COVID-19 Infection in Children with Pre-existing Heart Disease

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Keywords

Abbreviations:

AKI (acute kidney injury), BNP (brain natriuretic peptide), CAVC (complete atrioventricular canal), CRP (c-reactive protein), COVID-19 (coronavirus disease-2019), CXR (chest radiograph), ECMO (extracorporeal membrane oxygenation), PCR (polymerase chain reaction), SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2)

We present seven children with congenital heart disease and coronavirus disease-2019. Of these, five were under one-year-of-age and three had atrioventricular canal defect and trisomy 21. All seven developed acute decompensation, with one death in an 18-year-old with hypertrophic cardiomyopathy and other co-morbidities.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel virus causing the coronavirus disease-2019 (COVID-19) pandemic. Much is unknown about its clinical course and management, particularly among children with pre-existing cardiac conditions. In adults, COVID-19 has associated cardiac manifestations including heart failure, cardiogenic shock, acute myocardial injury, arrhythmia and is associated with increased mortality [1]. We share our early multicenter experience with children admitted from March 27th, 2020 to April 27th, 2020 with a history of congenital heart disease who were hospitalized with COVID-19 as diagnosed by SARS-CoV-2 polymerase chain reaction (PCR). The pertinent details for each case are summarized in the Table.

Table 1Characteristics, clinical management, and outcomes of children with COVID-19 and congenital heart disease

ALCAPA, anomalous left coronary artery from the pulmonary artery; BNP, brain natriuretic peptide; CAVC, complete atrioventricular canal; COVID-19, coronavirus disease-2019; CRP, C-reactive protein; CXR, chest radiograph; DCM, dilated cardiomyopathy; DILV, double inlet left ventricle; ECHO, echocardiogram; ECMO, extracorporeal membrane oxygenation; FiO2, fraction of inspired oxygen; HCM, hypertrophic cardiomyopathy; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; LV, left ventricular; MV, mechanical ventilation; NIPPV, non-invasive positive pressure ventilation; NT pro-BNP, N-terminal-pro-hormone brain natriuretic peptide; PEEP, peak end expiratory pressure; PH, pulmonary hypertension; PRVC, pressure regulated volume control; PS, pressure support; RV, right ventricular; TOF, tetralogy of fallot; TV, tidal volume; VDR, volumetric diffusive respirator; VT, ventricular tachycardia.

Case 1

An ex-35-week, 3-month-old male with trisomy 21, and unrepaired complete atrioventricular canal (CAVC) defect with marginally compensated heart failure on maximal medical therapy of furosemide, chlorothiazide, and digoxin presented with tachycardia, tachypnea and hypoxemia in the setting of two days of fever and irritability.

His chest radiograph (CXR) was concerning for bilateral scattered atelectasis and hyperinflation. Venous blood gas demonstrated hypercarbia of 51 mmHg. He was SARS-CoV-2 positive by PCR on admission. He had no known sick contacts.

He was given broad spectrum antibiotics for 24 hours. He required up to 8L high-flow nasal cannula of respiratory support, and weaned off respiratory support on hospital day 4. He was discharged on hospital day 6.

He remained stable as an outpatient until his planned readmission 4 weeks after discharge for complete surgical repair. One week after his surgical repair he had hypercarbic respiratory failure of unclear etiology. Post-operative catheterization was notable for a mildly elevated pulmonary vascular resistance with a pulmonary blood flow to systemic blood flow ratio of 1.7:1 in the setting of a residual VSD. He subsequently had his VSD closed and was discharged home on overnight oxygen and sildenafil. At 95 days after initial discharge he remained stable as an outpatient.

Case 2

A 3-month-old female with trisomy 21 and unrepaired CAVC defect with compensated heart failure maintained on furosemide, spironolactone, carvedilol presented with respiratory distress and hypoxemia.

Her CXR was concerning for pneumonia and pulmonary edema (Figure1; available at www.jpeds.com). Echocardiogram at baseline showed mild to moderate common AV valve regurgitation with mildly dilated and hypertrophied right ventricle. Echocardiogram after admission showed severe left atrioventricular valve regurgitation, otherwise stable. She had an elevated brain natriuretic peptide (BNP), and C-reactive protein (CRP). On admission a standard respiratory viral panel was negative. SARS-CoV-2 PCR testing sent on hospital day 13 using the respiratory viral sample obtained on admission was positive. She had no known sick contacts.

