A term infant girl with uneventful antenatal history had an erythematous rash followed by fever from day 8. She was diagnosed with late-onset sepsis and was treated accordingly. She received immunoglobulin for persistent thrombocytopenia, after which there was transient improvement. The patient was transferred to our hospital on day 25 after recurrence of fever, watery diarrhea, and a generalized maculopapular rash. On admission, she had tachycardia, tachypnoea, anemia, thrombocytopenia, hypoalbuminemia, and generalized edema. Reverse transcriptase–polymerase chain reaction results for coronavirus disease 2019 (COVID-19) was positive. Within 12 hours of admission, she developed cardiogenic shock with pulmonary edema and needed invasive ventilation. Echocardiography revealed ejection fraction of 40% with mild pericardial effusion. N-terminal pro–brain natriuretic peptide was 33000 g/L, D-dimer 16500 µg/L, and ferritin 16000 ng/mL. Methylprednisolone, immunoglobulin, and enoxaparin was started, with a diagnosis of multisystem inflammatory syndrome in children, associated with COVID-19. She developed seizures, pulmonary hemorrhage, and cardiac arrest the following day, along with acute kidney injury. She was extubated after 5 days. Steroid was stopped after 5 days because she developed hypertension and echocardiography had normalized. Five days after extubation, she again developed respiratory distress and was ventilated again for 2 days. Echocardiography revealed moderate left ventricular dysfunction, along with secondary elevation of ferritin. Methylprednisolone was restarted and continued for 5 days followed by tapering dose of oral prednisolone, on which she was finally discharged. Although mild myocarditis with COVID-19 has been reported, multisystem inflammatory syndrome in children in a newborn with refractory myocarditis, along with gastrointestinal and renal manifestations, is a rare entity. Dermatologic manifestation of neonatal COVID-19 is also unique.
A term infant girl with uneventful antenatal history was noted to be febrile on day 8 with an erythematous, generalized fleeting rash, with facial sparing (Fig 1A). As fever persisted, the patient was hospitalized on day 10, and she was provisionally diagnosed with late-onset sepsis and started on meropenem and amikacin. However, noting a progressive rise in C-reactive protein (CRP) with thrombocytopenia (Table 1), on day 12, she was referred to another hospital. On second admission, sepsis screen was repeated (Table 1) and blood culture results revealed coagulase-negative Staphylococcus aureus. Meropenem was continued and teicoplanin was added. Within 48 hours (day 17), she was noted to be afebrile and rashes had subsided. She received intravenous immunoglobulin (IVIG) at 1g/kg after 2 successive days of platelet transfusions because platelet count persistently remained <8 × 109 per microliter. This was followed by a progressive rise in platelet count. Echocardiography was normal. Ultrasonography of abdomen revealed hepatomegaly with minimal ascites. She had clinical improvement and was on oral feeds by day 17.
A, Erythematous rashes over legs on day 8. B, Erythematous maculopapular rash on neck on day 24. C, Necrotic patch over left groin on day 24. D, Disseminated maculopapular rash over upper arm on day 24.
A, Erythematous rashes over legs on day 8. B, Erythematous maculopapular rash on neck on day 24. C, Necrotic patch over left groin on day 24. D, Disseminated maculopapular rash over upper arm on day 24.
