Introduction
Background
The incidence of acute rheumatic fever (ARF) has declined in most developed countries, and many physicians have little or no practical experience with the diagnosis and management of this condition. Occasional outbreaks in the United States make complacency a threat to public health.
Diagnosis rests on a combination of clinical manifestations that can develop in relation to group A streptococcal pharyngitis. These include chorea, carditis, subcutaneous nodules, erythema marginatum, and migratory polyarthritis. Because the inciting infection is completely treatable, attention has been refocused on prevention.
Clinical manifestations and time course of acute ...
Clinical manifestations and time course of acute rheumatic fever.
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Clinical manifestations and time course of acute ...
Clinical manifestations and time course of acute rheumatic fever.
Pathophysiology
Although the inciting bacterial agent is well known, susceptibility factors remain unclear. The location of the streptococcal infection seems to play an important role. The clinical syndrome typically follows a streptococcal pharyngitis, but streptococcal cellulitis has never been implicated.
The earliest and most common feature is a painful migratory arthritis, which is present in approximately 80% of patients. Large joints such as knees, ankles, elbows, or shoulders are typically affected. Sydenham chorea was once a common late-onset clinical manifestation but is now rare. Carditis (with progressive congestive heart failure, a new murmur, or pericarditis) may be the presenting sign of unrecognized past episodes and is the most lethal manifestation.
Genetics may contribute, as evidenced by an increase in family incidence. No significant association with class-I human leukocyte antigens (HLAs) has been found, but an increase in class-II HLA antigens DR2 and DR4 has been found in black and white patients, respectively. Evidence suggests that elevated immune-complex levels in blood samples from patients with ARF are associated with HLA-B5.1
Frequency
United States
The incidence of an acute rheumatic episode following streptococcal pharyngitis is 0.5-3%. The peak age is 6-20 years. Although the incidence of ARF has steadily declined, the mortality rate has declined even more steeply. Credit can be attributed to improved sanitation and antibiotic therapy. Several sporadic outbreaks in the United States could not be blamed directly on poor living conditions. New virulent strains are the best explanation.
International
Most major outbreaks occur under conditions of impoverished overcrowding where access to antibiotics is limited. Rheumatic heart disease accounts for 25-50% of all cardiac admissions internationally. Regions of major public health concern include the Middle East, the Indian subcontinent, and some areas of Africa and South America. As many as 20 million new cases occur each year. The introduction of antibiotics has been associated with a rapid worldwide decline in the incidence of ARF. Now, the incidence is 0.23-1.88 patients per 100,000 population. From 1862-1962, the incidence declined from 250 patients to 100 patients per 100,000 population, primarily in teenagers. Notably, natives of Polynesian ancestry in Hawaiian and Maori populations are an exception. The incidence continues to be 13.4 patients per 100,000 hospitalized children per year.2
Mortality/Morbidity
* Mortality rates are steadily improving because of better sanitation and health care.
* The current pattern of morbidity is difficult to measure because the first attack of rheumatic fever follows an unpredictable course. As many as 90% of episodes are clinically contained within 3 months.
* Carditis causes the most severe clinical manifestation because heart valves can be permanently damaged. The disorder also can involve the pericardium, myocardium, and the free borders of valve cusps. Death or total disability may occur years after the initial presentation of carditis.
Race
* An association between certain class-II HLA antigens (DR2 in blacks and DR4 in whites) and ARF has been reported.
Sex
* No general clear-cut sex predilection for the syndrome has been reported, but its manifestations seem to be sex variable. For example, certain clinical manifestations (ie, chorea and tight mitral stenosis) are predominant in women, while men are more likely to develop aortic stenosis.
Age
* The initial attack of ARF occurs most frequently in persons aged 6-20 years and rarely occurs in persons older than 30 years.
* The disease may cluster in families.
* In some countries, a shift into older groups may be a trend.
Clinical
History
* Diagnosis is challenging for several reasons, as follows:
o Approximately 70% of older children and young adults recollect pharyngitis. However, only approximately 20% of young children recollect pharyngitis. Therefore, younger children who present with signs or symptoms consistent with acute rheumatic fever (ARF) merit a higher index of suspicion.
o The rate of isolation of group A streptococci from the oropharynx is extremely low in all populations.
* Usually, a latent period of approximately 18 days occurs between the onset of streptococcal pharyngitis and ARF. This latent period is rarely shorter than 1 week or longer than 5 weeks.
o Typically, the first manifestation is a very painful migratory polyarthritis. Often, associated fever and constitutional toxicity develop.
o Acute attacks usually resolve within 12 weeks.
* Guidelines for diagnosis published more than 50 years ago by T. Duckett Jones3 have been slightly revised by the American Heart Association (AHA).4 Prior history of a preceding group A streptococcal infection is helpful but not required. In addition, 2 major manifestations or 1 major and 2 minor manifestations must be present.
o Major manifestations include carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules.
o Minor manifestations include arthralgias and fever. Laboratory findings include elevated levels of acute-phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein) and a prolonged PR interval. A prolonged PR interval is not specific and has not been associated with later cardiac sequelae. The utility of echocardiography is also controversial.