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Fig. 1Chest radiograph of a 3-month-old female with trisomy 21 and unrepaired CAVC obtained on admission with cardiomegaly, shunt vascularity, lung hyperinflation and new linear areas of airspace opacity representing atelectasis vs. underlying superimposed pneumonia

She was diagnosed with worsening heart failure with acute respiratory failure and required aggressive diuresis, milrinone and mechanical ventilation. A dexmedetomidine infusion was started due to persistent narrow-complex tachycardia to the 200’s to improve diastolic filling. After a 10 day course of Remdesivir she was persistently SARS-CoV-2 positive by PCR, and received 5 convalescent plasma infusions with subsequent negative SARS-CoV-2 PCR testing. Her hospital course was complicated by staphylococcal scalded skin syndrome, acute kidney injury (AKI) secondary to heart failure, and medical necrotizing enterocolitis. She was extubated on hospital day 33 to non-invasive positive pressure ventilation.

She remained inpatient, on milrinone until surgical repair on hospital day 54. On hospital day 111 she was off respiratory support, with compensated heart failure on oral therapy.

Case 3

A 6-month-old male with a history of anomalous left coronary artery from the pulmonary artery surgically repaired at 2-months-of-age with moderate post-operative supravalvar aortic stenosis, and severe left ventricular dysfunction with compensated heart failure maintained on enalapril, digoxin, carvedilol, furosemide, and aspirin presented with hypoxemia in the setting of two days of fever, decreased oral intake, and increased work of breathing.

His CXR showed cardiomegaly, ground-glass opacity consistent with pneumonia, and increased pulmonary vascularity. Baseline echocardiogram had severe left ventricular dysfunction (left ventricular ejection fraction of 20%) and moderate supravalvar aortic stenosis (peak gradient of 35mmHg) in the region of the aortic transection from his LeCompte maneuver. Echocardiogram obtained during admission showed new pulmonary hypertension with right ventricular dysfunction, and left ventricular ejection fraction of 20% unchanged from patient’s baseline. He had elevated N-terminal-pro-hormone BNP, troponin, and lactate concerning for worsening heart failure. He had markedly elevated inflammatory markers including ferritin, lactate dehydrogenase, CRP, procalcitonin, and interleukin-6. He was SARS-CoV-2 positive by PCR on admission. Patient had contact with three family members prior to admission who had mild symptoms consistent with COVID-19 infection, and eventually tested positive for SARS-CoV-2 positive.

He required intubation and substantial ventilatory support due to acute respiratory distress syndrome. During intubation he developed bradycardia and ventricular tachycardia requiring epinephrine and cardiopulmonary resuscitation. Epinephrine and milrinone infusions were started for decompensated heart failure. Inhaled nitric oxide was added for pulmonary hypertension with rapid improvement in oxygenation. He received tocilizumab and remdesivir. During hospital day 5-14 his inflammatory markers improved, and he weaned off epinephrine. Milrinone was continued until after extubation and initiation of enalapril. On hospital day 20 he was successfully extubated. He was discharged home on hospital day 35 on an enteral heart failure regimen, Lovenox, and full oral feeds.; At 58 days after discharge he remained stable as an outpatient.

Case 4

An ex-36-week 6-month-old male with a history of left ventricular non-compaction and dilated cardiomyopathy with depressed biventricular function with compensated heart failure maintained on captopril, carvedilol, digoxin, aspirin, furosemide, and spironolactone presented with emesis and diarrhea in the setting of one day of fever, increased work of breathing, cough, nasal congestion, and decreased oral intake.

He was SARS-CoV-2 positive by PCR on admission with no known sick contacts. Stool studies sent for rotavirus and norovirus were negative. Echocardiogram at baseline had mildly dilated left ventricle, mildly depressed left ventricular systolic function (left ventricular ejection fraction or 47 %), mildly impaired left ventricular diastolic function. Echocardiogram during admission was unchanged from baseline.

He required intravenous fluid resuscitation during admission. Home captopril and furosemide were held initially due to hypovolemia. He received empiric intravenous antibiotics for 48 hours. He was discharged home on hospital day 4 no longer on furosemide, but otherwise on his home regimen.

He was re-admitted two weeks later with fever, diarrhea, rash and tachypnea requiring intravenous fluid resuscitation. His SARS-CoV-2 PCR remained positive. He was discharged home after two days; 81 days after his initial hospital discharge he was stable as an outpatient.

Case 5

A 9 month-old-male with a history of trisomy 21, obstructive sleep apnea, hypothyroidism, tetralogy of Fallot, right dominant CAVC with parachute left AV valve, and pulmonary hypertension who had surgical repair at 3-months-of-age with placement of Melody Valve in the left atrioventricular valve position and compensated heart failure on furosemide, sildenafil, and oxygen at night presented with intermittent cough, increased work of breathing and hypoxemia in the setting of two days of fever.

His CXR was concerning for pulmonary edema and pneumonia (Figure 2; available at www.jpeds.com). He had an elevated CRP. N-terminal-pro-hormone BNP was elevated, however improved from baseline. ST-segment-changes were noted on telemetry, with reassuring electrocardiogram and serum troponin. He was SARS-CoV-2 positive by PCR on admission with a known sick contact in his mother who had symptoms of COVID-19 infection prior to his admission. She did not receive SARS-CoV-2 testing.

