Diagnostic challenge in a preterm infant with multiorgan failure: SARS-CoV-2 infection or neonatal multisystem inflammatory syndrome?

Coronavirus disease 2019 (COVID-19) causes various clinical manifestations in neonates. COVID-19 may present asymptomatically or severely as respiratory failure, lethargy, and multiorgan failure [[1]Dong Y. Mo X. Hu Y. Qi X. Jiang F. Jiang Z. et al.Epidemiology of COVID-19 among children in China.Pediatrics. 2020; 145Crossref PubMed Scopus (2655) Google Scholar,[2]Raschetti R. Vivanti A.J. Vauloup-Fellous C. Loi B. Benachi A. De Luca D. Synthesis and systematic review of reported neonatal SARS-CoV-2 infections.Nat Commun. 2020; 11: 5164Crossref PubMed Scopus (228) Google Scholar]. Myocarditis, high levels of cardiac enzymes, coronary aneurysms, renal failure, feeding intolerance, hypoxemia, persistent pulmonary hypertension, and disseminated intravascular coagulation (DIC) may occur in neonatal multisystem inflammatory syndrome (MIS-N) [[3]Pawar R. Gavade V. Patil N. Mali V. Girwalkar A. Tarkasband V. et al.Neonatal multisystem inflammatory syndrome (MIS-N) associated with prenatal maternal SARS-CoV-2: a case series.Children. 2021; 8Crossref PubMed Scopus (62) Google Scholar,[4]Farias E.C.F. Justino M.C.A. Mello M. Multisystem inflammatory syndrome in a child associated with coronavirus disease 19 in the Brazilian amazon: fatal outcome in an infant.Rev Paul Pediatr. 2020; 38e2020165Crossref Scopus (16) Google Scholar]. Herein, we report the case of a preterm infant who tested positive in the polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus (SARS-CoV-2) and died of multiorgan failure. A male infant was born by vaginal delivery at 32 weeks of gestation with a birthweight of 2135 g. The mother tested positive for SARS-CoV-2. She was asymptomatic; however, repeated PCR was positive. After delivery, the baby was separated from the mother and placed in a negative-pressure isolation room. The baby did not require resuscitation but developed respiratory distress soon after birth and was supported by nasal continuous positive airway pressure. Chest radiographs showed ground-glass opacities and air bronchograms. Surfactant was administered because of increased respiratory distress and oxygen requirements, and ampicillin and gentamicin were started. Because of the mother's positive SARS-CoV-2 PCR result, a nasopharyngeal swab was performed shortly after birth; however, the neonate tested negative. The initial laboratory results were normal (Table 1). A second specimen was obtained for SARS-CoV-2 to complete isolation; however, on postnatal day (PND) 4, the neonate tested positive for the delta variant. After the positive SARS-CoV-2 PCR result, leukopenia, lymphocytopenia, and high C-reactive protein and procalcitonin levels were observed. Although these findings may be related to the positive SARS-CoV-2 PCR test, late-onset sepsis could not be excluded. Vancomycin and meropenem were initiated after blood and cerebrospinal fluid cultures were obtained. To evaluate the cardiac effects of SARS-CoV-2, echocardiography was performed, and the ejection fraction (EF) was 68 %. The electrocardiogram was normal because of the high levels of cardiac enzymes and markers (Table 1). On PND 5, the infant had feeding difficulties, prolonged capillary refill, and lactic acidosis. The infant presented with sudden sinus bradycardia and then ventricular extrasystoles. The rhythm became asystole, and cardiopulmonary resuscitation was initiated. Sinus rhythm was observed at the end of the fifth minute. After resuscitation, the heart rate was <100 beats/min, and ventricular extra beats persisted. Dopamine, adrenaline, and isoproterenol infusions were initiated. After resuscitation, arterial blood gases showed progressive lactic acidosis. Echocardiography revealed right atrial and ventricular dilatation and worsening contractility with an EF of 48 %. The levels of cardiac enzymes and markers were elevated (Table 1). This worsening cardiac condition was thought to be due to acute COVID-19 or MIS-N secondary to maternal COVID-19. Positive SARS-CoV-2 PCR results on PND 3 were considered perinatal transmission. Methylprednisolone (2 mg/kg/day) and intravenous immunoglobulin (IVIG, 1 g/kg/dose) were administered for 3 days. Ground-glass opacity was observed on chest computed tomography. Respiratory insufficiency, acute renal failure, hepatic failure, and coagulopathy occurred during the clinical course. Cranial tomography revealed diffuse hemorrhage, cerebral edema, and tonsillar herniation. The patient died on PND 11 because of multiorgan failure.Table 1Laboratory findings of the patients.DOL 1DOL 4DOL 5DOL 5DOL 7DOL 8DOL 9DOL 10DOL 11Hemoglobin (g/dL)16.914.512.911.98.511.812.41115.5Platelet count (mm3)331,000225,000284,000284,000171,000269,00097,000233,000126,000White blood cell