* The Jones criteria4 should be viewed as a guide to determine who is at high risk but cannot be used to define diagnosis with absolute certainty.
o An exception includes chorea, which can present as the sole manifestation of ARF, in spite of negative laboratory results.
o Another possible exception is indolent carditis.
* A throat culture with results positive for Streptococcus is found in approximately 25% of patients at the time of presentation.
Physical
* Physical findings can be nonspecific and misleading; therefore, a high index of suspicion is required for diagnosis.
* Suspicious signs for carditis include new or changing valvular murmurs, cardiomegaly, congestive heart failure, and/or pericarditis.
* Nearly 60% of patients with carditis develop isolated mitral valve involvement, followed in prevalence by combined mitral and aortic valve involvement.
* When present, Sydenham chorea is seldom evident at the time of initial presentation.
* Erythema marginatum and subcutaneous nodules are rare (<10% of patients).
Erythema marginatum, the characteristic rash of a...
Erythema marginatum, the characteristic rash of acute rheumatic fever.
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Erythema marginatum, the characteristic rash of a...
Erythema marginatum, the characteristic rash of acute rheumatic fever.
* Arthritis, which occurs in 80% of patients, usually involves multiple large joints, particularly the knees, ankles, elbows, and wrists.
o Hips and smaller joints of hands and feet are less commonly involved.
o Migratory polyarthritis is usually associated with a febrile illness. It involves a series of painful joints, followed by another series of painful joints.
o This form of arthritis rarely causes permanent joint deformity.
* Unusual presentations, such as indolent carditis and isolated chorea, may also occur. Even rarer manifestations include epistaxis and abdominal pain due to serositis.
Causes
* Although the mechanism by which streptococcal organisms cause disease is not entirely clear, overwhelming epidemiologic evidence suggests that ARF is caused by streptococcal infection, and recurrences can be prevented with prophylaxis.
* Strains of group A streptococci that are heavily encapsulated and rich in M protein (signifying virulence in streptococcal strains) seem to be most likely to result in infection.
* Group A Streptococcus is thought to cause the myriad of clinical diseases in which the host's immunologic response to bacterial antigens cross-react with various target organs in the body, resulting in molecular mimicry. In fact, autoantibodies reactive against the heart have been found in patients with rheumatic carditis. The antibody can cross-react with brain and cardiac antigens, and immune complexes are present in the serum. The problem has been the uncertainty of whether these antibodies are the cause or result of myocardial tissue injury.Differential Diagnoses
Kawasaki Disease
Sepsis, Bacterial
Septic Arthritis
Systemic Lupus Erythematosus
Other Problems to Be Considered
Bacterial endocarditis
Still disease - Systemic-onset juvenile rheumatoid arthritis or adult Still disease
Vasculitis
Poststreptococcal reactive arthritis
Barash et al performed a retrospective study to compare clinical and laboratory features of acute rheumatic fever (ARF) versus poststreptococcal reactive arthritis to determine if the two diseases are separate clinical manifestations of the same disease or are in fact different diseases altogether. Based on a review of 68 patients with ARF and 159 patients with poststreptococcal reactive arthritis, the authors concluded that at least 4 factors differed significantly enough to show that the two diseases are distinct—ESR, C-reactive protein levels, duration of joint symptoms after initiation of anti-inflammatory treatment, and relapse of joint symptoms after treatment cessation. Using the differentiating factors, they were able to determine the correct diagnosis in more than 80% of cases.5
Workup
Laboratory Studies
* Acute rheumatic fever (ARF) is diagnosed based on clinical manifestations supported by laboratory tests.
* Group A streptococcal antigen detection tests are specific but not very sensitive.
* In contrast, antistreptococcal antibodies usually reach a peak titer (in Todd units) at the time of onset of rheumatic fever and are more useful.
o Specific antibodies to streptococcal antigens also indicate true infection rather than mere carriage of the organism. However, note that children without ARF may have an isolated positive antistreptolysin O (ASO) titer. This may also be found in patients with certain related diseases such as rheumatoid arthritis and Takayasu arteritis. Therefore, rising ASO titers should be combined with a careful clinical evaluation and the discovery of other antistreptococcal antibodies to support the diagnosis of ARF.
o Antistreptococcal antibodies include ASO, antideoxyribonuclease B (anti-DNAse B), antistreptokinase, antihyaluronidase, and anti-DNAase (anti-DNPase).
o These antibodies target extracellular products produced by streptococci.
o Although age, geographic location, and season affect the titers, an elevated titer of at least one of these antibodies indicates streptococcal infection in 95% of patients.
o ASO is found in 80-85% of patients with ARF.
* The sensitivity of throat culture as evidence of recent streptococcal infection is 25-40%.
o For comparison, the sensitivity of ASO titer (adults with >240 Todd U and children with >320 Todd U) is 80%.
o The sensitivity of an elevated ASO titer in addition to anti-DNAse B or antihyaluronidase is 90%.
