AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Rheumatic fever causes chronic progressive damage to the heart and its valves. Until 1960, it was a leading cause of death in children and a common cause of structural heart disease. The disease has been known for many centuries. Baillou (1538-1616) first distinguished acute arthritis from gout. Sydenham (1624-1668) described chorea but did not associate it with acute rheumatic fever (ARF). In 1812, Charles Wells associated rheumatism with carditis and provided the first description of the subcutaneous nodules. In 1836, Jean-Baptiste Bouillaud and, in 1889, Walter Cheadle published classic works on the subject.

The association between sore throat and rheumatic fever was not made until 1880. The connection with scarlet fever was made in the early 1900s. In 1944, the Jones criteria were formulated to assist disease identification. These criteria, with some modification, remain in use today. The introduction of antibiotics in the late 1940s allowed for the development of treatment and preventive strategies. The dramatic decline in the incidence of rheumatic fever is thought to be largely due to antibiotic treatment of streptococcal infection. 

However, research into the subtypes of streptococci have made it clear that differences among those types is also responsible for both the decline in overall US incidence and isolated outbreaks.

Pathophysiology

ARF is a sequela of a previous group A streptococcal infection, usually of the upper respiratory tract. One beta-streptococcal serotype (eg, M types 3, 5, 18, 19, 24) is linked directly to ARF. Two vaccines—one that is 26-valent and likely to proceed into clinical trials—are based on the M protein characteristics of responsible subtypes.

Good evidence suggests that there is genetic susceptibility to development of the disease.

Non–group A streptococci has never been shown to cause this disease.

The disease involves the heart, joints, central nervous system (CNS), skin, and subcutaneous tissues. It is characterized by an exudative and proliferative inflammatory lesion of the connective tissue, especially that of the heart, joints, blood vessels, and subcutaneous tissue.

Frequency

United States

Disease prevalence in the United States is a function of socioeconomic status, with higher frequency in areas of crowding. The United States had experienced a resurgence of rheumatic fever in the last 2 decades, with many of the reported cases involving persons in upper socioeconomic groups. The reason for this disparity is unclear but may be caused by the emergence of more virulent strains of group A streptococci. The overall incidence has been declining in developed nations but is still rampant in less developed ones.

The incidence is low in most parts of the country but is variable. In a study published in 2006, Martin and Barbadora showed that the disease remains a problem in western Pennsylvania with 121 new cases from 1994-2003.¹ Consistent with earlier reports, most patients were children and most had carditis.

ARF is common among American Samoans in Hawaii.²

Frequency of streptococcal infection, virulence of the bacterial strain, and M protein subtypes determine the incidence of rheumatic fever in the population.

As a sequela of beta-streptococcal exposure, ARF occurs during the school-aged years when streptococcal pharyngitis is most prevalent. Similarly, prevalence is higher in the colder months of the year when streptococcal pharyngitis is most likely to occur.

International

ARF is a major problem in the high-risk areas of the tropics, in countries with limited resources, and in communities with minority indigenous populations. Although older literature estimates that 25-40% of cases worldwide appear in those nations, a recent paper suggests the figure may be closer to 95%.

In those less developed nations, post ARF heart disease is the most commonly acquired heart disease in hospitalized children, adolescents, and young adults. In some areas, the incidence of this entity exceeds that of congenital heart disease. Some studies point out the association with heart failure and death in pregnant women.

McDonald et al have suggested that in Aboriginal communities of central and northern Australia, group A streptococcal pyoderma is much more likely to cause ARF than is streptococcal pharyngitis.³

Wang et al reported on a possible ARF resurgence in Taiwan.⁴ Authors in India and Turkey make a plea for more liberal application of the Jones criteria in order to avoid misdiagnosis.^{5, 6} Meira et al report on the high incidence in Brazil.⁷ Others have reminded the medical community that good reporting of prevalence in underdeveloped nations is lacking.

Mortality/Morbidity

Morbidity from acute rheumatic fever (ARF) is directly proportional to the rate of streptococcal infections. Infections that are not treated adequately are most likely to cause the major sequelae noted in the list of Jones criteria in Physical. Morbidity also is related to the care that the patient receives.