Important Laboratory Parameters and Echocardiogram Finding
| Blood | Day 12 | Day 13 | Day 14 | Day 17 | Day 24 | Day 25 | Day 26 | Day 28 | Day 33 | Day 35 | Day 42 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Hb, mg/dL | 10.8 | 9.0 | 8.2 | 8.5 | 7.8 | 6.5 | 12.5 | 11.5 | 10.1 | 7.7 | 13.5 |
| TLC, mm3 | 23 × 103 | 15 × 103 | 14 × 103 | 22 × 103 | 7 × 103 | 12 × 103 | 18.8 × 103 | 17 × 103 | 8 × 103 | 18 × 103 | 15 × 103 |
| DC | N78, L22 | N80, L18 | N71, L21 | N70, L28 | N43, L55 | N66, L23 | N72, L20 | N40, L50 | N58, L36 | N68, L25 | N75, L18 |
| PLT, mm3 | 105 × 103 | 10 × 103 | 5 × 103 | 110 × 103 | 90 × 103 | 100 × 103 | 130 × 103 | 150 × 103 | 80 × 103 | 135 × 103 | 135 × 103 |
| CRP, mg/L | 28 | 78.5 | 37.7 | 9.5 | 44 | 29 | 68 | 49 | 63.9 | 99.6 | 13 |
| Ferritin, µg/L | — | 550 | — | — | — | 16 500 | — | 1702 | 1265 | 1911 | — |
| NT-ProBNP, pg/mL | — | — | — | — | — | — | 33000 | — | — | 11 900 | — |
| D-dimer, ng/mL | — | — | — | — | — | 16 500 | — | 1702 | — | 1265 | 1140 |
| Echocardiography | — | — | Normal | — | — | Systolic dysfunction, EF 40% | — | Good LV function, EF 64% | — | LV dysfunction, EF 35% | Good LV function, EF 60% |
| Blood | Day 12 | Day 13 | Day 14 | Day 17 | Day 24 | Day 25 | Day 26 | Day 28 | Day 33 | Day 35 | Day 42 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Hb, mg/dL | 10.8 | 9.0 | 8.2 | 8.5 | 7.8 | 6.5 | 12.5 | 11.5 | 10.1 | 7.7 | 13.5 |
| TLC, mm3 | 23 × 103 | 15 × 103 | 14 × 103 | 22 × 103 | 7 × 103 | 12 × 103 | 18.8 × 103 | 17 × 103 | 8 × 103 | 18 × 103 | 15 × 103 |
| DC | N78, L22 | N80, L18 | N71, L21 | N70, L28 | N43, L55 | N66, L23 | N72, L20 | N40, L50 | N58, L36 | N68, L25 | N75, L18 |
| PLT, mm3 | 105 × 103 | 10 × 103 | 5 × 103 | 110 × 103 | 90 × 103 | 100 × 103 | 130 × 103 | 150 × 103 | 80 × 103 | 135 × 103 | 135 × 103 |
| CRP, mg/L | 28 | 78.5 | 37.7 | 9.5 | 44 | 29 | 68 | 49 | 63.9 | 99.6 | 13 |
| Ferritin, µg/L | — | 550 | — | — | — | 16 500 | — | 1702 | 1265 | 1911 | — |
| NT-ProBNP, pg/mL | — | — | — | — | — | — | 33000 | — | — | 11 900 | — |
| D-dimer, ng/mL | — | — | — | — | — | 16 500 | — | 1702 | — | 1265 | 1140 |
| Echocardiography | — | — | Normal | — | — | Systolic dysfunction, EF 40% | — | Good LV function, EF 64% | — | LV dysfunction, EF 35% | Good LV function, EF 60% |
DC, differential count; EF, ejection Fraction; Hb, hemoglobin; PLT, platelet count; TLC, total leukocyte count; —, not applicable.
On day 24, fever recurred with a rise in sepsis markers (Table 1). On day 25, acute-onset, disseminated, erythematous, maculopapular skin lesions were noted (Figs 1B–D). There was sparing of the face, with involvement of the neck, elbow, and knees and a necrotic lesion on the left groin. Repeat blood culture did not grow any organism. The patient was shifted to our hospital on day 25.