* Acute-phase reactants such as C-reactive protein and ESR are usually elevated and helpful in monitoring disease activity.
* Other laboratory tests may be helpful but not for definitive diagnosis. Synovial fluid analysis reveals a sterile inflammatory reaction, usually with fewer than 20,000 cells/μL (mainly polymorphonuclear) without crystals.
Imaging Studies
* Echocardiography is more sensitive than standard auscultation for helping detect regurgitant lesions, but the prognostic significance of these subauscultory findings is unclear.
* Standard auscultation is favored for detecting carditis and can reveal mitral regurgitation in as many as 80% of patients.
* Chest radiograph may reveal cardiomegaly.
Chest radiograph showing cardiomegaly due to card...
Chest radiograph showing cardiomegaly due to carditis of acute rheumatic fever.
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Chest radiograph showing cardiomegaly due to card...
Chest radiograph showing cardiomegaly due to carditis of acute rheumatic fever.
Other Tests
* ECG is helpful for diagnosing carditis and may reveal a prolonged PR interval, but this finding is not necessarily associated with later cardiac sequelae.
* Conventional throat swab cultures may demonstrate streptococcal organisms.
Procedures
* Synovial tissue biopsy is rarely performed.
* Endomyocardial biopsies have not contributed significantly to diagnosis thus far.
Histologic Findings
Synovial biopsy reveals mild inflammatory changes. The synovial membrane may be thickened, erythematous, and covered by a fibrinous exudate. Focal fibrinoid lesions in the heart and histiocytic granulomas called Aschoff nodules may be late findings. Pancarditis develops with involvement of all layers of the heart. Subcutaneous nodule histopathology reveals edema, fibrinoid necrosis, and mononuclear cell infiltrate.Treatment
Medical Care
Treatment strategies can be divided into management of an acute rheumatic fever (ARF) attack, management of the current infection, and prevention of further infection and attacks.
* The primary goal of treating an ARF attack is to eradicate streptococcal organisms and bacterial antigens from the pharyngeal region.
o Penicillin is the drug of choice in persons who are not at risk of allergic reaction.
o A single parenteral injection of benzathine benzylpenicillin can ensure compliance.
o Oral cephalosporins, rather than erythromycin, are recommended as an alternative in patients who are allergic to penicillin. However, be cautious of the 20% cross-reactivity of the cephalosporins with penicillin.
* By promptly treating streptococcal pharyngitis in susceptible hosts, repetitive exposure to pathologically reactive antigens can be avoided. However, management of the current infection will probably not affect the course of the current attack.
* Antimicrobial therapy does not alter the course, frequency, or severity of cardiac involvement.
* Analgesia is optimally achieved with high doses of salicylates, often inducing dramatic clinical improvement.
o A lower dose may be required to avert symptoms of nausea and vomiting.
o When salicylates are used as therapy, the dosage should be increased until the drug produces either a clinical effect or systemic toxicity characterized by tinnitus, headache, or hyperpnea.
* Corticosteroids should be reserved for the treatment of severe carditis.
o After 2-3 weeks, the dosage may be tapered, reduced by 25% each week.
o Overlap with high-dose salicylate therapy is recommended as the dosage of the prednisone is tapered over a 2-week period to avoid poststeroid rebound. In extreme cases, intravenous methylprednisolone may be used.
* Mild heart failure usually responds to rest and corticosteroid therapy.
* Digoxin can be useful in patients with severe carditis, but its use should be monitored closely because of the possibility of heart block.
* Nocturnal tachycardia may be a sign of cardiac involvement that may be responsive to digoxin. Vasodilators and diuretics also may be used.
* Protracted Sydenham chorea has responded to haloperidol.
o Chorea requires long-term antimicrobial prophylaxis, even if no other manifestations of rheumatic fever evolve.
o The signs and symptoms of chorea usually do not respond well to treatment with antirheumatic agents.
o Complete physical and mental rest is essential because the manifestations of chorea may be exaggerated by emotional trauma.
o Glucocorticoids or salicylates have little or no effect on chorea.
o Because chorea disappears with sleep, adequate sedation should be provided.
* Prevention has been successful in developed societies. The recommended approach can be divided into primary and secondary prevention.
o Primary prevention: Eradicate Streptococcus from the pharynx, which generally entails administering a single intramuscular injection of benzathine benzylpenicillin.
o Secondary prevention: The AHA Committee on Acute Rheumatic Fever recommends a regimen consisting of benzathine benzylpenicillin at 1.2 million units intramuscularly every 4 weeks. However, in high-risk situations, administration every 3 weeks is justified and advised. High-risk situations include patients with heart disease who are at risk of repetitive exposure.
o Oral prophylaxis, which is less reliable, consists of phenoxymethylpenicillin (penicillin V) or sulfadiazine. These can be used in compliant patients.
o If penicillin allergy is suspected, oral cephalosporins should be used.
o Although no consensus on the required duration of antibacterial prophylaxis has been reached, the AHA recommends that prophylaxis be continued for at least 10 years after the last episode of rheumatic fever or until patients are well into adulthood. For those with heart disease who are at risk of repetitive exposures, prophylaxis should be continued for a longer duration, probably indefinitely. However, discontinuing prophylaxis may be reasonable in patients in their third decade of life in whom more than 5 years have passed since their last attack and who are free from rheumatic heart disease. The principles of treatment include the following:
+ The risk of rheumatic fever recurrence is greatest during the first 3-5 years following the attack.
