OBJECTIVES

To compare symptoms and outcomes among infants aged ≤90 days tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a broad, international sample of emergency departments (EDs).

METHODS

This was a secondary analysis of infants aged 0 to 90 days with suspected SARS-CoV-2 infections tested using molecular approaches and with 14-day follow-up. The parent studies were conducted at 41 EDs in 10 countries (the global Pediatric Emergency Research Network; March 2020–June 2021) and 14 EDs across Canada (Pediatric Emergency Research Canada network; August 2020–February 2022). Symptom profiles included presence and number of presenting symptoms. Clinical outcomes included hospitalization, ICU admission, and severe outcomes (a composite of intensive interventions, severe organ impairment, or death).

RESULTS

Among 1048 infants tested for SARS-CoV-2, 1007 (96.1%) were symptomatic at presentation and 432 (41.2%) were SARS-CoV-2–positive. A systemic symptom (any of the following: Apnea, drowsiness, irritability, or lethargy) was most common and present in 646 (61.6%) infants, regardless of SARS-CoV-2 status. Although fever and upper respiratory symptoms were more common among SARS-CoV-2–positive infants, dehydration, gastrointestinal, skin, and oral symptoms, and the overall number of presenting symptoms did not differ between groups. Infants with SARS-CoV-2 infections were less likely to be hospitalized (32.9% vs 44.8%; difference −11.9% [95% confidence interval (CI) −17.9% to −6.0%]), require intensive care (1.4% vs 5.0%; difference −3.6% [95% CI −5.7% to −1.6%]), and experience severe outcomes (1.4% vs 5.4%; difference −4.0% [95% CI −6.1% to −1.9%]).

CONCLUSIONS

SARS-CoV-2 infections may be difficult to differentiate from similar illnesses among the youngest infants but are generally milder. SARS-CoV-2 testing can help inform clinical management.

What’s Known on This Subject:

Children with coronavirus disease 2019 report milder symptoms and have better prognoses than adults. However, infants aged ≤90 days are a particularly vulnerable population, and clinical features and outcomes among the youngest infants with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections remain poorly characterized.

What This Study Adds:

In a prospective global sample of 432 infants 0 to 90 days old with SARS-CoV-2 infections and 616 without, symptoms at presentation were similar; however, SARS-CoV-2–positive infants were less likely to be hospitalized, require ICU admission, or experience severe outcomes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among children represent ∼25% of all SARS-CoV-2 infections.1  In studies focusing on pediatric coronavirus disease 2019 (COVID-19), most children have milder clinical symptoms and better prognoses than adults.2,3  Nonetheless, severe presentations and outcomes occur in children, as well as adults. A recent meta-analysis found that, among children hospitalized with COVID-19, ∼10% require admission to an ICU, and mortality is >1%.4  However, estimates regarding severe outcomes vary widely between research studies, greatly because of differences in study designs, regions, and definitions of severity. Most estimates of severe disease are based on studies of large, community-based administrative databases, hospitalized populations, and children admitted to ICUs.4 

Several studies have identified young age as a risk factor for severe COVID-19.5 8  Infants in the first months of life are a particularly vulnerable population with unique management considerations.9  However, there are limited data regarding the clinical features and disease courses of very young infants with SARS-CoV-2 infections. Data regarding severe outcomes among very young infants are mixed. Although some studies suggest that very young infants with SARS-CoV-2 infections are at increased risk of severe outcomes,5,6,10 12  other studies have reported the converse.13 15  It also remains unclear how outcomes among SARS-CoV-2–positive infants compare with test-negative infants with similar clinical presentations.

This study sought to compare clinical presentations and outcomes among infants aged ≤90 days with and without SARS-CoV-2 infections, in a prospective, multinational sample of infants tested in pediatric emergency departments (EDs).

This was a planned secondary analysis of a global prospective cohort of children aged ≤18 years who were tested in EDs for suspected SARS-CoV-2 infections as part of 2 prospective multiinstitutional studies. The Pediatric Emergency Research Network (PERN) COVID-19 study enrolled participants at any of 41 EDs in 10 countries between March 2020 and June 2021.15  The Pediatric Emergency Research Canada (PERC) COVID-19 study recruited participants at any of 14 pediatric EDs across Canada between August 2020 and February 2022.16  Data were combined as previously described.17 

All enrolling sites either had local research ethics board approval or established reliance agreements with the Cincinnati Children’s Hospital Medical Center institutional review board (ie, some participating sites for the PERN cohort). Informed consent was obtained from legal guardians of all participants, and participant assent was obtained as required by institutional policies. The Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines were followed for this study.18 

