Introduction

Although there is a growing literature on the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children, there is still limited knowledge regarding its effects on younger infants. The most common clinical features of coronavirus-disease-19 (COVID-19) in children are fever, cough, and fatigue, usually with self-limiting full recovery within 2 weeks from symptoms onset. However, a complicated clinical course of COVID-19 may sometimes require supportive care in children and admission to the pediatric intensive care unit (PICU) [1].

The aim of this work is to share our experience with four infants who required respiratory support and PICU admission for recurrent apneas during COVID-19, as well as to review the pertinent literature.

Materials and methods

We describe four young infants diagnosed with COVID-19, who needed respiratory support for sudden onset of recurrent apneas. This case series was collected from September 2021 to April 2022 in the PICU of the University Hospital of Padua, Italy. Furthermore, we conducted a literature review via PubMed (up to April 2022), using the following search string: (“COVID-19”[Mesh] or “SARS-CoV-2”[Mesh] OR Covid*) and (Apnea* or “Apnea”[Mesh]) and (Newborn* or Infant* or Premature* or “Infant, Newborn”[Mesh]). Manual reference-check of the retrieved articles was also performed. We included in this review infants < 60 days of corrected age with COVID-19-associated apneas.

Results

Cases description (Table 1)

Table 1 Clinical and diagnostic features of our cohort and previously published patients with COVID-associated apneas
Full size table

Patient #1

This 7-day-old boy was brought to the emergency department (ED) for rhinitis, fever, and poor feeding. He was born at term from vaginal delivery and had an unremarkable perinatal history. On admission, vital signs and clinical examination were normal, and blood exams showed negative inflammatory markers and cultures. SARS-CoV-2 polymerase chain reaction (PCR) resulted positive. On day 5, he showed recurrent episodes of apnea with profound desaturation, refractory to high-flow nasal cannula (HFNC) support, requiring invasive mechanical ventilation (MV). Cranial ultrasound (CUS) was normal and chest X-ray (CXR) showed bilateral consolidations (Supplementary Fig. 1). Upon further respiratory worsening, he was pronated and treated with inhaled nitric oxide, remdesivir, steroids, antibiotics, and surfactant, with slow clinical improvement. The patient was extubated after 11 days, at first on non-invasive ventilatory (NIV) support, then in HFNC. Bacterial and viral superinfections were ruled out throughout the course of the disease by several blood cultures and tracheal aspirates. At the 6-month follow-up, there were no neurological sequelae; a lung high-resolution computed tomography (Supplementary Fig. 2) showed ground-glass appearance with diffuse changes, suggesting the presence of possible slow-resolving lesions that will be evaluated with a longer follow-up.

Patient #2

This 24-day-old boy presented to the ED with rhinitis, fever, poor feeding, and drowsiness. He was born at term from C-section with unremarkable perinatal history. On admission, he was in poor general conditions with cold extremities and mottled skin. SARS-CoV-2 PCR resulted positive. During ED observation, he showed episodes of apnea with profound desaturation, resolving with tactile stimulation. He was started on HFNC, caffeine, antibiotics, and steroids, but upon further respiratory worsening, he was transferred to the PICU and pressure-control (PC)-NIV was started. On admission, electroencephalogram (EEG) was normal, lumbar puncture resulted negative (including SARS-CoV-2 PCR), and urine and blood toxic substances were negative. No more apneas were observed in the PICU and after 24 h he was switched to HFNC, for 2 days. At the 2-month follow-up, brain magnetic resonance imaging (MRI) and EEG were normal.

Patient #3

This 26-day term newborn was hospitalized for bronchiolitis positive to rhinovirus and parainfluenza. On day 3, already recovering from bronchiolitis, she came into contact with SARS-CoV-2 and turned positive 5 days later, presenting fever and poor feeding. She developed rhinitis, cough, and recurrent apneas while awake with no initial impact on vital signs, but her clinical picture worsened while asleep with desaturations and bradycardia. She therefore needed PICU transfer and a rapid switch from HFNC to PC-NIV. Caffeine treatment was started, and the respiratory support was continued for 72 h. No relevant findings were shown on electrocardiogram, EEG, polysomnography, and CUS. No further neuroimaging studies were performed on follow-up.

Patient #4

This was a formerly extremely premature infant, born at 25 + 1 weeks of gestational age. She had a complicated postnatal course with respiratory distress syndrome, retinopathy, and late-onset sepsis. She was hospitalized until 40 weeks of postmenstrual age and finally diagnosed with moderate bronchopulmonary dysplasia. At 2 days of adjusted age, she was brought to the ED for poor feeding and her SARS-CoV-2 PCR resulted positive. In the following 24 h, she developed recurrent apneas with desaturations, despite caffeine administration, and HFNC. She was then transferred to the PICU and shifted to PC-NIV for 72 h. EEG and CUS did not show any pathological findings. The child was discharged after 10 days with the same oxygen support as before the admission.