+ Prophylaxis must continue indefinitely in patients with established heart disease or in those frequently exposed to streptococci.
+ Treatment for an indefinite period is required among patients with frequent exposure to streptococci or for those who are difficult to monitor.
* In underdeveloped countries, prophylaxis should be continued as follows:
o Continue for 5 years after the first attack.
o Continue indefinitely in patients with established heart disease.
o Continue indefinitely in patients who are frequently exposed to streptococci, are less than optimal, and are difficult to monitor.
* The decision to withdraw the antibacterial drugs should be individualized after carefully assessing the risk of repetitive exposures.
Surgical Care
* Valve replacement should be considered in patients with active carditis, especially in cases that are refractory to medical care or require high doses of vasodilators and diuretics.
* Regurgitant lesions respond to valve replacement, while pure stenotic lesions may benefit from more conservative balloon mitral commissurotomy.
Consultations
* Primary care physicians should be considered the patient's advocate and guide to medical resources.
* Rheumatologists usually assist in diagnosis in the face of a substantial differential. Then, they can advise on the therapy plan.
* A cardiologist should be consulted when cardiac involvement is present.
* A neurologist may offer interventions to help manage chorea.
Diet
* No dietary factors are known.
Activity
* All patients should be restricted to bed rest and monitored closely for carditis.
* Aggressive use of acutely inflamed joints or other exercise may cause permanent joint injury to acutely inflamed joints.
* When carditis has been documented, a 4-week period of bed rest is recommended. As soon as the signs of acute inflammation subside, patients should resume active ambulation as tolerated.
* Most patients can be treated safely in an outpatient setting.
Medication
Treatment and prevention may involve multiple fields of discipline, including infectious diseases, cardiology, and neurology. For this reason, several different classes of medications are used. These include antibiotic, neuroleptic, and cardiac medications.
Antibiotics
Antibiotics are the initial pharmacotherapy for prevention and treatment of rheumatic fever.
Penicillin G procaine (Crysticillin)
Long-acting parenteral penicillin indicated in the treatment of moderately severe infections caused by microorganisms sensitive to penicillin G. IM administration only.
Adults: Deep IM injection into the upper outer quadrant of the buttock only.
Infants and small children: IM injection into midlateral aspect of the thigh is suggested.
Some authors prefer 10 d of therapy.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
2.4 million U IM once
Pediatric
<30 lb: 600,000 U IM once
30-60 lb: 900,000-1,200,000 U IM once
* Dosing
* Interactions
* Contraindications
* Precautions
Increases risk of bleeding when administered concurrently with warfarin; ethacrynic acid, aspirin, indomethacin, and furosemide may compete with penicillin G for renal tubular secretion, thereby increasing penicillin serum concentrations
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Never use IV route to administer penicillin G procaine; administer for more than 10 d to eliminate the organism and prevent complications such as endocarditis and rheumatic fever; perform cultures after treatment to confirm streptococci eradication
Penicillin G benzathine (Bicillin L-A)
Interferes with synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. Long-acting depot form of penicillin G. Because of its prolonged blood level, several authors believe this to be the DOC. Others prefer daily injections with short-acting penicillin.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
2.4 million U IM once
Pediatric
<30 lb: 600,000 U IM once
30-60 lb: 900,000-1,200,000 U IM once
* Dosing
* Interactions
* Contraindications
* Precautions
Probenecid can increase penicillin effectiveness by decreasing clearance; tetracyclines are bacteriostatic, possibly decreasing penicillin effect
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal dysfunction (adjust dose accordingly)
Penicillin VK (Beepen-VK, Betapen-VK, Robicillin VK, Veetids)
Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication. Inadequate concentrations may produce only bacteriostatic effects. PO alternative.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
500 mg PO q6h for 10 d
Pediatric
<12 years: 25-50 mg/kg/d PO divided tid/qid, not to exceed to 3 g/d
>12 years: Administer as in adults
* Dosing
* Interactions
* Contraindications
* Precautions
Probenecid can increase effects of penicillin by decreasing clearance; coadministration of tetracyclines can decrease effects of penicillin
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in impaired renal function (adjust dose accordingly)
Erythromycin (EES, E-Mycin, Ery-Tab, Erythrocin)
Alternative for patients allergic to penicillin (although not the DOC).
Drug may inhibit RNA-dependent protein synthesis by stimulating the dissociation of peptidyl t-RNA from ribosomes. Inhibits bacterial growth.