On admission, she was febrile, pale, and tachycardic (heart rate 180–200 beats per minute) with hepatosplenomegaly and greenish, watery stool. She was hemodynamically stable and, on minimal oxygen of 2 L/minute, could maintain saturation of 95%. Antibiotics were changed to cefoperazone-sulbactum, flucloxacillin, and clindamycin, considering a differential diagnosis of staphylococcal or pseudomonal sepsis. The result of reverse transcriptase–polymerase chain reaction (RT-PCR) for coronavirus disease 2019 (COVID-19), which was done routinely as hospital protocol in view of the COVID-19 pandemic, was positive on admission. Overnight, there was rapid deterioration, with progressively increasing respiratory distress and mixed respiratory and metabolic acidosis in arterial blood gas, for which she needed invasive ventilation. Chest radiograph revealed pulmonary edema and cardiomegaly. Echocardiography revealed significant systolic dysfunction, with ejection fraction of 40% and mild pericardial effusion. Adrenaline infusion was started and continued for 3 days. With high-grade fever and multisystemic involvement (respiratory involvement needing ventilation, cardiac involvement, dermatologic involvement in the form of rash, and gastrointestinal involvement in the form of diarrhea), as well as high inflammatory markers like elevated CRP; ferritin; N-terminal pro–brain natriuretic peptide (NT-ProBNP); and D-dimer, a diagnosis of multisystem inflammatory syndrome in children (MIS-C), associated with COVID-19, was suspected. She was initiated on IVIG 2 g/kg over 24 hours, along with methylprednisolone at 2 mg/kg/day. Enoxaparin was also started at therapeutic dose (1 mg/kg/dose twice daily), which was subsequently changed to prophylactic dose (1 mg/kg/dose once daily) because D-dimer reduced to <1500 µg/L after 7 days. We decided not to use any antiviral.
On day 27, the patient had a short-duration seizure, which was controlled with phenobarbitone. Lumbar puncture was not done because she was too unstable. EEG was not done because seizures never recurred, and phenobarbitone was stopped after 5 days. An MRI scan on day 43 revealed no abnormality. On the same day (ie, day 27), she also had pulmonary hemorrhage and cardiac arrest and was resuscitated, as per neonatal guidelines. Postresuscitation, she developed acute kidney injury with oliguria (urine output 0.7 mL/kg/hour) and deranged renal function (serum creatinine 1.9 mg/dL). Ultrasonography of kidneys was suggestive of renal parenchymal disease, with normal Doppler flow in the renal vessels. She was conservatively managed with albumin (serum albumin was 1.8 mg/dL) and furosemide. Anemia (hemoglobin 6.7 mg/dL) was corrected with a packed red blood cell transfusion. The patient was finally extubated to heated, humidified high-flow nasal cannula after 5 days, and feeds were initiated. Bronchoalveolar lavage revealed Klebsiella, and antibiotics were changed to tigecycline and colistin in renal-adjusted dose, as per sensitivity reports. High-resolution computed tomography of the thorax revealed atelectasis of both lower lobes of lung. Repeat COVID-19 RT-PCR result was negative at 7 days. Repeat echocardiography at day 30 suggested normal cardiac function, with ejection fraction of 64%. Steroids were stopped after 5 days because the patient developed hypertension, which was controlled with amlodipine and propranolol.
She developed feeding intolerance followed by a gradual deterioration of her respiratory status 5 days after extubation (day 35) and had to be reventilated after a failed continuous positive airway pressure trial. Repeat echocardiography revealed moderate left ventricular (LV) systolic dysfunction and generalized LV-wall hypokinesia, with ejection fraction of 35% to 40%. She had a second rise in ferritin (Table 1). Milrinone was administered, and methylprednisolone was restarted. The patient showed clinical improvement over the next 2 days and was extubated to heated, humidified high-flow nasal cannula on day 37 of life. She was febrile yet again. Bronchoalveolar lavage revealed Klebsiella, which was now sensitive to meropenem, which she received for 2 weeks. Feeding was re-established, and sepsis markers and renal function improved over the next few days. Intravenous methylprednisolone was given for 5 days followed by oral prednisolone. She was eventually discharged on day 50 of life on tapering dose of prednisolone, subcutaneous low molecular-weight heparin (prophylactic dose), and vitamin supplements. She is well on follow-up, with no further recurrence of any clinical signs of illness and normal echocardiogram, with good LV function and 65% ejection fraction.
