6 weeks after the infection. Anti-DNAse B (anti-deoxyribonuclease B) titers begin to increase after 1 to 2 weeks with a peak after 6 to 8 weeks and may be used if ASO titers are inconclusive.

Other baseline laboratory investigations should include a complete blood count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The CRP and ESR are both markers of inflammation with high sensitivity but low specificity. They are useful to assess response to antiinflammatory therapy, resolution, and recurrence of the disease process.

Cardiac Evaluation

Cardiac Catheterization

Cardiac catheterization is not performed in the setting of ARF. In patients with chronic RHD, diagnostic catheterization is now reserved for the few patients in whom the symptoms, clinical findings, and noninvasive imaging are discrepant. However, therapeutic cardiac catheterization and balloon valvuloplasty continue to remain central in management of valvar RHD.

Management And Therapy

Acute Rheumatic Fever and Rheumatic Carditis

The age-old adage “rheumatic fever licks the joint but bites the heart” still holds true. The joint disease in rheumatic fever is usually self-limiting. Management is thus focused on treating and preventing the long-term cardiac complications.

Antiinflammatory therapy with either salicylates or steroids is usually started at the time of diagnosis for patients with ARF. They provide prompt symptomatic relief, although their efficacy in altering the natural history of the disease is debatable. Most experts recommend that patients with mild degrees of carditis be started on high-dose aspirin, but patients with more severe forms of carditis and heart failure should be initially started on steroids for 2 weeks and later switched to aspirin. The duration of antiinflammatory therapy should be 4 to 6 weeks or until there is laboratory evidence of resolution of inflammatory markers. Other antiinflammatory agents such as immunoglobulins and pentoxifylline may be tried in resistant patients, although neither has been found to be consistently beneficial. Patients with active carditis should have some level of activity restriction. Supportive therapy for heart failure includes the use of diuretics, digoxin, and afterload reduction. In rare cases, mitral valve surgery may be required in the setting of intractable heart failure.

Sydenham’s chorea is usually self-limited. Traditionally, it has been treated with sedation and antiseizure and antipsychotic medications. Steroids, immunoglobulins, and plasmapheresis have been tried without conclusive evidence demonstrating a significant benefit.

All patients with ARF should be treated with antibiotics to eliminate GAS from the throat even with negative culture results. Oral penicillin V is the drug of choice. Alternatives include single-dose benzathine penicillin injection or a course of oral ampicillin or amoxicillin. Macrolides or first-generation cephalosporins can be used in patients who are allergic to penicillin. It should be noted that some patients who are allergic to penicillin may also be allergic to cephalosporins. Because the risk of valvar heart disease is greatly increased with each subsequent attack of ARF, all patients should be placed on an antibiotic regimen for secondary prophylaxis to prevent future recurrences (Table 49-1).

Table 49-1 Antibacterial Therapy for Group A Streptococcus Pharyngitis and Acute Rheumatic Fever

Penicillin V	Weight ≤27 kg: 250 mg PO BID or TID for 10 days Weight >27 kg: 500 mg PO BID or TID daily for 10 days
	or
Amoxicillin	50 mg/kg PO SID (maximum, 1 g) for 10 days
	or
Benzathine penicillin G	Weight ≤27 kg: 0.6 million U IM once Weight >27 kg:1.2 million U IM once
Patients Allergic to Penicillin
Narrow-spectrum cephalosporins: cephalexin, cephadroxil	Dose varies with selection for 10 days
	or
Clindamycin	20 mg/kg/d PO in three doses (maximum, 1.8 g/d) for 10 days
	or
Azithromycin	12 mg/kg PO SID (maximum, 500 mg) for 5 days
	or
Clarithromycin	15 mg/kg/day in two doses (maximum, 250 mg BID) for 10 days
Secondary Prophylaxis After ARF or in Patients with Chronic RHD
Benzathine penicillin G	Weight ≤27 kg: 0.6 million U IM every 3 to 4 weeks Weight >27 kg: 1.2 million U IM every 3 to 4 weeks
	or
Penicillin V	250 mg PO BID
Patients Allergic to Penicillin
Sulfadiazine or sulfisoxazole	Weight ≤27 kg: 0.5 g PO SID Weight >27 kg: 1 g PO SID
	or
Macrolide or azalide	Variable
Duration of Secondary Prophylaxis
Rheumatic fever with carditis and residual heart disease	10 years or until 40 years of age (whichever is longer), sometimes lifelong
Rheumatic fever with carditis but no residual heart disease	10 years or until 21 years of age (whichever is longer)
Rheumatic fever without carditis	5 years or until 21 years of age (whichever is longer)