In children, age, weight, and the severity of infection determine proper dosage. When bid dosing is desired, half-total daily dose may be taken every 12 h. For more severe infections, dose may be doubled.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
250 mg erythromycin stearate, base, or estolate salts (or 400 mg ethylsuccinate) PO q6h or 500 mg PO q12h for 10 d; not to exceed 1 g/d; alternatively, 333 mg (as the base) q8h
Pediatric
30-50 mg/kg/d (base or ethylsuccinate) PO divided q6-8h; not to exceed 1 g/d
* Dosing
* Interactions
* Contraindications
* Precautions
Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis; inhibits CYP1A2 CYP3A4 isoenzymes
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity, severe hepatic impairment
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in liver disease (estolate formulation may cause cholestatic jaundice); adverse GI effects are common; discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur
Anti-inflammatory agents
These agents inhibit inflammation to prevent destruction in the joints and heart.
Aspirin (Ascriptin, Bayer Buffered Aspirin, Ecotrin)
For treatment of mild to moderate pain and headache. Considered the first DOC for the treatment of arthritis due to acute rheumatic fever (ARF).
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
6-8 g/d PO for 2 mo or until ESR has returned to normal, adjust dose according to serum levels
Pediatric
80-100 mg/kg/d PO for 2 mo or until ESR has returned to normal, adjust dose according to serum levels
* Dosing
* Interactions
* Contraindications
* Precautions
Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs; serum levels of 20-30 mg/100 dL required to control inflammatory response; high doses may cause gastric irritation or salicylate toxicity (ie, serum levels >20 mg/100 dL) and require dose reduction or alternative treatment with corticosteroids
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; aspirin-sensitive asthma; because of association with Reye syndrome, do not use in children <16 y who have influenza or varicella infections
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May cause transient decrease in renal function and aggravate chronic kidney disease; avoid with severe anemia or blood coagulation defects
Glucocorticosteroids
These agents demonstrate anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids produce profound and varied metabolic effects. These agents also modify the body's immune response to diverse stimuli.
Prednisone (Deltasone, Liquid-Pred, Meticorten, Orasone, Sterapred)
Patients with carditis require prednisone. The goal is to decrease myocardial inflammation. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. After 2-3 wk, dosage may be tapered, reduced 25% each week.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
1-2 mg/kg/d PO for 2-3 wk initially; then discontinue by gradual taper over 3 wk; not to exceed 80 mg/d
Pediatric
0.05-2 mg/kg/d PO for 2-3 wk initially; then discontinue by gradual taper over 3 wk
* Dosing
* Interactions
* Contraindications
* Precautions
May cause water and salt retention, thereby exacerbating hypertension and increasing requirement for antihypertensive drugs in patients with hypertension; may aggravate hyperglycemia, thereby increasing requirement for hypoglycemic agents in patients with diabetes; coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (adjust dose); hypokalemia may occur with coadministration of diuretics
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; may cause hyperglycemia, edema, weight gain, osteonecrosis, myopathy, dyspepsia, peptic ulcer, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, cataracts, glaucoma, and infections
Neuroleptic agents
These agents are used for chorea associated with ARF.
Haloperidol (Haldol)
Dopamine receptor blocker used for irregular spasmodic movements of the limbs or facial muscles.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
0.5-2 mg PO bid/tid
Pediatric
<3 years: Not established
3-12 years
Initial: 0.05 mg/kg/d or 0.25-0.5 mg/d PO divided bid/tid, may increase by 0.25-0.5 mg/d PO q5-7d
Maintenance: 0.05-0.15 mg/kg/d PO in 2-3 divided doses; not to exceed 0.15 mg/kg/d
>12 years: Administer as in adults
* Dosing
* Interactions
* Contraindications
* Precautions
May increase tricyclic antidepressant serum concentrations; may increase hypotensive action of antihypertensive agents; phenobarbital or carbamazepine may decrease effects; coadministration with anticholinergics may increase intraocular pressure; encephalopathylike syndrome associated with concurrent administration of lithium
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; narrow-angle glaucoma; bone marrow suppression; severe cardiac or liver disease; severe hypotension; subcortical brain damage
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Severe neurotoxicity manifesting as rigidity or inability to walk or talk may occur in patients with thyrotoxicosis also receiving antipsychotics; monitor for hypotension with parenteral administration; caution in diagnosed CNS depression or cardiac disease; if history of seizures, benefits must outweigh risks; significant increase in body temperature may indicate intolerance to antipsychotics (discontinue if it occurs)
Positive inotropic agents
Digoxin may be indicated for patients with congestive heart failure.
Digoxin (Lanoxin)
Acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
0.125-0.375 mg PO qd
Pediatric
Digitalizing dose (administer in divided doses over 24 h)
2-5 years: 30-40 mcg/kg PO
5-10 years: 20-35 mcg/kg PO
>10 years: 10-15 mcg/kg PO
Maintenance doseTreatment
Medical Care
Treatment strategies can be divided into management of an acute rheumatic fever (ARF) attack, management of the current infection, and prevention of further infection and attacks.
