In the third week of April, 2020, a 17-year-old obese male (body mass index = 30 kg/m2) with spondylolysis and a remote history of asthma (not requiring medication for >5 years) presented to a hospital in New York City. He reported 7 days of fever and neck pain (worse with lateral movement, but not with flexion) as well as 6 days of diffuse abdominal pain, nonbloody diarrhea and nonbloody, nonbilious emesis. He had no neck stiffness, headache, photophobia, phonophobia or preceding trauma, and denied rhinorrhea, congestion, cough, shortness of breath or chest pain.
In the Emergency Department, he was febrile (103°F), tachycardic (150 bpm) and hypotensive (79/66 mm Hg). On examination, he had diffuse abdominal pain without rebound or guarding, but otherwise appeared stable. He received an IV fluid bolus with initial resolution of tachycardia and low blood pressure; however, his cardiovascular status remained labile. Initial labs revealed a normal white blood cell count with mild lymphopenia (0.9 × 103/µL). Nasopharyngeal swab obtained due to the ongoing pandemic was tested for the SARS-CoV-2 virus via polymerase chain reaction (Cepheid Xpert Xpress SARS-CoV-2 RT-PCR assay) and returned positive. Inflammatory markers, including C reactive protein (167 mg/L), ferritin (1274.6 ng/mL) and D-Dimer (1218 ng/mL), were all elevated (Table 1). Initial Troponin I level was 2.97 ng/ml. Two hours later, a repeat Troponin I level was 6.17 ng/mL and a brain natriuretic peptide (BNP) was 2124 pg/mL. Labs were also notable for mild coagulopathy and hyponatremia (sodium 128 mmol/L) as well as acute kidney injury (creatinine 1.25 mg/dL). Abdominal ultrasound was normal aside from possible hepatic steatosis. Electrocardiogram (ECG) revealed sinus tachycardia and T-wave inversion particularly in the inferior leads. Chest radiograph demonstrated low lung volumes, normal cardiothymic silhouette and mild, hazy ground glass opacities at the lower lobes bilaterally with no focal consolidation, pleural effusion, or pneumothorax. Initial transthoracic echocardiogram demonstrated left ventricular ejection fraction qualitatively noted to be mildly depressed without obvious intracardiac clots or pericardial effusion. The patient was admitted to the Pediatric Intensive Care Unit (PICU) with COVID-19 complicated by fluid-responsive septic shock and myocarditis.
Hydroxychloroquine (400 mg BID on day 1, followed by 200 mg BID to complete 5 days) was started; however, it was stopped on day 3 when serial ECG demonstrated prolonged QTc interval not present initially. Due to concern for possible bacterial sepsis with an intrabdominal source, blood culture was sent and piperacillin/tazobactam started. Antibiotics were stopped when the culture returned negative at 48 hours.
Results of Cardiac magnetic resonance imaging revealed normal size left ventricle (LV) with mildly decreased systolic function (LVEF 40%) and normal right ventricular size with mildly diminished systolic function (RVEF of 39%). There was an area of mid-wall late gadolinium enhancement at the inferior LV–RV junction corresponding to an area of increased T2 signal, as well as an area of hypokinesia. These findings were consistent with myocarditis. Serial Troponin I and BNP levels were followed and normalized by the day of discharge.
In an effort to look for other common etiologies of myocarditis, multiplex respiratory and GI pathogen PCRs were sent and were negative. PCRs from blood, including enterovirus, adenovirus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 and parvovirus b19, were also sent and returned negative.
Enoxaparin was started on admission at prophylactic dose (40 mg subcutaneous injection every 12 hours) due to concerns for elevated risk of clotting among patients with COVID-19. Renal function was monitored closely, with initial creatinine clearance (CrCl) at 55 mL/min/m2. CrCl improved daily and achieved a level of 98.9 mL/min/m2 at the time of discharge. Upon discharge, the patient was instructed to complete a 2-week course of anticoagulation therapy with apixaban (2.5 mg twice a day).
Blood pressure normalized on hospital day 1, but the patient remained febrile (with average temperatures of 102–103°F) and tachycardic (ranging from 90 to 120 bpm) until hospital day 4. While his initial oxygen saturation on room air was >98%, he desaturated to 90% on hospital day 2 and required 2 days of supplemental oxygen via nasal cannula (maximum support 4 L) before returning to room air. While attempts were made early in the admission to obtain Remdesivir via compassionate use protocols, the patient’s parents and medical team jointly decided to hold this treatment given his overall improvement with supportive care. Though Tylenol and Ibuprofen were both used during admission, no other anti-inflammatory agents or IVIG were deemed indicated. Given clinical improvement and lab normalization, the patient was discharged on hospital day 5.