Discussion
The World Health Organization (WHO) described COVID-19 as a public health emergency on January 31, 2020.1 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected all age groups. However, there are limited case reports in the neonatal population.2–4 They are usually asymptomatic or present with subtle clinical manifestations.5 There are sporadic case reports of neonates testing positive for SARS-CoV-2 within 48 hours of birth. However, vertical transmission is still not an established entity.6 In April 2020, a new syndrome related to COVID-19 was first reported in a cohort of children from the United Kingdon and subsequently from many other countries all over the world. It is given many names, with MIS-C being the most widely accepted. Although, initially, it was thought to affect only children, now it has also been reported in adults, although much less commonly. Both WHO and Centers for Disease Control and Prevention have published diagnostic criteria for MIS-C (Table 2).
Diagnosis of MIS-C
| CDC Case Definition | WHO Case Definition |
|---|---|
| All 4 criteria must be met: | All 6 criteria must be met |
| 1. Age <21 y | 1. Age 0–19 y |
| 2. Clinical presentation consistent with MIS-C, including all of the following: | 2. Fever for ≥3 d |
| Fever: documented fever >38.0 °C (100.4 °F) or subjective fever for ≥24 h and ≥2 organ systems involved: | — |
| Cardiovascular (eg, shock, elevated troponin, elevated BNP, abnormal echocardiogram, and arrhythmia) | — |
| Respiratory (eg, pneumonia, ARDS, and pulmonary embolism) | — |
| Renal (eg, AKI and renal failure) | — |
| Neurologic (eg, seizure, stroke, and aseptic meningitis) | — |
| Hematologic (eg, coagulopathy) | — |
| Gastrointestinal (eg, abdominal pain, vomiting, diarrhea, elevated liver enzymes, ileus, and gastrointestinal bleeding) | — |
| Dermatologic (eg, erythroderma, mucositis, and other rash) | — |
| Laboratory evidence of inflammation, including but not limited to the following: | — |
| Elevated CRP, ESR, procalcitonin, and fibrinogen | — |
| Elevated D-dimer, ferritin, LDH, and IL-6 | — |
| Neutrophilia and lymphocytopenia | — |
| Hypoalbuminemia | — |
| Illness requiring hospitalization | — |
| 3. No alternative plausible diagnoses | 3. Clinical signs of multisystem involvement (at least 2 of the following): |
| — | Rash; bilateral, nonpurulent conjunctivitis; or mucocutaneous inflammation signs (oral, hands, or feet) |
| — | Hypotension or shock |
| — | Cardiac dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiographic findings or elevated troponin and/or BNP) |
| — | Evidence of coagulopathy (prolonged PT or PTT; elevated D-dimer) |
| — | Acute gastrointestinal symptoms (diarrhea, vomiting, or abdominal pain) |
| 4. Recent or current SARS-CoV-2 infection or exposure (any of the following): | 4. Elevated markers of inflammation (eg, ESR, CRP, or procalcitonin) |
| Positive SARS-Cov-2 RT-PCR | — |
| Positive antigen test | — |
| Positive serology | — |
| Exposure to COVID-19 in the last 4 wk | — |
| — | 5. No other obvious microbial cause of inflammation, including bacterial sepsis or toxic shock syndromes |
| — | 6. Evidence of SARS-CoV-2 infection (any of the following): |
| — | Positive SARS-Cov-2 RT-PCR |
| — | Positive antigen test |
| — | Positive serology |
| — | Exposure to COVID-19 in the last 4 wk |
| CDC Case Definition | WHO Case Definition |
|---|---|
| All 4 criteria must be met: | All 6 criteria must be met |
| 1. Age <21 y | 1. Age 0–19 y |
| 2. Clinical presentation consistent with MIS-C, including all of the following: | 2. Fever for ≥3 d |
| Fever: documented fever >38.0 °C (100.4 °F) or subjective fever for ≥24 h and ≥2 organ systems involved: | — |
| Cardiovascular (eg, shock, elevated troponin, elevated BNP, abnormal echocardiogram, and arrhythmia) | — |
| Respiratory (eg, pneumonia, ARDS, and pulmonary embolism) | — |
| Renal (eg, AKI and renal failure) | — |
| Neurologic (eg, seizure, stroke, and aseptic meningitis) | — |
| Hematologic (eg, coagulopathy) | — |
| Gastrointestinal (eg, abdominal pain, vomiting, diarrhea, elevated liver enzymes, ileus, and gastrointestinal bleeding) | — |