count (mm3)14,500130033204720743010,99015,96022,57056,110Absolute neutrophil count (mm3)2000830239028802840667012,890––Absolute lymphocyte count ALC (mm3)99002404901170306024701670–7670Creatinine (mg/dL)0.760.910.920.870.731.221.691.891.34Total/direct Bilirubin (mg/dL)3.99/0.397.7/0.6312.4/0.6713.10/0.919.4/1.0612.30/1.778.75/1.877.1/3.476.28/4.22Albumin (g/L)30.932.835.533.224.537.128.830.01.95Alanine aminotransferase (U/L)1191110968123968405106Aspartate aminotransferase (U/L)96414656224142177893582297Lactate dehydrogenase (U/L)1056–102510952500>250013,272>25002730SARS-CoV-2 PCRNegativePositivePositivePositiveAnti SARS-Co-V2 nucleocapsid antibody (total) (COI)(pos ≥1.00 COI)0.0840.317Anti SARS-Co-V2 nucleocapsid antibody (IgM) (COI)(pos ≥0,9 COI)0.100.29C-reactive protein (mg/L)0.511.45251.82017.610.66.64.9Procalcitonin (ng/mL)0.871.96–Interleukin −6 (pg/mL)280Ferritin (ng/mL)26,436Fibrinogen (g/L)2.011.321.140.743.27D-dimer (ng/mL)11567498High limitHigh limitHigh limitActivated partial thromboplastin time (sec)44.167.743.532.635.231.3International normalization ratio1.372.092.362.501.81.71Prothrombin time (sec)15.524.127.429.120.719.6Erythrocyte sedimentation rate (mm/h)3Troponin T (pg/ml)74,24 (0–14)15021050NT-Pro-BNP (pg/ml)11,206 (0–125)>35,000>35,000CK-MB (ng/mL)8.73 (0–4.87)Cerebrospinal fluid glucose (mg/dl)56Cerebrospinal fluid protein (mg/dl)97.8 Open table in a new tab COVID-19-associated myocarditis has been reported in older children; however, reports in neonates are limited [[5]Sanna G. Serrau G. Bassareo P.P. Neroni P. Fanos V. Marcialis M.A. Children's heart and COVID-19: up-to-date evidence in the form of a systematic review.Eur J Pediatr. 2020; 179: 1079-1087Crossref PubMed Scopus (90) Google Scholar]. In this case, troponin level elevation and wide QRS arrhythmia were observed during the asymptomatic period. The most important marker for the diagnosis of myocarditis is troponin, which should be evaluated with electrocardiographic and echocardiographic findings [[6]Trogen B. Gonzalez F.J. Shust G.F. COVID-19-Associated myocarditis in an adolescent.Pediatr Infect Dis J. 2020; 39: e204-e205Crossref PubMed Scopus (35) Google Scholar]. Although the troponin level was moderately high, the electrocardiogram and echocardiogram results were normal. MIS-N is a sign of antibody-mediated immunological activation that affects several organs and is not an infection. In MIS-N, SARS-CoV-2 antibodies should be positive; however, the SARS-CoV-2 antigen should be negative. These antibodies may be produced by the neonate during the recovery period from SARS-CoV-2 infection. They may also be transferred transplacentally from the mother [[3]Pawar R. Gavade V. Patil N. Mali V. Girwalkar A. Tarkasband V. et al.Neonatal multisystem inflammatory syndrome (MIS-N) associated with prenatal maternal SARS-CoV-2: a case series.Children. 2021; 8Crossref PubMed Scopus (62) Google Scholar]. Neonates with MIS-N may be critically ill with myocarditis, myocardial dysfunction, coronary aneurysms, DIC, necrotizing enterocolitis-like illness, hypoxemia, and renal failure [[7]Sankaran D. Nakra N. Cheema R. Blumberg D. Lakshminrusimha S. Perinatal SARS-CoV-2 infection and neonatal COVID-19: a 2021 update.NeoReviews. 2021; 22: e284-e295Crossref PubMed Google Scholar]. Multiorgan failure due to maternal COVID-19 has been reported in two cases from Saudi Arabia. Both neonates were treated with IVIG along with steroids and recovered completely [[8]Shaiba L.A. Hadid A. Altirkawi K.A. Bakheet H.M. Alherz A.M. Hussain S.A. et al.Case report: neonatal multi-system inflammatory syndrome associated with SARS-CoV-2 exposure in two cases from Saudi arabia.Front Pediatr. 2021; 9652857Crossref Scopus (25) Google Scholar]. A case series of 20 neonates with MIS-N, cardiac involvement with prolonged QT corrected for heart rate interval, atrioventricular block, cardiogenic shock or coronary dilation, respiratory failure, fever, feeding intolerance, melena, and renal failure was reported. All neonates had high levels of inflammatory biomarkers and received steroids and IVIG, and two neonates died [[3]Pawar R. Gavade V. Patil N. Mali V. Girwalkar A. Tarkasband V. et al.Neonatal multisystem inflammatory syndrome (MIS-N) associated with prenatal maternal SARS-CoV-2: a case series.Children. 2021; 8Crossref PubMed Scopus (62) Google Scholar]. In this case, respiratory distress syndrome, arrhythmia, DIC, and pulmonary hypertension were similar in clinical presentation to MIS-N. Because COVID-19 and MIS-N could not be differentiated in the acute phase, IVIG and steroids were also administered; unfortunately, the patient died. This report is limited by the lack of placental specimens and postmortem biopsy material to elucidate the pathophysiology of organ involvement. The authors declare no conflicts of interest relevant to this article.