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Fig. 2Chest radiograph of a 9 month-old-male with a history of trisomy 21, obstructive sleep apnea, tetralogy of Fallot, pulmonary vascular hypertension, and right dominant AVC with parachute left AV valve who had surgical repair at 3-months-of-age with placement of Melody Valve in the left AV valve position obtained on hospital day 2 at time of transfer to the cardiac intensive care unit with increased airspace opacification in the right upper lobe along with increased right pleural effusion apically and laterally. Persistent perihilar and lower lobe opacities are also noted

After admission he required escalation to 10L high-flow nasal cannula of respiratory support. He was started on empiric intravenous antibiotics for 48 hours, and intravenous diuretics. Over the next week he was able to wean on respiratory support and diuretics until he was on his home regimen. He was discharged home on hospital day 8.

He was readmitted one month after discharge for hypoxemia secondary to fluid overload. He improved with intravenous diuresis, and required a maximum of 2L nasal cannula. His SARS-CoV-2 PCR remained positive. He was discharged home on hospital day 6 on his home regimen. The patient died 2.5 months after his initial hospital discharge. His cause of death was thought to be related to his residual cardiac disease.

Case 6

An obese 18-year-old female with metabolic syndrome, type II diabetes, chronic hypertension and a cardiac history of hypertrophic cardiomyopathy maintained on metoprolol presented with fever and respiratory distress.

Her CXR had signs of diffuse bilateral airspace opacities. Echocardiogram at baseline demonstrated left ventricular hypertrophy. Echocardiogram on admission showed preserved biventricular systolic function, and left ventricular hypertrophy similar to baseline. She was SARS-CoV-2 positive by PCR on admission with no known sick contacts.

She initially required intubation and mechanical ventilation for hypoxemic respiratory failure, then developed rapid decompensation with an oxygenation index of 51. She was transitioned to venovenous extracorporeal membrane oxygenation (ECMO) for refractory hypoxemic respiratory failure. She became hemodynamically unstable despite vasoactive medications, in the setting of ST-segment changes on electrocardiogram, and elevated serum troponin. She was escalated to venoarterial-ECMO for acute decompensated heart failure. Within 24 hours she developed rapid ventricular tachycardia (Figure 3; available at www.jpeds.com) requiring defibrillation, and infusions of amiodarone and lidocaine. For COVID-19 she received hydroxychloroquine, azithromycin, tocilizumab, and convalescent plasma. For presumed myocarditis she received intravenous immunoglobulin and methylprednisolone. Over the next 2 weeks she improved and was transitioned back to venovenous-ECMO on ICU day 17, with decannulation 4 days later.

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Fig. 3Rhythm strip of an 18-year-old female with hypertrophic cardiomyopathy obtained during admission with ventricular bigeminy transitioning into monomorphic ventricular tachycardia at 300 beats per minute with significant effect on arterial line tracing

She remained on mechanical ventilation, vasoactive support, anti-arrhythmic agents and on renal replacement therapy for AKI until she had recurrence of ventricular tachycardia and died on hospital day 31.

Case 7

An obese 19-year-old female with type II diabetes mellitus, stage II chronic kidney disease, mild intermittent asthma and a cardiac history of double inlet left ventricle with Fontan palliation followed by cardiac transplant 8 years ago presented with five days of diarrhea, decreased appetite with poor oral intake for four days, and loss of taste for three days. She was maintained on atorvastatin, lisinopril, cellcept, tacrolimus prior to presentation.

Creatinine was elevated concerning for AKI. NT-proBNP was elevated. She was SARS-CoV-2 positive by PCR on admission. Baseline echocardiogram showed normal biventricular function after orthotopic heart transplant, with borderline dilated right ventricle. Echocardiogram during admission was unchanged. An electrocardiogram showed new first degree atrioventricular-block with a prolonged PR-interval from her baseline of 180 ms to 214 ms. BK virus urine and serum tests were negative. Stool studies were negative.

She required intravenous fluid resuscitation for hypovolemia. Her mycophenolate mofetil was halved while she was actively infected with COVID-19; she remained on tacrolimus. Her creatinine improved however did not return to baseline. She was discharged on hospital day 9 on her home regimen with the exception of lisinopril which was held due to her AKI.; At 72 days after hospital discharge she was stable as an outpatient.

Discussion

In this series of hospitalized patients with pre-existing cardiac conditions, we observed that new or worsening heart failure was common. Each of these cases is believed to represent acute COVID-19 infection, and not Multisystem Inflammatory Syndrome in Children [

Center for Disease Control and Prevention Health Alert Network. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19) [Internet]. United States: CDCHAN; 2020 May 14 [cited 2020 Jul 1]. Available from: https://emergency.cdc.gov/han/2020/han00432.asp