| Dermatologic (eg, erythroderma, mucositis, and other rash) | — |
| Laboratory evidence of inflammation, including but not limited to the following: | — |
| Elevated CRP, ESR, procalcitonin, and fibrinogen | — |
| Elevated D-dimer, ferritin, LDH, and IL-6 | — |
| Neutrophilia and lymphocytopenia | — |
| Hypoalbuminemia | — |
| Illness requiring hospitalization | — |
| 3. No alternative plausible diagnoses | 3. Clinical signs of multisystem involvement (at least 2 of the following): |
| — | Rash; bilateral, nonpurulent conjunctivitis; or mucocutaneous inflammation signs (oral, hands, or feet) |
| — | Hypotension or shock |
| — | Cardiac dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiographic findings or elevated troponin and/or BNP) |
| — | Evidence of coagulopathy (prolonged PT or PTT; elevated D-dimer) |
| — | Acute gastrointestinal symptoms (diarrhea, vomiting, or abdominal pain) |
| 4. Recent or current SARS-CoV-2 infection or exposure (any of the following): | 4. Elevated markers of inflammation (eg, ESR, CRP, or procalcitonin) |
| Positive SARS-Cov-2 RT-PCR | — |
| Positive antigen test | — |
| Positive serology | — |
| Exposure to COVID-19 in the last 4 wk | — |
| — | 5. No other obvious microbial cause of inflammation, including bacterial sepsis or toxic shock syndromes |
| — | 6. Evidence of SARS-CoV-2 infection (any of the following): |
| — | Positive SARS-Cov-2 RT-PCR |
| — | Positive antigen test |
| — | Positive serology |
| — | Exposure to COVID-19 in the last 4 wk |
AKI, acute kidney injury; ARDS, adult respiratory distress syndrome; BNP, B-type natriuretic peptide; CDC, Centers for Disease Control and Prevention; ESR, erythrocyte sedimentation rate; IL-6, interleukin 6; LDH, lactate dehydrogenase; PT, prothrombin time; PTT, partial prothrombin time.
In the first publication of a neonate with SARS-CoV-2, the infant presented on day 17 of life with fever, cough, and rhinorrhoea and responded to supportive treatment.6 COVID-19 has also been reported in a 26-week preterm neonate.7 Caregivers of neonates have reported fever, cough, rhinorrhoea, apnoea, tachypnoea, tachycardia, vomiting, abdominal distention, and diarrhea as presenting signs. They have been noted to have elevated CRP and deranged liver enzymes. Elevated myocardial enzymes have also been noted.8
The patient’s mother tested negative for COVID-19. No family members had signs and symptoms suggestive of SARS-CoV-2. She was in 2 different hospitals previously and may have contracted the virus there. In the first 2 hospitals, she was not tested for COVID-19.
She was diagnosed with COVID-19 on day 25 of life. She had fever, tachypnoea, and tachycardia with a fleeting maculopopular, erythematous rash. There is no previous documentation of dermatologic manifestation in the neonatal population affected with SARS-CoV-2. Our index case initially had an erythematous rash, with central clearing on day 10 of life, which may have been an early sign and was missed. She also received IVIG 1g/kg for thrombocytopenia. Whether this dose of IVIG inadvertently made a transient improvement of signs and symptoms due to COVID-19, which subsequently worsened, will remain a conjecture. She again developed erythematous, maculopapular rash with necrotic changes on her third week of life, along with recurrence of fever. As the parents did not consent, biopsy could not be done.
She developed features suggestive of fulminant COVID-19 myocarditis characterized by poor cardiac contractility and elevated cardiac enzymes and NT-ProBNP and needed ionotropes twice. Mild myocarditis in neonates has been revealed in literature.9 She also had markedly elevated inflammatory markers and D-dimer, thereby fulfilling all the criteria for MIS-C (Table 2). Possibly, this is the first reported case of MIS-C in a newborn who had refractory myocarditis, dermatologic involvement in the form of rash, gastrointestinal involvement in the form of diarrhea, renal involvement in the form of high creatinine, and maybe central nervous system involvement in the form of convulsion. She needed prolonged steroid therapy and IVIG. Dermatologic manifestation as a presentation of neonatal COVID-19 has also not been previously reported.
