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Instructive Cases

Ischemic Lesions in the Brain of a Neonate With SARS-CoV-2 Infection

Brum, Andrea C. MD*; Glasman, M. Patricia MD*; De Luca, M. Cristina MD*; Rugilo, Carlos A. MD*,†; Urquizu Handal, M. Inés MD*; Picon, Armando O. MD*; Cook, Cristina MD*,‡; Vain, Nestor E. MD*,§

Author Information
The Pediatric Infectious Disease Journal: September 2021 - Volume 40 - Issue 9 - p e340-e343
doi: 10.1097/INF.0000000000003244
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Abstract

The coronavirus disease 2019 (COVID-19) caused by a new strain known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is predominantly a respiratory infection, but it may affect many other systems. The elderly population is at increased risk for the most serious form of the disease and a higher mortality. The pediatric population has been relatively spared in presenting severe manifestations, complications, or mortality.1

Infections in neonates have been usually considered acquired by contact during or after birth. However, vertical transmission has been suspected.2–4 We are reporting here a case of a term newborn with acquired SARS-CoV-2 infection and multisystem involvement, including central nervous system (CNS) impact. Images and laboratory findings suggest ischemic brain lesions associated with coagulation abnormalities which, to our knowledge, have not been previously reported in neonates with COVID-19 disease.

CASE

A baby boy born at term with a birth weight of 3.421 kg, with no significant perinatal history, was brought to the emergency room at seventeen days of life because of fever (38°C) during the previous 12 hours and a generalized tonic seizure.

The parents, the newborn and a 5-year-old sister, were staying at that time in preventive home isolation because 6 days before the onset of symptoms they attended a family meeting where they were in close contact with three family members who in the following 3 days became symptomatic and tested positive for SARS-CoV-2.

The patient’s nasopharyngeal swab real-time reverse transcription polymerase chain reaction test (RT-PCR) obtained upon admission was positive for SARS-CoV-2 while both parents, who were asymptomatic, tested negative.

The infant was lethargic and with a poor feeding attitude. He was hemodynamically stable with no respiratory involvement and a normal chest radiograph. No skin rashes were observed. Complete blood count, C-reactive protein, electrolytes, blood glucose, liver and renal function studies were normal.

Blood, urine and cerebrospinal fluid (CSF) samples for cultures were obtained and treatment with ceftriaxone 100 mg/kg/d and acyclovir 60 mg/kg/d was started. The CSF demonstrated glucose 49 mg/dL, total proteins 0.54 g/L, 10 white blood cells/mm3 (PMN 90% y MN 10%) with some RBCs.

All cultures returned negative. RT-PCR for viruses (Biofire Filmarray meningitis/encephalitis panel, BioFire Diagnostics, Salt Lake City, UT) and for SARS-CoV-2 in CSF were also negative. Antibiotics were discontinued after seventy-two hours.

A few hours after admission the infant presented a new seizure episode. He was treated with a loading dose of phenobarbital followed by maintenance (5 mg/kg/d).

A brain magnetic resonance imaging (MRI) study was obtained. It showed 2 small focal lesions in the left frontal white matter with restriction on diffusion-weighted imaging and apparent diffusion coefficient map compatible with acute ischemic foci. No significant vascular malformations or other abnormalities were observed (Fig. 1).

FIGURE 1.
FIGURE 1.:
This is the patients' MRI: Axial T1-weighted (A) and axial T2-weighted image (B): There are no signal abnormalities in the brain parenchyma. Axial DWI image (C) and axial ADC image (D) show 2 small foci of restriction in the left frontal subcortical white matter compatible with acute ischemic lesions (arrowheads).

Because of the MRI findings, coagulation studies were carried out, demonstrating abnormal findings: D-Dimer 1.68 μg/mL (normal:≤ 0.50), fibrinogen 175 mg/dL (normal: 200–400), kaolin activated partial thromboplastin time 34 seconds and prothrombin time 121%. These results were considered compatible with a consumption coagulopathy in a COVID + patient. Until resolution of coagulation laboratory findings and negative COVID PCR test, a short anticoagulation treatment with 0.1 mg/kg/d acenocoumarol was initiated and subsequently modified to achieve the 2–3 international normalized ratio desired during de acute phase. However, D-Dimer continued to rise and 4 days later reached 2.57 μg/mL. It started decreasing on the 6th day of therapy to get to normal values by day 25 (0.19 μg/mL). The Table 1 summarizes laboratory findings.