All infants aged ≤90 days enrolled in the 2 parent studies were included in this analysis. Both parent studies included infants tested for suspected SARS-CoV-2 infections on the basis of exposure or symptoms using a nucleic acid test (eg, polymerase chain reaction) performed on specimens obtained from the nares, nasopharynx, or throat. Additional testing was at the discretion of the treating physician based on site-specific clinical guidelines. Initially, participants were enrolled into the parent studies consecutively, starting with the first test performed daily, regardless of SARS-CoV-2 test result, to a maximum of 5 enrollments per day per site. In regions with low SARS-CoV-2 prevalence, this led to overenrollment of SARS-CoV-2–negative participants. Therefore, to standardize recruitment and to minimize the potential for selection bias, starting September 2020, sites consecutively enrolled as many SARS-CoV-2–positive participants as possible, along with 2 consecutive test-negative participants for every test-positive participant enrolled. Participants were classified as positive for acute SARS-CoV-2 infection if they had a positive nucleic acid test during the index ED visit or at any time in the subsequent 14 days.

Data regarding demographic characteristics, epidemiologic risk factors, and clinical symptoms were collected from caregivers in person at the time of enrollment or by telephone. Approximately 14 days after the ED visit, a telephone follow-up survey was also administered to ensure capture of any severe outcomes occurring after hospital discharge. Standardized data collection was performed in accordance with a manual of operations. Medical record review was performed a minimum of 30 days after the index ED visit to ascertain all treatments and interventions provided, and to identify any severe outcomes that occurred at the index ED visit and within the subsequent 14 days.

Symptom profiles included the presence and total number of symptoms from illness onset to index ED visit presentation.16  Caregivers were asked to indicate if a list of a priori identified symptoms were new and/or associated with the current illness. The symptom list was applied to the entire cohort (ie, there was not a unique list relevant only to very young infants) and were classified as previously described.16  Apnea, drowsiness, irritability, and lethargy were grouped together as systemic symptoms. Fever was defined as a temperature of ≥38.0°C in the ED or measured within the preceding 24 hours. Dehydration was deemed present if decreased urine output or a refusal to drink was reported by the parent/caregiver. Upper airway symptoms included rhinorrhea or nasal congestion; lower airway symptoms included chest pain, shortness of breath, sputum production, or wheezing; gastrointestinal symptoms included abdominal pain, anorexia, diarrhea, or vomiting; and rash/oral changes included extremity changes, oral changes, and any rash to skin, hands, or feet.

Clinical outcomes included hospitalization, ICU admission, or the occurrence of a severe outcome. Severe outcomes were defined as previously described in 1 of the parent studies15  and included any of the following events: Cardiac arrest, cardiac ischemia, congestive heart failure, endocarditis, myocarditis, pericarditis, stroke, disseminated intravascular coagulation, mastoiditis, sepsis with bacteremia, septic shock, toxic shock syndrome, encephalitis, meningitis, acute respiratory distress syndrome, empyema, necrotizing or cryptogenic organizing pneumonia, pleural effusion or pneumothorax or pneumomediastinum requiring drainage, respiratory failure, or death. A participant was also classified as having a severe outcome if any of the following predefined intensive interventions was performed: Chest drainage, extracorporeal membrane oxygenation, inotropic support, positive pressure ventilation, or renal replacement therapy.15 

On the basis of previous work estimating the prevalence of severe outcomes,15  a minimum sample of 285 infants per group was required to have 80% power (α = .05) to test for a hypothesized difference in the proportion of children experiencing a severe outcome between SARS-CoV-2–positive and –negative infants, with estimated event rates of 1% and 5%, respectively.

Participants were classified as positive or negative for SARS-CoV-2 infection. Infants who were SARS-CoV-2–positive and coinfected with other detectable viral pathogens were categorized in the SARS-CoV-2–positive group for analytic purposes. Demographic and clinical characteristics, outcomes, and symptom profiles were summarized with frequencies, percentages, and 95% confidence intervals (CIs) for dichotomous measures, and medians and interquartile ranges (IQRs) for continuous measures. To calculate the proportion of participants experiencing the outcomes of interest, all eligible infants were included in the denominator. We compared outcome measures between the SARS-CoV-2 test-positive and test-negative groups using χ2 tests and Fisher’s exact tests, as appropriate, for categorical variables, and Mann-Whitney U tests for continuous variables. Comparisons were conducted for the full study sample of infants, as well as subanalyses among infants stratified in commonly used age categories for this population; 0 to 28 days, 29 to 60 days, and 61 to 90 days. All analyses were 2-sided, and statistical significance was defined by a P < .05, with adjustment for multiplicity of comparisons via the Benjamini-Hochberg approach.19  Analyses were performed using SPSS Statistics version 25 (IBM Corporation).

