Case Report: Hyperglycemia-an Ominous Symptom of Disease Course of Covid-19 in Full-term Newborn

The first four weeks after birth seem to be a relatively safe period in relation to the first pandemic of the century. Although SARS-CoV-2 can be transmitted from the mother to the newborn through droplets, the clinical symptoms are usually nonsignificant and uncomplicated. It is especially truth when SARS-CoV-2 infection concerns the full-term newborn. We present the fatal disease course of COVID-19 in full term newborn delivered vaginally with appropriate weight and with Apgar score 10. On the fourteenth day of life, neonate rapidly deteriorated and within the next three days died of hyperglycemia that stimulated an inflammatory reaction.


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kg normal saline bolus, and the fluid infusion was continued in a dose of 10ml/kg/h. Furthermore, after cardiologist's suggestion, dopamine (5ug/kg/min) and corotrope (0.75ug/kg/min) was started. On admission to the emergency department, as per current hospital policy, infant nasopharyngeal swab was tested for the presence of SARS-CoV-2 RNA and real-time polymerase chain reaction (RT-PCR) was performed. Both the E and N2 genes were detected in nasopharyngeal swab. Child was then transferred to the neonatal intensive care unit (NICU).
On arrival to the NICU, the patient was persistently tachycardic with heart rates ranging from 190 to 210 BPM and periodically increasing to 240 BPM. He was successfully treated with adenosine and infusion of MgSO 4 which improved the patient's heart rate to 170-190 BPM over the next 2 hours. Total parenteral nutrition was introduced, and mechanical ventilation (SIMV) was continued.
Antibiotics (ampicillin and gentamycin) were also administered after drawing blood culture. At the opportunity of re-intubation, the bronchoalveolar lavage fluid was collected for RT-PCR and the results for E and N2 genes SARS-CoV-2 were positive. It confirmed diagnosis of COVID-19 in newborn.
From the admission to the NICU, infant was continuously unconscious and intermittently presented with irritability, hypotonia or hypertonia and opisthotonos. Routine blood tests (including glucose, C-reactive protein, procalcitonin, D-Dimer, ferritin, troponin I, NT-proBNP, and liver enzymes concentrations) were repeated and blood for culture was obtained (for enteroviruses and fungi). The laboratory findings showed significantly elevated blood glucose (504mg/dL), troponin I (682.3ng/mL-normal value <47.3) and NT-proBNP (52814pg/mL -normal value <125) concentrations with mildly elevated procalcitonin. At the same time, C-reactive protein, D-Dimer, ferritin, and liver enzymes levels were normal. The patient received continuous infusion of insulin with the increasing doses of 0.05 IU/kg/h to 0.3 IU/kg/h, however the results of blood glucose measurements were still unsatisfactory and presented the levels between 300 and 400 mg/dL. Blood culture was negative either for bacteria or fungi and enteroviruses.
Unfortunately, the blood test with RT-PCR for SARS-CoV-2 genes was not available at hospital analytical laboratory. detected. The results confirmed the wide-spread infection of SARS-CoV-2 in the brain tissue. Macroscopically, the brain tissue had a reduced consistency, its surface was smooth, the sulci were tightened, and the gyri were widened and flat. Histological specimens taken from various parts of the brain revealed the presence of inflammation of small meningeal and cerebral vessels (Figure 1) with endothelial cells apoptosis and multiple microthrombi ( Figure   2). Small calcifications in the walls of intracerebral vessels were also observed. The entire picture of the brain corresponded to severe cerebral oedema during acute necrotizing encephalopathy.   How SARS-CoV-2 affects the brain is not fully understood.
A possible mechanism of entry of the virus into brain is axonal transport via the cribriform plate, adjacent to the olfactory bulb [2,3]. The slow circulation in the brain capillaries can also facilitate the interaction of the viral S protein with the ACE2 on brain endothelial cells. Moreover, ACE2 receptors have been also discovered in substantia nigra, ventricles, middle temporal gyrus, the posterior cingulate cortex, and the olfactory bulb [4].

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The damaging effects of neonatal hyperglycemia on the brain during central nervous system development were reported in several studies and occurred even without concurrent bacterial or viral infections [5,6]. The diabetic brain exhibits neurological alterations in structure, neurotransmitters, electrophysiology, cognitive function neural density and apoptotic activity [7]. Besides the induction of pro-apoptotic proteins expression, hyperglycemia was shown to induce neuronal cell death also due to extracellular ROS generation which promoted oxidative stress and brain damage [8]. Also, it is known that hyperglycemia has a significant impact on the interactions between leukocytes and endothelial cells [9]. It was found that hyperglycemia increases the rolling, adhesion and transmigration of neutrophils and macrophages what markedly stimulates them to produce pro-inflammatory cytokines and proteolytic enzymes (elastase) [10].
The "inflammatory storm" developing during the SARS-CoV-2 infection causes a significant injury of the endothelial cells and activates different processes like thrombosis, necrosis, apoptosis and efferocytosis [11]. Both, thrombosis that occurs in microcirculation and necrosis that destroys endothelial cells, devastate the blood perfusion in different organs, including brain [12]. These mechanisms cause a wide-spread injuries of central nervous system (Figure 1-2). SARS-CoV-2 was shown to bind to ACE-2 receptors through its spike proteins. ACE-2 is expressed in multiple organs, including exocrine and endocrine tissues of pancreas. Cases of pancreatitis in patients with COVID-19 have been reported in both adults and children [13]. A study of patients with diabetes strongly suggests that the localization of ACE-2 expression in endocrine part of the pancreas allows SARS coronavirus to enter and damage pancreatic islets, causing acute diabetes [14]. SARS-CoV-2 have been reported to trigger transient insulin resistance and hyperglycemia.
We found the regular structure of pancreas in the tissue samples, obtained during autopsy, and stained with hematoxylineosin, however in samples assessed by immunohistochemistry, the number of pancreatic islets was significantly decreased Initially, we suspected that the reason for hyperglycemia was the congenital diabetes mellitus in newborn and as an underlying comorbidity, it severely complicated clinical course of COVID-19 in infant. However, the results of the genetic analysis did not show defects, that could explain clinical symptoms of congenital diabetes mellitus in our patient. Among the wide spectrum of symptoms of Bardet-Biedl syndrome is diabetes mellitus, however the symptoms of disease do not appear in heterozygous carriers of pathogenic BBS10 mutation. Finally, we concluded that SARS-CoV-2 infection, most likely transmitted from the mother to the newborn, was the primary cause of pancreas damage, and the main reason for persistent hyperglycemia. On the ground of several mechanisms that we described above, the extremely high blood glucose concentrations significantly potentiated and escalated the inflammatory response, particularly in vascular bed of the brain and caused the critical oedema, leading to the brain herniation and death.
In summary, our intent with this case report was to caution neonatologists and pediatricians against hyperglycemia, caused by a different reason, that may stimulate the inflammatory reactions and aggravate the results of treatment of COVID-19 in full-term newborns.

Ethics statement
The patient's parents provided informed consent for the publication of this case report.