* The primary goal of treating an ARF attack is to eradicate streptococcal organisms and bacterial antigens from the pharyngeal region.
o Penicillin is the drug of choice in persons who are not at risk of allergic reaction.
o A single parenteral injection of benzathine benzylpenicillin can ensure compliance.
o Oral cephalosporins, rather than erythromycin, are recommended as an alternative in patients who are allergic to penicillin. However, be cautious of the 20% cross-reactivity of the cephalosporins with penicillin.
* By promptly treating streptococcal pharyngitis in susceptible hosts, repetitive exposure to pathologically reactive antigens can be avoided. However, management of the current infection will probably not affect the course of the current attack.
* Antimicrobial therapy does not alter the course, frequency, or severity of cardiac involvement.
* Analgesia is optimally achieved with high doses of salicylates, often inducing dramatic clinical improvement.
o A lower dose may be required to avert symptoms of nausea and vomiting.
o When salicylates are used as therapy, the dosage should be increased until the drug produces either a clinical effect or systemic toxicity characterized by tinnitus, headache, or hyperpnea.
* Corticosteroids should be reserved for the treatment of severe carditis.
o After 2-3 weeks, the dosage may be tapered, reduced by 25% each week.
o Overlap with high-dose salicylate therapy is recommended as the dosage of the prednisone is tapered over a 2-week period to avoid poststeroid rebound. In extreme cases, intravenous methylprednisolone may be used.
* Mild heart failure usually responds to rest and corticosteroid therapy.
* Digoxin can be useful in patients with severe carditis, but its use should be monitored closely because of the possibility of heart block.
* Nocturnal tachycardia may be a sign of cardiac involvement that may be responsive to digoxin. Vasodilators and diuretics also may be used.
* Protracted Sydenham chorea has responded to haloperidol.
o Chorea requires long-term antimicrobial prophylaxis, even if no other manifestations of rheumatic fever evolve.
o The signs and symptoms of chorea usually do not respond well to treatment with antirheumatic agents.
o Complete physical and mental rest is essential because the manifestations of chorea may be exaggerated by emotional trauma.
o Glucocorticoids or salicylates have little or no effect on chorea.
o Because chorea disappears with sleep, adequate sedation should be provided.
* Prevention has been successful in developed societies. The recommended approach can be divided into primary and secondary prevention.
o Primary prevention: Eradicate Streptococcus from the pharynx, which generally entails administering a single intramuscular injection of benzathine benzylpenicillin.
o Secondary prevention: The AHA Committee on Acute Rheumatic Fever recommends a regimen consisting of benzathine benzylpenicillin at 1.2 million units intramuscularly every 4 weeks. However, in high-risk situations, administration every 3 weeks is justified and advised. High-risk situations include patients with heart disease who are at risk of repetitive exposure.
o Oral prophylaxis, which is less reliable, consists of phenoxymethylpenicillin (penicillin V) or sulfadiazine. These can be used in compliant patients.
o If penicillin allergy is suspected, oral cephalosporins should be used.
o Although no consensus on the required duration of antibacterial prophylaxis has been reached, the AHA recommends that prophylaxis be continued for at least 10 years after the last episode of rheumatic fever or until patients are well into adulthood. For those with heart disease who are at risk of repetitive exposures, prophylaxis should be continued for a longer duration, probably indefinitely. However, discontinuing prophylaxis may be reasonable in patients in their third decade of life in whom more than 5 years have passed since their last attack and who are free from rheumatic heart disease. The principles of treatment include the following:
+ The risk of rheumatic fever recurrence is greatest during the first 3-5 years following the attack.
+ Prophylaxis must continue indefinitely in patients with established heart disease or in those frequently exposed to streptococci.
+ Treatment for an indefinite period is required among patients with frequent exposure to streptococci or for those who are difficult to monitor.
* In underdeveloped countries, prophylaxis should be continued as follows:
o Continue for 5 years after the first attack.
o Continue indefinitely in patients with established heart disease.
o Continue indefinitely in patients who are frequently exposed to streptococci, are less than optimal, and are difficult to monitor.
* The decision to withdraw the antibacterial drugs should be individualized after carefully assessing the risk of repetitive exposures.
Surgical Care
* Valve replacement should be considered in patients with active carditis, especially in cases that are refractory to medical care or require high doses of vasodilators and diuretics.
* Regurgitant lesions respond to valve replacement, while pure stenotic lesions may benefit from more conservative balloon mitral commissurotomy.
Consultations
* Primary care physicians should be considered the patient's advocate and guide to medical resources.
* Rheumatologists usually assist in diagnosis in the face of a substantial differential. Then, they can advise on the therapy plan.
* A cardiologist should be consulted when cardiac involvement is present.
* A neurologist may offer interventions to help manage chorea.
Diet
* No dietary factors are known.
Activity
* All patients should be restricted to bed rest and monitored closely for carditis.
* Aggressive use of acutely inflamed joints or other exercise may cause permanent joint injury to acutely inflamed joints.