From the 16 920 participants prospectively enrolled in the original PERN and PERC COVID-19 study group pediatric cohorts, 1048 infants (6.1%) were ≤90 days old and included in this analysis (Table 1); 432 (41.2%) were SARS-CoV-2–positive and 616 (58.8%) were SARS-CoV-2–negative. A majority of infants were aged 29 to 60 days (528; 50.4%), male (592; 56.5%), and were recruited in Canada (609; 58.1%). Overall, 28 (2.8%) were noted to be moderately or severely ill at presentation. There were 373 (35.6%) who underwent additional viral testing besides SARS-CoV-2, and other viruses were detected among 16 of 143 (11.2%) SARS-CoV-2–positive and 82 of 230 (35.7%) SARS-CoV-2–negative infants. SARS-CoV-2–positive and –negative infants were similar in age, sex, presence of chronic conditions, and general appearance at ED presentation.

TABLE 1

Demographic and Clinical Characteristics of Included Infants, n (%)

Study Population, (N = 1048)SARS-CoV-2–Positive, (n = 432)SARS-CoV-2–Negative, (n = 616)
Demographic information 
 0–28 d old 115 (11.0) 38 (8.8) 77 (12.5) 
 29–60 d old 528 (50.4) 206 (47.7) 322 (52.3) 
 61–90 d old 405 (38.6) 188 (43.5) 217 (35.2) 
Sex, male 592 (56.5) 236 (54.6) 356 (57.8) 
Any chronic medical conditiona 67 (6.4) 20 (4.6) 47 (7.6) 
Country 
 Canada 609 (58.1) 222 (51.4) 387 (62.8) 
 United States 312 (29.8) 147 (34.0) 165 (26.8) 
 Australia 3 (0.3) 0 (0.0) 3 (0.5) 
 New Zealand 2 (0.2) 0 (0.0) 2 (0.3) 
 Spain 45 (4.3) 15 (3.5) 30 (4.9) 
 Argentina 8 (0.8) 4 (0.9) 4 (0.6) 
 Costa Rica 61 (5.8) 36 (8.3) 25 (4.1) 
 Paraguay 4 (0.4) 4 (0.9) 0 (0.0) 
 Italy 4 (0.4) 4 (0.9) 0 (0.0) 
General appearance 
 Well-appearing 787 (75.1) 334 (77.3) 453 (73.5) 
 Mildly ill 75 (7.2) 27 (6.3) 48 (7.8) 
 Moderately ill 20 (1.9) 5 (1.2) 15 (2.4) 
 Severely ill 5 (0.5) 0 (0) 5 (0.8) 
 Not available 161 (15.4) 66 (15.3) 95 (15.4) 
Investigations performed 
 Chest radiographyb 254 (24.4) 109 (25.4) 145 (23.6) 
 Blood culturesc 452 (43.2) 212 (49.1) 240 (39.1) 
 Additional viral studies (ie, besides SARS-CoV-2 testing) 373 (35.6) 143 (33.1) 230 (37.3) 
Treatments received 
 Oxygen supplementationd 78 (7.5) 20 (4.7) 58 (9.5) 
 Intravenous fluidse 255 (24.4) 98 (22.8) 157 (25.6) 
 Antibioticsf 266 (25.5) 96 (22.3) 170 (27.7) 
Study Population, (N = 1048)SARS-CoV-2–Positive, (n = 432)SARS-CoV-2–Negative, (n = 616)
Demographic information 
 0–28 d old 115 (11.0) 38 (8.8) 77 (12.5) 
 29–60 d old 528 (50.4) 206 (47.7) 322 (52.3) 
 61–90 d old 405 (38.6) 188 (43.5) 217 (35.2) 
Sex, male 592 (56.5) 236 (54.6) 356 (57.8) 
Any chronic medical conditiona 67 (6.4) 20 (4.6) 47 (7.6) 
Country 
 Canada 609 (58.1) 222 (51.4) 387 (62.8) 
 United States 312 (29.8) 147 (34.0) 165 (26.8) 
 Australia 3 (0.3) 0 (0.0) 3 (0.5) 
 New Zealand 2 (0.2) 0 (0.0) 2 (0.3) 
 Spain 45 (4.3) 15 (3.5) 30 (4.9) 
 Argentina 8 (0.8) 4 (0.9) 4 (0.6) 
 Costa Rica 61 (5.8) 36 (8.3) 25 (4.1) 
 Paraguay 4 (0.4) 4 (0.9) 0 (0.0) 
 Italy 4 (0.4) 4 (0.9) 0 (0.0) 
General appearance 
 Well-appearing 787 (75.1) 334 (77.3) 453 (73.5) 
 Mildly ill 75 (7.2) 27 (6.3) 48 (7.8) 
 Moderately ill 20 (1.9) 5 (1.2) 15 (2.4) 
 Severely ill 5 (0.5) 0 (0) 5 (0.8) 
 Not available 161 (15.4) 66 (15.3) 95 (15.4) 
Investigations performed 
 Chest radiographyb 254 (24.4) 109 (25.4) 145 (23.6) 
 Blood culturesc 452 (43.2) 212 (49.1) 240 (39.1) 
 Additional viral studies (ie, besides SARS-CoV-2 testing) 373 (35.6) 143 (33.1) 230 (37.3) 
Treatments received 
 Oxygen supplementationd 78 (7.5) 20 (4.7) 58 (9.5) 
 Intravenous fluidse 255 (24.4) 98 (22.8) 157 (25.6) 
 Antibioticsf 266 (25.5) 96 (22.3) 170 (27.7) 
a