At a follow-up cardiology appointment 1 week after discharge, repeat trans-thoracic echocardiogram demonstrated normal ejection fraction (59%) with qualitatively improved function. However, tissue Doppler imaging signals of the mitral valve annulus were still abnormally diminished with low global longitudinal strain rate, consistent with residual myocardial dysfunction. Repeat ECG demonstrated persistent T-wave inversions in lead III.
Cardiac involvement, including myocarditis, has been previously reported as a complication of COVID-19 in adults, but to our knowledge, this is the first case documenting acute myocarditis associated with SARS-CoV-2 in a pediatric patient.1,2 While initial reports of COVID-19 focused largely on respiratory complications, there is growing evidence that cardiovascular complications are contributing greatly to the morbidity and mortality resulting from this disease.3
Myocardial injury, as demonstrated by elevated cardiac biomarkers, has been seen in multiple reviews of adult patients admitted for COVID-19. A single-center retrospective study of 138 patients hospitalized with COVID-19 in Wuhan, China, reported that cardiac injury (demonstrated by elevated high-sensitivity Troponin I, new ECG changes, or new echocardiographic abnormalities) was present in 7.2% of patients overall and 22% of those admitted to the ICU.2 Another cohort study identified elevated troponin in 19.7% of patients hospitalized with confirmed COVID-19.3 Prior to the emergence of SARS-CoV-2, cardiovascular injury, including myocarditis, was identified as a serious complication of the other severe coronaviruses, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).4,5
Viral infections, such as enterovirus and adenovirus, are recognized as common causes of myocarditis, manifesting as localized or global myocardial inflammation, tissue necrosis and ventricular dysfunction.6 Injury to cardiac tissue during viral myocarditis can occur both from direct viral invasion and from exaggerated secondary immune responses.6 Multiple studies evaluating the use of immune-modulating agents, including systemic corticosteroids and immune globulin intravenous for treatment of myocarditis, have been performed; however, results remain controversial.
The mechanisms of cardiac injury secondary to COVID-19 remains unclear. SARS-CoV-2, a novel, enveloped RNA virus, requires the angiotensin-converting enzyme 2 (ACE2) receptor for binding and cellular entry. ACE2 is highly expressed not only in lung alveolar cells but also in intestinal epithelium, renal and cardiac cells.7 Viral entry via the ACE2 receptor is hypothesized to facilitate direct damage to target cells in COVID-19, including possible cardiotoxicity via entry into myocardiocytes.2,8 However, while RT-PCR for SARS-CoV-2 has been positive in postmortem biopsies of heart tissue, pathologic studies have not identified obvious histologic changes in cardiac tissue secondary to the virus.9,10 Of note, viral DNA was also detected in the heart tissue of 35% of the patients with the 2002–2003 SARS-CoV upon postmortem analysis.7 In mouse models of SARS-CoV, pulmonary infection with the virus led to myocardial disease in an ACE2-dependent manner, in which viral entry into cells was coupled with downregulation of ACE2 protein production.7
Other possible mechanisms for cardiac injury in COVID-19 include immune-mediated injury secondary to excessive cytokine release or T-cell dysregulation, microvascular damage, endothelial shedding/dysfunction and hypoxia-mediated injury.1,8 An increased incidence of abnormal coagulation parameters, including disseminated intravascular coagulation, have been noted in cases of SARS-CoV-2, which is thought to increase the risk of thrombosis and ischemic events.2,3
The current case differs from prior adult studies in several respects. This adolescent patient developed acute myocarditis in the absence of obvious preceding respiratory symptoms, and clinical and laboratory evidence of myocarditis improved rapidly despite levels of troponin I that rose well above the 99th percentile. Follow-up echocardiography demonstrated normalized ejection fraction with only residual signs of myocardial dysfunction. This rapid improvement suggests that, in the absence of predisposing heart conditions, higher levels of cardiac health prior to infection among pediatric patients may be protective against the higher morbidity and mortality associated with SARS-CoV-2 cardiac involvement in adults. Though the mechanisms of myocardial involvement and injury secondary to COVID-19 remain unclear, we hope this case will prompt broader recognition and study of this possible manifestation of COVID-19 in pediatric patients.
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