TABLE 1. - Laboratory Findings
Initial 48 h 4th d 8th d 15 d 22 d 29 d Discharge 7 d After Discharge 17 d After Discharge
Hematocrit (%) 45 38 38.5 38 32.6 29.6 29 30 -
WBC (mm3) 5500 4900 3300 6300 11100 6500 8600 8100 -
Neutrophil count 3047 421 90 252 888 897 714 1050 -
Platelets (mm/3) 317,000 251,000 210,000 221,000 360,000 360,000 391,000 359,000 -
PT (%) 104 - - 87 34 16 23 12 82
KPTT (s) 39 - - 42 54 86 - - 38
INR - - - 1.07 2.14 4.35 3.08 4.74 -
Fibrinogen (mg%) - - 175 141 - - 123 - -
D-Dimer (mcg/mL) - - 1.68 2.57 - - 0.19 - -
CRP (mg/L) 0.7 8.6 2.6 - - < 0,3 0.4 - -
Troponin T (ng/L) - 35 39 - - 63 44 - 26
NT-proBNP (pg/mL) - - 2180 - - 431 - - -
CPK (UI/I) - 67 57 - - 124 - - 98
CPK indicates creatine phosphokinase; CRP, C-reactive protein; PT, prothrombin time; WBC, white blood cells.

The patient evolved stable, afebrile, without repeating seizures or other neurologic signs. A polysomnographic study, including electroencephalogram, was done at 28 days of hospitalization and showed a normal pattern.

From the cardiovascular aspect, the infant was asymptomatic. An electrocardiogram and a cardiac ultrasound performed 4 days after admission were normal. However, increased levels of troponin T: 39 ng/L (normal ≤ 15) and N-terminal pro b-type natriuretic peptide (NT-proBNP): 2180 pg/mL (normal < 2000) and normal creatine phosphokinase were observed. Troponin T levels raised to 63 ng/L after 22 days of hospitalization with a subsequent decrease until discharge. Considering the potential risk of progressive myocarditis, he continued hospitalized for an additional week until verifying a marked decrease in troponin T levels. NT-proBNP normalized at 22 days of admission.

After 2 days of admission, the infant presented an increase in C-reactive protein (8.6 mg/L) and neutropenia, which became progressively more profound reaching a lowest value of 90 total neutrophils/mm3 the 4th day of his hospitalization. On the following days, neutrophils slowly increased to 890 neutrophils/mm3, the maximum value obtained during hospitalization (Table 1).

At 21 days of the beginning of clinical signs, the patient’s nasopharyngeal swab RT-PCR remained positive for SARS-CoV-2, and it became negative at 28 days. Qualitative antibody detection was performed 23 days after onset of symptoms and was positive for IgG and negative for IgM.

The patient was discharged 29 days after initial signs. A week later anticoagulation treatment was discontinued.

On follow-up, at 85 days of life, physical examination including neurologic assessment and otoacoustic emissions as well as growth and development appeared normal. Control blood testing showed: 1050 neutrophils/mm3, troponin T 26 ng/L and quantitative IgG levels of 3.9 U/mL (ADVIA Centaur SARS-CoV-2 IgG Siemens).

DISCUSSION

We are reporting a case of a 17 days old neonate who was seen at the emergency department of our hospital with severe systemic SARS-CoV-2 infection including multi-organ involvement: neurologic (seizures), hematologic (neutropenia and consumption coagulopathy) and cardiac compromise.

Most pediatric COVID-19 cases range from asymptomatic to mild-moderate disease. Infected children usually show typical symptoms of acute respiratory infections including fever (49.6%) and cough (45.5%). Clinical presentation in newborns could be slightly different than in older children, with a higher proportion of them (12%) presenting a severe course.5

Some reports strongly suggest vertical transmission from mother to infant through the placenta, while perinatal and postnatal environmental exposure appears more common.3,6,7

There are no specific clinical signs described for neonatal COVID-19 infections. In children, severe CNS compromise has been rarely reported. Acute disseminated encephalomyelitis has been described.8 To our knowledge, this is the first report of a newborn infected with SARS-CoV-2 with CNS involvement including seizures, lethargy and documented ischemic lesions.