In all the previously described cases, except for case #3, the nasal swab excluded coinfection with other common respiratory viruses and bacteria (including Bordetella pertussis).

Results from literature review and our case series (Table 1 and Supplementary Table 1)

From the literature search, we retrieved eight reports of 13 infants ≤ 2 months of corrected age, for a total of 17 infants including patients from our Center [2,3,4,5,6,7,8,9,10].

Patients were mainly males (59%), and six patients (35%) were ex-premature. One term-baby suffered from mild hypoxic-ischemic encephalopathy and laryngomalacia [5]. In most of the cases (88%), apnea was among the presenting symptoms, with 2 cases reporting recurrence of apneas 3–4 weeks after the disease onset [5, 9]. CXR was performed in 15 infants (88%) which showed signs of parenchymal SARS-CoV-2 involvement in 7 (47%) cases. The whole cohort had negative nasal swabs for other common respiratory viruses.

Regarding neurological work-up, CUS was performed in about half of the children (53%), lumbar puncture in 5 cases (29%), EEG in 4 cases (23%), brain MRI in 4 cases (24%), and polysomnography in one case. In all but one case [6], EEG resulted normal. Ten children required PICU admission, with 5 (29%) requiring intubation, and three (20%) NIV as the maximum respiratory support. Eight children (47%) received caffeine treatment.

Discussion

Neurological manifestations of COVID-19 are well described in adults and children. The proposed neuropathological mechanisms include direct neurotropic effect, viral-triggered systemic inflammatory responses, vascular and prothrombotic effects, and/or immune-mediated para-infectious effects [11]. Young infants as well have been reported to suffer from neurological impairment in COVID-19, with varying clinical scenarios such as encephalitis, acute seizures, non-specific neurological signs, and MRI abnormalities (white matter and ischemic lesions) [12]. Although the causality between COVID-19 and neuroimaging lesions has yet to be determined, these cases raise high clinical interest.

Central apneas are well-known clinical manifestations of syncytial respiratory virus, metapneumovirus, influenza, and parainfluenza viruses, as well as the previously known coronaviruses [3]. In the literature, there are few case reports presenting apneas as a sign of SARS-CoV-2 infection in young infants. To the best of our knowledge, we have performed the first review on this topic.

We observed that apneas were mainly an early symptom, often leading to diagnosis. Nonetheless, apneas could recur even up to 3–4 weeks from diagnosis through the course of the disease [5, 9]. This may pose a rationale for mid-term follow-up and precise medical and parental advice for young infants presenting in good clinical condition or asymptomatic with COVID-19.

Considering both our series and the included literature, 65% of patients had associated respiratory symptoms. CXR was negative in a large share (8/15, 53%), while it showed abnormalities of the pulmonary pattern in the others. These observations may pose the question whether these apneas may, at least partially, be explained by obstructive mechanisms. However, with respect to our cohort, all patients were described by the treating physician as being without any respiratory effort and with no signs of airway obstruction, leading therefore towards a diagnosis of central apnea and the following neurological work-up.

Overall, neurological investigations often resulted normal. Of note, the lumbar puncture did not aid changes in the clinical management of patients with apnea during COVID-19. Nonetheless, since the mechanism of apneas is yet to be fully understood, we suggest a case-by-case evaluation of the risk/benefit ratio of performing a lumbar puncture in these patients.

Caffeine and antibiotics were used in most cases (47%), while steroids were used in 29%. Half of the patients needed PICU admission and moderate-to-high respiratory support: 3/17 (18%) needed NIV and 5/17 (29%) MV. If compared to populations of newborns with SARS-Cov-2 infection [13], where the reported use of NIV and MV were 15% and 5%, respectively, our population with SARS-Cov-2 and apneas had higher percentages, suggesting apneas are warning signs for a complicated course of the disease.

This wide range of clinical scenarios may raise controversies on the best approach for these patients, both on the diagnostic and therapeutic level. As COVID-19 manifestations may mimic worse scenarios such as sepsis, stroke, or epilepsy syndromes, we believe that a wide diagnostic work-up should be considered for these patients with possible transfer to tertiary centers. When NIV is needed, we suggest PC-NIV may be the preferable modality to assure the presence of mandatory breaths even during apnea episodes.

Conclusion

Apneas during COVID-19 represent a possible life-threatening yet short-term symptom in young infants. Young infants with recurrent apneas during COVID-19 usually undergo an extensive work-up due to the possible differential diagnosis of this clinical presentation. Overall, neurological effects of COVID-19 on young infants need further study and the best diagnostic and therapeutic strategy is yet to be defined.