• The mortality rate has declined steadily over the last 3 decades. A partial explanation for the decrease in mortality rate may be the increase in antibiotic use. In developing nations and lower socioeconomic areas where rheumatic fever is more prevalent, ARF is a major cause of death and disability in children and adolescents.
• Cardiac involvement is the major cause of long-term morbidity. Valvular vegetations (endocarditis) are the cause of mitral valve regurgitation, the end result being left ventricular (LV) dilation and congestive heart failure (CHF). Myocarditis is present but not the cause of heart failure.
• Those with carditis as part of the initial episode are at greater risk of developing recurrences and of sustaining further cardiac injury.
• Carapetis et al estimated that worldwide, approximately 60% of all patients with ARF will develop rheumatic heart disease.⁸ Further, they estimate a world burden of 2.4 million children aged 5-14 years affected or a total population of 15-20 million living with rheumatic heart disease.
• Patients without carditis during the initial episode have a relatively low risk of developing carditis during recurrences, although scattered case reports of carditis occurring only during a recurrence exist.
• Migratory polyarthritis occurs early in the disease course and is a common complaint for patients with rheumatic fever. Joint involvement ranges from arthralgia without objective findings to overt arthritis with warmth, swelling, redness, and exquisite tenderness. The larger joints such as the knees, ankles, elbows, and wrists are involved most frequently. An inverse relationship between severity of joint involvement and risk of carditis appears to exist.
• In approximately 75% of cases, the acute attack lasts only 6 weeks.
• Ninety percent of cases resolve in 12 weeks or less.
• Fewer than 5% of patients have symptoms that persist for 6 months or more.

Race

In the United States, the attack rate is more a function of crowding than race, though the socioeconomic realities of those crowded conditions is no doubt a factor.

Sex

No sex predilection exists, except that mitral valve prolapse and Sydenham chorea occur more often in females than in males.

Age

Although individuals of any age group may be affected, most cases are reported in persons aged 5-15 years.

Yee lists rheumatic pericarditis and myocarditis as cardiac emergencies in the first year of life.⁹

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Acute rheumatic fever (ARF) is associated with 2 distinct patterns of presentation.  
• • The first pattern of presentation is sudden onset. It typically begins as polyarthritis 2-6 weeks after streptococcal pharyngitis and is usually characterized by fever and toxicity.
  • If the initial abnormality is mild carditis, ARF may be insidious or subclinical.
• Age at onset influences the order of complications. Younger children tend to develop carditis first, whereas older patients tend to develop arthritis first.

Physical

Diagnosis of ARF requires a high index of suspicion.

Guidelines of diagnosis used by the American Heart Association include major and minor criteria (ie, modified Jones criteria). In addition to evidence of a previous streptococcal infection, the diagnosis requires 2 major Jones criteria or 1 major plus 2 minor Jones criteria.

• Major criteria  
• • Carditis: This occurs in as many as 40% of patients and may include cardiomegaly, new murmur, congestive heart failure, and pericarditis, with or without a rub and valvular disease.
  • Migratory polyarthritis: This condition occurs in 75% of patients and is polyarticular, fleeting, and involves the large joints. Note that one group of authors has suggested that atypical cases may only involve small joints.⁵
  • Subcutaneous nodules (ie, Aschoff bodies): These nodules occur in 10% of patients and are edematous, fragmented collagen fibers. They are firm, painless nodules on the extensor surfaces of the wrists, elbows, and knees.
  • Erythema marginatum: This condition occurs in about 5% of patients. The rash is serpiginous and long lasting.
  • Chorea (also known as Sydenham chorea and "St Vitus dance"): This characteristic movement disorder occurs in 5-10% of cases. Sydenham chorea consists of rapid, purposeless movements of the face and upper extremities. Onset may be delayed for several months and may cease when the patient is asleep.
• Minor criteria  
• • Clinical findings include arthralgia, fever, and previous history of ARF.
  • Laboratory findings include elevated acute-phase reactants (eg, erythrocyte sedimentation rate, C reactive protein), a prolonged PR interval, and supporting evidence of antecedent group A streptococcal infections (ie, positive throat culture or rapid streptococcal screen and an elevated or rising streptococcal antibody titer).

Note that the current Jones criteria are different than the original. Numerous authors have suggested that more changes may be in order. For example, some have suggested that echocardiography be performed in all suspected cases in order to avoid both underdiagnosis and overdiagnosis. Carapetis and Currie suggest that cases are missed because some patients have only monoarthritis and not polyarthritis.¹⁰ They would like to see monoarthritis become a major criterion. These same authors suggest that the set point of fever at 38ºC might be too high. As mentioned above, at least one author reported on atypical cases in which arthritis involved small joints rather than large joints. Finally, Rayamajhi et al suggest that arthralgia be changed from a minor to a major Jones criterion.¹¹

Causes

• ARF has been linked definitively with a preceding streptococcal infection, usually of the upper respiratory tract. Evidence is very strong that the M protein in certain streptococci subtypes is responsible for antigenicity. 
• Although streptococcal skin infections also are extremely common, they have not been linked with ARF in the United States. Note the suggestion by McDonald et al that pyoderma may be the cause in Aboriginal populations of Australia.³

