Case 3: Fatigue, Ankle Pain, and a Murmur in a 6-Year-Old Girl

A healthy 6-year-old girl born in the United States and living in Belize since age 3 months presents with 4 weeks of fatigue, dyspnea on exertion, and intermittent ankle pain. Eight weeks prior to presentation, she had a febrile illness associated with abdominal pain, nonbloody diarrhea, and vomiting, which resolved in 1 week without intervention. She did not report sore throat, and no infectious evaluation was obtained given quick resolution of symptoms. She developed another febrile illness 2 weeks later, associated with nasal congestion, cough, fatigue, dyspnea on exertion, and intermittent left ankle pain. She was seen on several occasions by multiple primary care providers who recommended supportive care for a presumed viral infection. No infectious evaluation was performed, and she did not receive antimicrobial treatment. After 4 weeks of illness with intermittent fever, a pediatrician noted a new heart murmur on examination and obtained an echocardiogram, which revealed severe mitral regurgitation. She was admitted to a hospital in Belize, where she was started on ceftriaxone and ibuprofen (a nonsteroidal anti-inflammatory drug [NSAID]) as needed before transfer to the United States.On presentation, she is afebrile and has been afebrile for 1 week. She reports intermittent left ankle pain, which resolved prior to admission. Other vitals show a heart rate of 84 beats/min, blood pressure of 99/43 mm Hg, respiratory rate of 28 breaths/min, and oxygen saturation of 100% on room air. The physical examination is significant for a tired-appearing female with a grade III/VI holosystolic murmur that is loudest at the cardiac apex with a hyperdynamic precordium. Her oropharynx is clear without erythema or tonsillar exudate. She has no palpable lymphadenopathy or rash. Her musculoskeletal examination does not show any joint tenderness, swelling, warmth, or limitations in range of motion. Initial laboratory data show the following: elevated white blood count of 19.14 × 103/μL (19.14 × 109/L) (reference range, 4.27–11.40 × 103/μL [4.27–11.40 × 109/L]) with normal differential of 46.5% neutrophils, 41.8% lymphocytes, 8.3% monocytes, 1.9% eosinophils, 0.6% basophils, and 0.9% immature granulocytes; anemia with hemoglobin of 9.2 g/dL (92 g/L) (reference range, 10.6–13.4 g/dL [106–134 g/L]); elevated platelets of 463 × 103/μL (463 × 109/μL) (reference range, 100–369 × 103/μL [100–369 × 109/L]); elevated C-reactive protein of 4.8 mg/dL (48 mg/L) (reference range, <1 mg/dL [<10 mg/L]); elevated erythrocyte sedimentation rate > 145 mm/h (reference range, <1–20 mm/h); elevated B-type natriuretic peptide (BNP) of 413.5 pg/mL (413.5 × 103 pg/L) (reference range, <100.0 pg/mL [100.0 × 103 pg/L]); elevated N-terminal pro-brain natriuretic peptide (NT pro-BNP) of 2470.0 pg/mL (2470.0 × 103 pg/L) (reference range, <125.0 pg/mL [125.0 × 103 pg/L]); and a normal troponin of 0.011 ng/mL (11 ng/L) (reference range, <0.030 ng/mL [30 ng/L]). A chest x-ray shows an enlarged cardiac silhouette with mild pulmonary interstitial edema (Figure 1A). An electrocardiogram shows normal sinus rhythm with left atrial enlargement and biventricular hypertrophy (Figure 1B). An echocardiogram reveals severe mitral valve regurgitation with severe left atrial dilation, normal biventricular function, and a small pericardial effusion. The mitral valve leaflet tips are thickened, with evidence suggestive of chordal tear leading to flail leaflet tips (Figure 2, Video 1). Additional evaluation reveals the diagnosis.The differential diagnosis for a child presenting with a new murmur related to mitral valve regurgitation is broad. Congenital heart disease, including mitral valve prolapse, dilated cardiomyopathy, or hypertrophic cardiomyopathy, can result in severe mitral regurgitation. However, providers should expect a heart murmur to be more long-standing prior to symptom onset in congenital heart disease. Evaluation for infective endocarditis or myocarditis should always be completed in a patient presenting with fever and mitral valve abnormalities. Postinfectious phenomena such as acute rheumatic fever (ARF) should also be considered, especially in a patient from an endemic country. Valvular abnormalities can rarely be seen in various autoimmune or autoinflammatory conditions, including systemic lupus erythematosus, scleroderma, sarcoidosis, or systemic-onset juvenile idiopathic arthritis. These