Reports of abnormal neuroimaging findings in children with COVID-19 began to emerge. These may result from a variety of mechanisms including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the CNS, and postinfectious immune-mediated processes.9

One of the major manifestations of systemic COVID-19 disease in adults is acute cerebrovascular disease (predominantly ischemic), but whether SARS-CoV-2 is an important risk factor for ischemic stroke in children with no underlying risk factors is yet undetermined.10

In our case, the patient debuted with seizures. The MRI findings were compatible with ischemia in the left frontal white matter without evidence of vascular malformations. The CSF RT-PCR was negative for SARS-CoV-2. A hypercoagulable state was found. We could infer that the cerebral ischemic images (Fig. 1) could be secondary to the alteration in coagulation and not due to the direct action of the virus since it was not possible to detect it in CSF, as it occurred in other publications.9,11

Hematologic complications, such as lymphopenia and hypercoagulability, have been reported in adults with coronavirus disease and are considered markers of poor prognosis.12,13 Our patient presented with leukopenia, neutropenia and hypercoagulability. Neutropenia persisted at time of discharge, and he was still being treated with oral anticoagulants (Table 1). In a review in children with COVID-19 and hematologic manifestations, leukopenia was frequently found.14 While lymphopenia has been reported as a common finding, neutropenia has been rarely found.15,16 A follow-up evaluation at 85 days of life demonstrated a continuous decrease in troponin T levels, normalized neutrophil count and quantitative IgG levels confirming SARS-CoV-2 previous infection.

In children, a multisystem inflammatory syndrome (MIS-C) has been reported. It is defined by World Health Organization, as the persistence of fever for more than 3 days, and multisystem inflammatory condition, which may include rash, hypotension, myocardial dysfunction, elevated troponin/NT-proBNP, coagulopathy and elevated markers of inflammation.17 Therapy for MIS-C includes the use of intravenous immunoglobulin and systemic corticosteroids. A case of MIS-C in a neonate has recently been reported.18 Since our patient had a fever for less than 3 days and he demonstrated rapid clinical improvement, MIS-C syndrome was judged unlikely and the use of those therapies was not considered.

A review of multiple studies identified an unexpectedly high incidence of neurologic symptoms in children with MIS-C.19

The most frequent brain abnormalities found were lesions in the splenium of the corpus callosum that appear as discrete, ovoid, T2 hyperintense foci, sometimes extending into the adjacent white matter, with variable associated restricted diffusion. Another frequent finding was myositis of the visualized musculature of the neck or face.8

In patients with MIS-C, cardiac manifestations are frequent, including myocardial and coronary involvement.20 Our patient presented only an increase in cardiac enzymes without other manifestations. It is possible to infer that the ischemia mechanism was secondary to a prothrombotic consumption coagulopathy state.

It is important to highlight that the infection in our patient was probably acquired during a meeting organized by the family. Current health recommendations provided by World Health Organization and in Argentina by the Ministry of Health discourage social meetings specially those involving the vulnerable population.21,22 The underestimation or omission of these measures exposed this newborn to an unnecessary risk.

Protection by antibodies reaching the fetus through the placenta is possible in mothers who were infected during pregnancy.3 Vaccines against SARS-CoV-2 have not yet been sufficiently studied in pregnant women and children. However, it has recently been reported the presence of IgG in an infant born to a vaccinated mother.23 It is likely that if this finding is confirmed, when vaccines are proven safe and effective during pregnancy newborn infants will become protected such as it occurs with other vaccines (whooping cough, measles). Meanwhile, we all have to be very careful keeping in mind current recommendations of social distance especially in newborn infants.

CONCLUSIONS

This case highlights that SARS-CoV-2 neonatal infection can be associated with multi-organic involvement. In our patient, significant CNS compromise associated to ischemic lesions and laboratory findings of consumption coagulopathy were found. Neonatologists and pediatricians should be aware of this unusual way of presentation of COVID-19 in newborn infants.

ACKNOWLEDGMENTS

The authors are grateful to Norma Rossato MD for careful review and to Liliana Vazquez MD for advice in the clinical description of the case. Informed consent: The parents granted written informed consent for this case report and the use of images and laboratory data.

REFERENCES

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Keywords:

newborn infant; brain ischemic lesion; consumption coagulopathy

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