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Leukemia
Juvenile rheumatoid arthritis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No specific confirmatory laboratory tests exist. However, several laboratory findings indicate continuing rheumatic inflammation. Some are part of the Jones minor criteria.
• Streptococcal antibody tests disclose preceding streptococcal infection.
• Isolate group A streptococci via throat culture. A significant percentage will result in a culture positive for group A beta-hemolytic Streptococcus (GABHS).
• Acute-phase reactants (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] in serum and leukocytosis) may show an increase in serum complement, mucoproteins, alpha-2, and gamma globulins. Anemia is usually caused by suppression of erythropoiesis.
• PR-interval prolongation is present in approximately 25% of all cases and is neither specific to nor diagnostic of ARF.
• Although are a few small studies show the contrary, troponins have not been shown to be helpful in making the diagnosis because ischemia and necrosis are not the major cardiac problems.
• Synovial fluid analysis may demonstrate an elevated white blood cell count with no crystals or organisms.
• Differences exist among nations in terms of diagnosing and treating GABHS pharyngitis. Most North American, French, and Finnish guidelines consider diagnosis of streptococcal infection essential (with either rapid antigen detection or with formal culture) and advise antibiotic therapy when streptococci is detected. Several European guidelines consider streptococcal infection a self-limited disease and do not recommend antibiotics.

Imaging Studies

• Echocardiography may be helpful in establishing carditis. Some suggest it be performed in all suspected cases.
• Chest radiography should be performed to determine presence of cardiomegaly and congestive heart failure.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Although no specific prehospital interventions exist, the patient’s presentation may warrant establishment of intravenous access and placement of a cardiac monitor.

Emergency Department Care

• The emergency medicine physician's primary responsibilities are to suspect the diagnosis and to treat complications.
• Consider early administration of antibiotics.
• Acute rheumatic fever (ARF) usually is preventable if antibiotics are initiated within 9 days of the onset of streptococcal infection. The Infectious Disease Society of America recommends that the diagnosis of GABHS infection be confirmed. In children and adolescents, a negative rapid antigen test (streptococcal screen) result should be followed by culture unless the physician has determined that in his or her own practice the rapid antigen test is comparable to a throat culture. Because of the low incidence of ARF in adults, a negative, properly performed rapid antigen test is considered acceptable evidence that streptococcal infection is not present.
• The best approach to treating the patient with pharyngitis is beyond the scope of this discussion. However, the number needed to treat to prevent one case of ARF is estimated to be 100.

Consultations

Because of the many clinical features of ARF, consider consulting a cardiologist, a rheumatologist, and a neurologist.

• Carditis is not only a major clinical finding, but it also is the cause of much of the disability.
• Arthritis is one of the major manifestations.
• Movement disorders associated with ARF may be difficult to differentiate from those of other clinical problems.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical therapy involves the following 5 areas:

1. Treat group A streptococcal infection regardless of organism detection.
2. Steroids and salicylates are useful in the control of pain and inflammation.
3. Heart failure may require digitalis, fluid and sodium restriction, diuretics, and oxygen.
4. Administer prophylaxis against GABHS infections to patients who have developed ARF. Most authorities suggest that prophylaxis be given for 5 years. For those who have rheumatic carditis, some authorities suggest lifelong prophylaxis.
5. Phenobarbital and haloperidol may be helpful in controlling chorea.
6. Note that clinical trials for a 6-valent and a 26-valent vaccine are likely to take place in the near future. Phase I trials have been very promising.

Drug Category: Antimicrobials

Because of the direct link between ARF and group A beta-streptococcal infection, the first step in treatment is the eradication of the organism.

Antibiotic regimens used for prevention of recurrence are mentioned briefly under Further Outpatient Care.

Drug Name	Penicillin G procaine (Crysticillin, Wycillin)
Description	Long-acting parenteral penicillin (IM only) indicated in the treatment of moderately severe infections caused by penicillin G–sensitive microorganisms. Some prefer 10-d therapy. Administer by deep IM injection only into the upper outer quadrant of the buttock. In infants and small children, the midlateral aspect of the thigh may be the best site for administration.
Adult Dose	2.4 million U IM once
Pediatric Dose	Infants and children <30 lb: 600,000 U IM Children 30-60 lb: 900,000 to 1.2 million U IM
Contraindications	Documented hypersensitivity
Interactions	Increases risk of bleeding when administered concurrently with warfarin; ethacrynic acid, aspirin, indomethacin, and furosemide may compete with penicillin G for renal tubular secretion increasing penicillin serum concentrations
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 >10 d to eliminate organism and prevent complications, such as endocarditis and rheumatic fever; perform cultures after treatment to confirm streptococci eradication