conditions are less likely in this patient given her acute onset of symptoms and lack of other history or examination findings consistent with a systemic autoimmune or autoinflammatory condition. Other connective tissue diseases such as Ehlers-Danlos syndrome or Marfan syndrome can also be associated with mitral valve abnormalities and should be suspected in patients with skin translucency or hyperextensibility or Marfanoid habitus.After admission, additional laboratory evaluation reveals a positive anti-streptolysin O (ASO) titer of 1:1600 IU/mL and elevated anti-DNASE B antibody of 274 U/mL (274 × 103 U/L) (reference range, 0–250 U/mL [0–250 × 103 U/L]). A throat culture is negative for group A streptococcus (GAS). Blood cultures are negative, which is reassuring against infective endocarditis. Her acuity of symptoms makes congenital mitral valve abnormalities less likely. Given her presentation, laboratory findings, and echocardiogram findings, the patient is diagnosed with ARF with severe carditis.Although the incidence of ARF in high-income nations has declined, the global burden of ARF continues to be significant in marginalized or economically disadvantaged populations. Its chronic sequela, ie, rheumatic heart disease (RHD), remains one of the most common causes of cardiac disease in children worldwide, with a recent report identifying more than 33 million current cases and more than 233 000 RHD-related deaths per year globally.1,2 ARF is a postinfectious response to GAS (also called Streptococcus pyogenes) infection and is characterized by varying degrees of inflammation affecting multiple organs, including joints, skin/subcutaneous tissue, the central nervous system, and the heart. ARF is thought to be due to an autoimmune response to a GAS infection mediated through molecular mimicry in which antibodies produced against streptococcal antigens, including GAS M protein and the carbohydrate antigen (N-acetyl-β-D-glucosamine), cross-react with human proteins that are also found in various organs, including the heart, leading to inflammation and injury.3 The incidence of ARF is highest in children aged between 5 and 14 years, which parallels the peak of GAS infections and is the same in male and female individuals, but the risk of developing RHD is 1.5- to 2-times higher in female individuals.4 Population differences of ARF suggest that the development of this postinfectious complication is likely dependent on both the genetic susceptibility of the host and the specific strain of GAS1 in addition to risk factors seen in marginalized populations, such as lack of access to medical care and overcrowding.Although our understanding of the underlying mechanisms of ARF has improved in recent years, clinicians diagnose ARF using the Jones criteria, in which patients need to fulfill either 2 major manifestations or 1 major plus 2 minor manifestations (Figure 3).3 Patients should also have laboratory evidence of an antecedent GAS infection with an increased or rising ASO titer or other streptococcal antibodies (anti-DNASE B antibody), a positive throat culture for GAS, or a positive rapid GAS carbohydrate antigen test.1,5 The exception to this applies to patients who present with isolated chorea or indolent carditis because these manifestations can occur months after the inciting infection; therefore, streptococcal serologic testing may be negative. The most common presenting symptom of ARF is fever, which affects >90% of patients. The arthralgia (joint pain) or arthritis (joint pain associated with joint swelling, warmth, or stiffness) associated with ARF affects approximately 75% of patients and is typically a migratory polyarthritis involving several large joints, but it can also be monoarticular.1,3 It is unique in that it responds quickly to NSAIDs such as aspirin, ibuprofen, or naproxen, and joint symptoms that do not significantly improve with NSAIDs should prompt providers to consider an alternative diagnosis. Chorea, or involuntary movements of the face, limbs, or trunk, can occur in up to 30% of patients with ARF, can uniquely present in isolation without other features,1 and is commonly associated with emotional lability or muscle weakness.5 Carditis is present in approximately 50% of ARF cases and is manifested as valvulitis or regurgitation of left-sided heart valves (mitral more common than aortic valve).1 Whereas cardiac complications may result in permanent damage, other organ manifestations in ARF, including