Among Young Infants With Uncomplicated COVID-19: Should We Broaden Diagnostic Tests for Infectious Causes of Apnea?

To the Editors:

We read the recent publication by Hobbs et al[1] on the characteristics and complications of COVID-19 in hospitalized infants with interest. The authors reported that the most severe cases were in infants <6 months of age, with respiratory complications being the most frequent. Among all patients (severe and nonsevere), there were no reports of apnea. To the best of our knowledge publications about COVID-19 associated apnea in infants are scarce[2] and published before the delta variant of SARS-CoV-2 became widespread.

Here, we present 5 cases of apnea as the initial manifestation of uncomplicated COVID-19 in young infants treated at our hospital in Croatia (November 2021 to February 2022) (Table 1). The definition of apnea agreed by the American Academy of Pediatrics was used. Except for 1 moderate preterm neonate with intraventricular hemorrhage and another newborn with a small patent foramen ovale, the other infants were healthy with unremarkable prenatal and neonatal medical histories. At the time of admission 4 children appeared well with normal vital signs, although 1 child was hypoxic with physical findings suggestive of bronchiolitis. In all patients, we ruled out other common infectious causes of apnea (normal blood tests, excluded other respiratory viruses and pertussis) and several different diagnoses (cardiac and neurological abnormalities). The association between apnea and COVID-19 was further confirmed by documentation of SARS-CoV-2 infection among patient’s family members and rapid clinical improvement with complete recovery with or without methylxanthine treatment.

TABLE 1.

Demographic, Clinical, Diagnostic and Treatment Data of Patients

Case 1		Case 2	Case 3	Case 4	Case 5
General data
Gender	Male	Female	Male	Male	Female
Birth age (wks)	38	39	38	34	40
Comorbidities	None	None	None	None	None
Age (d)	13	91	23	36	32
Date	November 15, 2021	November 18, 2021	November 19, 2021	January 28, 2022	February 2, 2022
Apnea (duration)	November 15–17, 2021	November 18, 2021	November 20–22, 2021	January 28–29, 2022	February 2–March 2, 2022
Fever/cough	+/+	+/+	+/+	+/+	–/–
Diagnostic procedures
SARS-CoV-2[*]	+	+	+	+	+
Respiratory viruses[†]	–	–	–	–	–
BP/BPP[‡]	–	–	–	–	–
Chest radiograph	Normal	Normal	Normal	Normal	Normal
Cranial ultrasonography	Normal	Not done	Normal	IVH[§]	Normal
Transthoracic echocardiography	PFO[¶]	Not done	Normal	Normal	Normal
Treatment (d)
Oxygen	6	1	1	–	–
Aminophylline	6	–	4	–	–

PCR from NP swab.

Multiplex PCR from NP aspirate for influenza A/B, human metapneumovirus, respiratory syncytial virus, bocavirus, adenovirus, enterovirus, coronaviruses, parainfluenza virus types 1, 2, 3, and 4, parechoviruses and rhinoviruses.

PCR from NP aspirate for BP/BPP.

IVH (grade 2).

PFO (3–4 mm).

BP/BPP indicates Bordetella pertussis/parapertussis; IVH, intraventricular hemorrhage; NP, nasopharyngeal; PCR, polymerase chain reaction; PFO, patent foramen ovale.

Apnea in infants can result from prematurity or other underlying conditions. Infants presenting with apnea were previously categorized as “apparent life-threatening events” but in 2016 American Academy of Pediatrics replaced this term to “brief resolved unexplained events” (BRUE) to distinguish benign events from life-threatening and to improve clinical management. However, based on many clinical guidelines and reports, infants with evidence of apnea are excluded from BRUE and should undergo further cardiac, neurologic, gastroenterologic, and hematologic evaluations to establish the underlying disorder.[3,4] Infectious diseases are common causes of apnea in young infants, especially in preterm neonates and infants <2 months of age. Sepsis, central nervous system, or respiratory infections are those which need to be excluded, especially when accompanied by fever or respiratory symptoms. The 2 principal infectious causes of apnea are respiratory syncytial virus and Bordetella pertussis; however, other respiratory viruses have also been reported in a small percentage of cases.[3-5] We observed that SARS-CoV-2 can cause apnea in young infants with otherwise asymptomatic or benign COVID-19. We also noticed a cluster of described clinical manifestation during predominant circulation of the delta (until late December 2021) and omicron (from January 2022) variants in the Croatian population. Based on our report, we suggest that testing for SARS-CoV-2 should be part of the initial evaluation of apnea in infants who were <3 months of age presenting to emergency pediatric departments. Additionally, although the majority of neonatal SARS-CoV-2 infections are mild, caregivers should be aware of this potentially life-threatening complication, especially in very young patients who are discharged or treated in outpatient settings.