Drug Name	Penicillin VK (Beepen-VK, Betapen-VK, Robicillin VK, Veetids)
Description	Inhibits the biosynthesis of the cell-wall mucopeptide and is effective during the stage of active multiplication. Inadequate concentrations may produce only bacteriostatic effects. Penicillin VK is the oral alternative for the treatment of rheumatic fever.
Adult Dose	500 mg PO q6h for 10 d
Pediatric Dose	<12 years: 25-50 mg/kg/d PO divided tid/qid; not to exceed 3 g/d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing a decrease in the effectiveness of penicillins when administered concurrently
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in renal impairment

Drug Name	Erythromycin (EES, E-Mycin, Ery-Tab, Erythrocin)
Description	DOC for patients allergic to penicillin; inhibits RNA-dependent protein synthesis, possibly by stimulating the dissociation of peptidyl tRNA from ribosomes, which inhibits bacterial growth. In children, age, weight, and severity of infection determine the proper dosage. When bid dosing is desired, one-half the daily dose may be administered q12h. For more severe infections, the dose may be doubled.
Adult Dose	1 g/d PO divided bid for 10 d
Pediatric Dose	30-50 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	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
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; GI adverse effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Category: Glucocorticoids

These agents possess anti-inflammatory (ie, glucocorticoid) and salt-retaining (ie, mineralocorticoid) properties. Glucocorticoids cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Drug Category: Neuroleptic agents

These agents may help to control the chorea associated with ARF.

Drug Category: Inotropic agents

Some believe that digoxin may be helpful in congestive heart failure.

Drug Category: Anti-inflammatory agents

Reduce the inflammation associated with the disease process. Joints and heart are the targets of inflammation, but carditis is treated with glucocorticoids as noted above.

Drug Name	Naproxen (Anaprox, Naprelan, Naprosyn)
Description	For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis. NSAIDs decrease intraglomerular pressure and decrease proteinuria.
Adult Dose	250-500 mg PO bid; may increase to 1.5 g/d for limited periods
Pediatric Dose	<2 years: Not established >2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
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 D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Most patients with acute rheumatic fever (ARF) will be managed as inpatients by a multidisciplinary team of pediatrics, internal medicine, cardiology, infectious disease, and rheumatology specialists.

Further Outpatient Care

Several regimens exist to prevent recurrences—"secondary prevention."

• Duration of prophylaxis is determined by the number of previous attacks, time since last attack, the risk of exposure to streptococcal infections, patient age, and—very importantly—presence or absence of cardiac involvement. Although the emergency medicine physician is not likely to be the prescriber of such a regimen, it is worth knowing what our colleagues may prescribe.
• Penicillin is still the drug of choice and may be given daily by mouth or monthly by intramuscular injection. Macrolides are acceptable in penicillin-allergic patients.
• Those who have had carditis should be treated well into adulthood and may require lifelong prophylaxis.
• Those without carditis may be treated until they reach their 20s and after at least 5 years have elapsed since the past episode. Duration may increase if patients in this group are at risk for exposure to streptococcal infection.

Transfer

It is now a fact of life in American health care that many hospitals do not admit children. Transfer to an appropriate pediatric facility is essential.

Deterrence/Prevention

• Literature, much of it now dated, reports that ARF can effectively be prevented if appropriate antibiotics are given within 9 days of symptom onset. Most authorities believe this to be a valid conclusion.
• Differences exist among nations in terms of diagnosing and treating GABHS pharyngitis. Most North American, French, and Finnish guidelines consider diagnosis of streptococcal infection essential (with either rapid antigen detection or with formal culture) and advise antibiotic therapy when streptococci is detected. Several European guidelines consider streptococcal infection a self-limited disease and do not recommend antibiotics. The North American guidelines refer primarily to North American studies. European guidelines did not reference North American studies as frequently.

Complications

• Carditis
• Mitral stenosis
• Mitral regurgitation
• Aortic stenosis
• Congestive heart failure (CHF)

Prognosis

• Sequelae are limited to the heart and are dependent upon the severity of the carditis during the acute attack.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Diagnosis of acute rheumatic fever (ARF) usually is evident if considered in the differential of a child with suggestive signs and symptoms. The primary medicolegal pitfall is not making the diagnosis in a timely fashion. Failure to diagnose translates into failure to treat. Complications may occur in any patient but are much more likely if treatment is delayed.
• Although rare, ARF has been diagnosed in adults who had never been diagnosed as children. Misdiagnosis in the population is probably more likely than in children.
• Concern also arises over failure to recognize and treat a streptococcal infection that eventually leads to ARF.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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3. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat?. Lancet Infect Dis. Apr 2004;4(4):240-5. [Medline].
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24. Padmavati S. Rheumatic heart disease: prevalence and preventive measures in the Indian subcontinent. Keywords: rheumatic heart disease; rheumatic fever. Heart. Aug 2001;86(2):127. [Medline].
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Article Last Updated: Mar 25, 2008