fever, resolve without long-term complications.The Jones criteria was revised by the American Heart Association in 2015 and included adjustments to the major and minor manifestations depending on whether the patient is from a low- or moderate/high-risk population.5 A low-risk population is defined as ARF incidence ≤2 per 100 000 school-aged children or all-age RHD prevalence of ≤1 per 1000 population per year. The revised criteria also recommend obtaining an echocardiogram in patients in whom ARF is suspected to assess for evidence of carditis, particularly in moderate/high-risk populations, even if the examination is normal.5,6 The goal of this revision of the criteria was to improve its sensitivity to detect ARF in the moderate/high-risk populations while maintaining its specificity in the low-risk populations. However, as immigration and travel from high-risk, endemic areas to low-risk areas becomes more frequent, all primary care providers will need to maintain a high level of suspicion for ARF and RHD given the associated morbidity, and even mortality, caused by a missed diagnosis.Timely diagnosis and appropriate antimicrobial treatment of GAS infections is vital to the prevention of ARF and RHD, and increased primary prophylaxis is the sole reason incidence of ARF in high-income nations has declined.1 Providers should suspect GAS infection in a child presenting with a constellation of fever, pharyngitis, pustular tonsillar exudate, cervical lymphadenopathy, headaches, or gastrointestinal symptoms, including abdominal pain, vomiting, or nausea, which may have been the symptoms of our patient’s initial GAS infection. Throat culture is the clinical standard for the diagnosis of GAS pharyngitis. Rapid antigen or polymerase chain reaction (PCR) testing can also be used but has lower sensitivity and therefore should always be paired with a throat culture. A positive throat culture or rapid antigen or PCR test can be reflective of GAS colonization and not acute infection; therefore, test results should be correlated with the patient’s clinical presentation. The recommended antimicrobial treatment of GAS includes intramuscular benzathine penicillin G for a single dose or oral penicillin V for a 10-day course.7 In deciding between these 2 regimens, providers should consider several factors, including ease of adherence and cost. There are alternative antimicrobial regimens available for patients who have an allergy to penicillin, including a 10-day course of cephalexin or clindamycin or a 5-day course of azithromycin.7 A full therapeutic antimicrobial course should be given to patients with ARF at the time of diagnosis to eradicate residual GAS, even if a throat culture or rapid antigen test is negative at that time.1,8,9 Family members of patients newly diagnosed with ARF or with ARF recurrence also need to be tested for GAS pharyngitis, even in the absence of symptoms, and treated appropriately if detected.Patients with a history of ARF are at an increased risk of recurrence if they develop another GAS infection, and recurrence of rheumatic fever can lead to worsening of existing RHD or new development of RHD. This is concerning because streptococcal pharyngitis is often a self-limited condition for which patients may not seek medical attention. Therefore, continuous antimicrobial prophylaxis rather than recognition and treatment is preferred for the prevention of recurrent GAS infections. Prophylaxis should be started immediately at the time of ARF or RHD diagnosis. The recommended antimicrobial agent for continuous prophylaxis is intramuscular benzathine penicillin G, as studies have shown that risk of recurrence is higher for patients on oral antimicrobial prophylaxis.1,9 The injection should be given every 3 or 4 weeks, and providers should consider a 3-week schedule for patients living in endemic areas or in patients who have recurrence of ARF despite adherence to a 4-week schedule to ensure that drug levels remain therapeutic.1,9 Oral sulfonamides or macrolides can be used as secondary prophylaxis in patients with a penicillin allergy.3,8 Duration of prophylaxis is dependent on several factors, including the patient’s age, the time between their most recent episode of ARF, and whether the patient has persistent valvular disease. In general, prophylaxis should continue for 10 years or until the patient is aged 21 years (whichever is longer) for patients without valvular disease. In patients with moderate