Acknowledgments
We thank Drs Rajiv Sinha and Rajesh Singh for their contributions, help, and support.
Drs Saha and Mukherjee conceptualized the study, collected data, and drafted the initial manuscript; Dr Pal conceptualized the study, coordinated and supervised data collection, and critically reviewed the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
- COVID-19
coronavirus disease 2019
- CRP
C-reactive protein
- IVIG
intravenous immunoglobulin
- LV
left ventricular
- MIS-C
multisystem inflammatory syndrome in children
- NT-ProBNP
N-terminal pro–brain natriuretic peptide
- RT-PCR
reverse transcriptase– polymerase chain reaction
- SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
- WHO
World Health Organization
Comments
RE: The etiologies and outcomes of neurological involvement in neonatal MIS-C
According to the available data provided by Saha et al. [1] and literature reviews, at least 5 etiologies are hypothesized to participate in seizure occurrence. First, direct viral injury to neural cells is proposed as a potential etiology, thus the presence of SARS-CoV-2 RNA or protein fragments in cerebrospinal fluid may imply neuroinvasive or neurotropic properties. However, lumbar puncture was not done as the neonate was too unstable. Second, SARS-CoV-2 interference with angiotensin-converting enzyme 2 receptors in central nervous system initiates cerebral vasculitis, and then disrupts the autoregulation of intracranial and systemic blood pressure [3]. Hypertension was also documented in the neonate during hospitalization. Third, the excessive responses of innate/adaptive immune could disrupt the blood-brain barrier, activate glial cells, and further instigate neuroinflammation, manifesting as skyrocketing levels of total leucocyte count (18.8x103 /mm3), C-reactive protein (68 mg/L), ferritin (16500 µg/L), D-dimer (16500 ng/ml) in the neonate on seizure eve. Fourth, cerebral hypoxia may be associated with seizure occurrence in the neonate, due to multiple mechanisms including LVD (ejection fraction 40%), respiratory distress, anemia (hemoglobin 6.7 mg/dl), and mixed respiratory and metabolic acidosis. Last, but most important, intravenous immunoglobulin (IVIG) should be given in divided doses (1 g/kg/day over 2 days) in patients with LVD, according to American College of Rheumatology clinical guidance for MIS-C [4]. However, this neonate received IVIG 2 g/kg only within 24 hours, which may aggravate LVD and fluid overload.
Using the Overcoming COVID-19 US public health surveillance registry of children and adolescents hospitalized with COVID-19-related complications, LaRovere et al. [5] identified 43 from 1695 patients developing severe neurological involvement, in whom 17 survivors had new neurological deficits at hospital discharge, and 11 patients died; furthermore, neutrophil-to-lymphocyte ratios and D-dimer positively predicted the life-threatening neurological involvement. Based on very limited data, the hospital outcomes of severe neurological involvement are really poor. In the report of Saha et al. [1], although the neonate was eventually discharged without any clinical signs of illness on day 50 of life, the long-term impact on neurodevelopment after MIS-C should also deserve further investigation.
References
1. Saha S, Pal P, Mukherjee D. Neonatal MIS-C: managing the cytokine storm. Pediatrics. 2021 Aug 25: e2020042093.
2. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020; 383(4): 334-346.
3. Qiao J, Li W, Bao J, et al. The expression of SARS-CoV-2 receptor ACE2 and CD147, and protease TMPRSS2 in human and mouse brain cells and mouse brain tissues. Biochem Biophys Res Commun. 2020; 533(4): 867-871.
4. Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19: version 2. Arthritis Rheumatol. 2021; 73(4): e13-e29.
5. LaRovere KL, Riggs BJ, Poussaint TY, et al. Neurologic involvement in children and adolescents hospitalized in the United States for COVID-19 or multisystem inflammatory syndrome. JAMA Neurol. 2021; 78(5): 536-547.