* When carditis has been documented, a 4-week period of bed rest is recommended. As soon as the signs of acute inflammation subside, patients should resume active ambulation as tolerated.
* Most patients can be treated safely in an outpatient setting.
Medication
Treatment and prevention may involve multiple fields of discipline, including infectious diseases, cardiology, and neurology. For this reason, several different classes of medications are used. These include antibiotic, neuroleptic, and cardiac medications.
Antibiotics
Antibiotics are the initial pharmacotherapy for prevention and treatment of rheumatic fever.
Penicillin G procaine (Crysticillin)
Long-acting parenteral penicillin indicated in the treatment of moderately severe infections caused by microorganisms sensitive to penicillin G. IM administration only.
Adults: Deep IM injection into the upper outer quadrant of the buttock only.
Infants and small children: IM injection into midlateral aspect of the thigh is suggested.
Some authors prefer 10 d of therapy.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
2.4 million U IM once
Pediatric
<30 lb: 600,000 U IM once
30-60 lb: 900,000-1,200,000 U IM once
* Dosing
* Interactions
* Contraindications
* Precautions
Increases risk of bleeding when administered concurrently with warfarin; ethacrynic acid, aspirin, indomethacin, and furosemide may compete with penicillin G for renal tubular secretion, thereby increasing penicillin serum concentrations
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Never use IV route to administer penicillin G procaine; administer for more than 10 d to eliminate the organism and prevent complications such as endocarditis and rheumatic fever; perform cultures after treatment to confirm streptococci eradication
Penicillin G benzathine (Bicillin L-A)
Interferes with synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. Long-acting depot form of penicillin G. Because of its prolonged blood level, several authors believe this to be the DOC. Others prefer daily injections with short-acting penicillin.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
2.4 million U IM once
Pediatric
<30 lb: 600,000 U IM once
30-60 lb: 900,000-1,200,000 U IM once
* Dosing
* Interactions
* Contraindications
* Precautions
Probenecid can increase penicillin effectiveness by decreasing clearance; tetracyclines are bacteriostatic, possibly decreasing penicillin effect
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal dysfunction (adjust dose accordingly)
Penicillin VK (Beepen-VK, Betapen-VK, Robicillin VK, Veetids)
Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication. Inadequate concentrations may produce only bacteriostatic effects. PO alternative.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
500 mg PO q6h for 10 d
Pediatric
<12 years: 25-50 mg/kg/d PO divided tid/qid, not to exceed to 3 g/d
>12 years: Administer as in adults
* Dosing
* Interactions
* Contraindications
* Precautions
Probenecid can increase effects of penicillin by decreasing clearance; coadministration of tetracyclines can decrease effects of penicillin
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in impaired renal function (adjust dose accordingly)
Erythromycin (EES, E-Mycin, Ery-Tab, Erythrocin)
Alternative for patients allergic to penicillin (although not the DOC).
Drug may inhibit RNA-dependent protein synthesis by stimulating the dissociation of peptidyl t-RNA from ribosomes. Inhibits bacterial growth.
In children, age, weight, and the severity of infection determine proper dosage. When bid dosing is desired, half-total daily dose may be taken every 12 h. For more severe infections, dose may be doubled.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
250 mg erythromycin stearate, base, or estolate salts (or 400 mg ethylsuccinate) PO q6h or 500 mg PO q12h for 10 d; not to exceed 1 g/d; alternatively, 333 mg (as the base) q8h
Pediatric
30-50 mg/kg/d (base or ethylsuccinate) PO divided q6-8h; not to exceed 1 g/d
* Dosing
* Interactions
* Contraindications
* Precautions
Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis; inhibits CYP1A2 CYP3A4 isoenzymes
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity, severe hepatic impairment
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in liver disease (estolate formulation may cause cholestatic jaundice); adverse GI effects are common; discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur
Anti-inflammatory agents
These agents inhibit inflammation to prevent destruction in the joints and heart.
Aspirin (Ascriptin, Bayer Buffered Aspirin, Ecotrin)
For treatment of mild to moderate pain and headache. Considered the first DOC for the treatment of arthritis due to acute rheumatic fever (ARF).
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
6-8 g/d PO for 2 mo or until ESR has returned to normal, adjust dose according to serum levels
Pediatric
80-100 mg/kg/d PO for 2 mo or until ESR has returned to normal, adjust dose according to serum levels
* Dosing
* Interactions
* Contraindications
* Precautions
Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs; serum levels of 20-30 mg/100 dL required to control inflammatory response; high doses may cause gastric irritation or salicylate toxicity (ie, serum levels >20 mg/100 dL) and require dose reduction or alternative treatment with corticosteroids
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; aspirin-sensitive asthma; because of association with Reye syndrome, do not use in children <16 y who have influenza or varicella infections
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May cause transient decrease in renal function and aggravate chronic kidney disease; avoid with severe anemia or blood coagulation defects
Glucocorticosteroids
These agents demonstrate anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids produce profound and varied metabolic effects. These agents also modify the body's immune response to diverse stimuli.