RHD, prophylaxis should be continued until age 30 years. In patients with severe RHD, prophylaxis should continue until age 40 years,9 and some experts will recommend lifelong prophylaxis. The decision to stop secondary prophylaxis should be a shared agreement between the provider and patient after careful consideration regarding the risk of ARF recurrence based on specific epidemiologic factors. If patients on secondary prophylaxis are found to have a GAS pharyngitis infection, they should complete a course of primary prophylaxis or eradication, as discussed earlier, before restarting secondary prophylaxis. However, this should not happen in a patient on appropriate secondary prophylaxis and may be indicative of nonadherence or ineffective penicillin serum levels.Except for RHD, all other features of ARF will resolve spontaneously, without long-term sequela. However, patients may require supportive measures for debilitating symptoms. Arthritis associated with ARF is extremely responsive to NSAIDs, including anti-inflammatory dosing of aspirin (80–100 mg/kg/d divided 3 to 4 times per day) or naproxen (15–20 mg/kg/d divided 2 times per day). In most cases, other NSAIDs are preferred over aspirin given the need for frequent dosing for anti-inflammatory effects and the potential for the life-threatening complication of Reye syndrome.7 For chorea, the mainstay treatment is antibiotic therapy. Studies have shown that the intensity of chorea associated with ARF can improve with dopamine antagonists and/or systemic corticosteroids, although the latter treatment must be weighed against the adverse effects associated with chronic steroid use. The carditis of ARF is typically mild and managed supportively with diuretics and/or angiotensin-converting enzyme inhibitors. Surgical intervention is not common but can be considered in patients presenting with RHD with severe mitral regurgitation that may require surgical or percutaneous interventions. Although rare, fulminant heart failure due to severe mitral regurgitation from acute chordal rupture can be life-threatening and may require urgent surgery.3Using anti-inflammatory drugs to treat carditis remains controversial, as small randomized controlled trials comparing the use of steroids, aspirin, or placebo have not shown a reduction in valvular disease with steroids at 1 year of treatment. However, conclusive results cannot be made given the limitations of these trials, and many experts continue to recommend steroid therapy in cases of severe valvular dysfunction or severe RHD, especially in the setting of elevated inflammatory markers and for patients living in endemic areas. Adequately powered randomized controlled trials comparing anti-inflammatory therapies in ARF and RHD are needed.3The patient fulfilled revised Jones criteria, with Belize being an endemic country10 and with evidence of preceding GAS infection, 1 major criteria of carditis, and 3 minor criteria, including fever, arthralgia, and elevated inflammatory markers. Her echocardiogram findings were consistent with mitral valvulitis described in ARF.6 It is not clear if her initial gastrointestinal illness 8 weeks prior to presentation is relevant to this diagnosis however, this may represent a GAS infection. Due to her severe mitral valve disease with chordal tear in the setting of systemic inflammation, the patient was treated with systemic corticosteroids at 2 mg/kg/d and started a slow taper over 4 weeks once her inflammatory markers had normalized. She also completed a 10-day course of oral penicillin at the time of diagnosis and will continue secondary prophylaxis with intramuscular benzathine penicillin G injections every 3 weeks. For her congestive heart failure, she was started on furosemide and enalapril, with plans to undergo mitral valve repair 4 to 6 weeks after her ARF diagnosis.All primary care providers should have a high index of suspicion and be familiar with the revised Jones criteria to make a diagnosis of ARF in children, especially in children from endemic regions.An echocardiogram should be obtained in all cases in which ARF is suspected.Timely diagnosis and appropriate treatment of GAS infections is crucial for the prevention of primary ARF.All patients diagnosed with ARF should complete a course of antimicrobial treatment for eradication of the primary infection and start long-term secondary antimicrobial prophylaxis.We would like to thank Ms. Kaitlin Doan, who assisted in editing the video.