Prednisone (Deltasone, Liquid-Pred, Meticorten, Orasone, Sterapred)
Patients with carditis require prednisone. The goal is to decrease myocardial inflammation. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. After 2-3 wk, dosage may be tapered, reduced 25% each week.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
1-2 mg/kg/d PO for 2-3 wk initially; then discontinue by gradual taper over 3 wk; not to exceed 80 mg/d
Pediatric
0.05-2 mg/kg/d PO for 2-3 wk initially; then discontinue by gradual taper over 3 wk
* Dosing
* Interactions
* Contraindications
* Precautions
May cause water and salt retention, thereby exacerbating hypertension and increasing requirement for antihypertensive drugs in patients with hypertension; may aggravate hyperglycemia, thereby increasing requirement for hypoglycemic agents in patients with diabetes; coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (adjust dose); hypokalemia may occur with coadministration of diuretics
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; may cause hyperglycemia, edema, weight gain, osteonecrosis, myopathy, dyspepsia, peptic ulcer, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, cataracts, glaucoma, and infections
Neuroleptic agents
These agents are used for chorea associated with ARF.
Haloperidol (Haldol)
Dopamine receptor blocker used for irregular spasmodic movements of the limbs or facial muscles.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
0.5-2 mg PO bid/tid
Pediatric
<3 years: Not established
3-12 years
Initial: 0.05 mg/kg/d or 0.25-0.5 mg/d PO divided bid/tid, may increase by 0.25-0.5 mg/d PO q5-7d
Maintenance: 0.05-0.15 mg/kg/d PO in 2-3 divided doses; not to exceed 0.15 mg/kg/d
>12 years: Administer as in adults
* Dosing
* Interactions
* Contraindications
* Precautions
May increase tricyclic antidepressant serum concentrations; may increase hypotensive action of antihypertensive agents; phenobarbital or carbamazepine may decrease effects; coadministration with anticholinergics may increase intraocular pressure; encephalopathylike syndrome associated with concurrent administration of lithium
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; narrow-angle glaucoma; bone marrow suppression; severe cardiac or liver disease; severe hypotension; subcortical brain damage
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Severe neurotoxicity manifesting as rigidity or inability to walk or talk may occur in patients with thyrotoxicosis also receiving antipsychotics; monitor for hypotension with parenteral administration; caution in diagnosed CNS depression or cardiac disease; if history of seizures, benefits must outweigh risks; significant increase in body temperature may indicate intolerance to antipsychotics (discontinue if it occurs)
Positive inotropic agents
Digoxin may be indicated for patients with congestive heart failure.
Digoxin (Lanoxin)
Acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
0.125-0.375 mg PO qd
Pediatric
Digitalizing dose (administer in divided doses over 24 h)
2-5 years: 30-40 mcg/kg PO
5-10 years: 20-35 mcg/kg PO
>10 years: 10-15 mcg/kg PO
Maintenance doseFollow-up
Further Inpatient Care
* Although inpatient care is believed to be initially mandatory in individuals with active carditis, prolonged hospitalization is usually not necessary.
Further Outpatient Care
* Periodic monitoring at 3- to 4-month intervals is critical to evaluate for progress with the resumption of physical activity, resolution of the constitutional symptoms, and freedom from adverse effects from medications.
* Less frequent visits, perhaps once a year, are appropriate while following a prophylaxis regimen.
Transfer
* Transfer to a short-term–care facility should be arranged when patients have active life-threatening sequelae, notably carditis.
Deterrence/Prevention
* Patients should be educated to seek medical attention upon the first signs of pharyngitis.
* Once the disease is established, patients should be educated regarding benefits and risks of compliance with their medical regimen, which may be protracted.
Complications
* Acute episodes are self-limited, with an average duration of 3 months for untreated attacks. Recurrence tends to occur within the first few years of the attack.
* The outcome of carditis is likely to be more severe if patients have pre-existing heart disease. Carditis resolves without sequelae in 65-75% of patients.
* Severe cardiac failure, total disability, and death may occur years after the acute attack.
* The risk of developing a new episode is highest during the 5 years following an acute attack. This justifies prophylaxis for all patients for at least 5 years or until the patient reaches age 18 years.
Prognosis
* The course followed by a patient after a first attack is highly variable and unpredictable. Approximately 90% of episodes last less than 3 months. Only a minority persist longer, in the form of unremitting rheumatic carditis or prolonged chorea.
Miscellaneous
Medicolegal Pitfalls
* Pitfalls arise when misdiagnosis occurs. Many physicians who are unfamiliar with acute rheumatic fever (ARF) may not have a high enough index of suspicion for this disease. Inadequate treatment of streptococcal pharyngitis also may contribute to a legal quagmire.
* Inappropriate or inadequate referral also may invite litigation. Patients who are critically ill with cardiomyopathy must be efficiently transferred an intensive-care setting. In addition, patients must be educated about their disease and the chronicity of it.