One participant in the SARS-CoV-2–negative group had missing data.

b

Three participants in the SARS-CoV-2–positive and 2 in the SARS-CoV-2–negative group had missing data.

c

Two participants in the SARS-CoV-2–negative group had missing data.

d

Four participants in the SARS-CoV-2–positive and 3 in the SARS-CoV-2–negative group had missing data.

e

Two participants in the SARS-CoV-2–positive and 2 in the SARS-CoV-2–negative group had missing data.

f

One participant in the SARS-CoV-2–positive and 2 in the SARS-CoV-2–negative group had missing data.

Of the 1048 infants, 1007 (96.1%) were symptomatic at initial evaluation (Table 2). Systemic symptoms of apnea, drowsiness, irritability, or lethargy were the most common overall (646; 61.6%). Fever was present in 561 (53.5%) infants, and more frequent among those with SARS-CoV-2 infections (69.2% vs 42.5%; risk difference 26.7% [95% CI 20.8%–32.5%]). SARS-CoV-2–positive infants more frequently presented with upper respiratory symptoms (62.5% vs 51.0%; risk difference 11.5% [95% CI 5.5%–17.6%]) and cough (49.1% vs 39.6%; risk difference 9.5% [95% CI 3.4%–15.6%]), with fewer lower airway respiratory symptoms (30.8% vs 42.2%; risk difference −11.4% [95% CI −17.3% to −5.6%]). There was no difference in the prevalence of dehydration, gastrointestinal, systemic, or dermatologic symptoms between groups. The median duration of symptoms at the time of ED presentation was 2.0 (IQR 0.5–4.0) days, and did not differ between the SARS-CoV-2–positive and –negative groups. Similarly, the median number of symptoms at the time of the ED visit was 4.0 (IQR 2.0–6.0), which also did not differ between groups. Results were similar when stratified by month of life (Supplemental Table 4).

TABLE 2

Symptoms Reported at Emergency Department Presentation, Stratified by SARS-CoV-2 Status, n (%)

SymptomStudy Population, (N = 1048)SARS-CoV-2–Positive, (n = 432)SARS-CoV-2–Negative, (n = 616)Adjusted Pg
Fever 561 (53.5) 299 (69.2) 262 (42.5) <.001 
Dehydrationa 307 (29.3) 119 (27.5) 188 (30.5) .36 
Respiratory 
 Cough 456 (43.5) 212 (49.1) 244 (39.6) .01 
 Upper respiratoryb 583 (55.7) 270 (62.5) 314 (51.0) <.001 
 Lower respiratoryc 393 (37.5) 133 (30.8) 260 (42.2) <.001 
Gastrointestinald 492 (47.0) 188 (43.5) 304 (49.4) .11 
Systemice 646 (61.7) 258 (59.9) 388 (63.0) .36 
Rash or oral changesf 138 (16.2) 62 (16.5) 76 (15.9) .79 
Duration of symptoms at ED presentation, d; median (IQR) 2.0 (0.5–4.0) 2.0 (0.5–4.0) 2.0 (0.5–3.0) .27 
Number of presenting symptoms; median (IQR) 4.0 (2.0–6.0) 4.0 (2.0–6.0) 4.0 (2.0–6.0) .36 
 0 (asymptomatic) 41 (3.9) 8 (1.9) 33 (5.4)  
 1–3 symptoms 410 (39.1) 170 (39.4) 240 (39)  
 4–6 symptoms 353 (33.7) 158 (36.6) 195 (31.7)  
 ≥7 symptoms 244 (23.3) 96 (22.2) 148 (24)  
SymptomStudy Population, (N = 1048)SARS-CoV-2–Positive, (n = 432)SARS-CoV-2–Negative, (n = 616)Adjusted Pg
Fever 561 (53.5) 299 (69.2) 262 (42.5) <.001 
Dehydrationa 307 (29.3) 119 (27.5) 188 (30.5) .36 
Respiratory 
 Cough 456 (43.5) 212 (49.1) 244 (39.6) .01 
 Upper respiratoryb 583 (55.7) 270 (62.5) 314 (51.0) <.001 
 Lower respiratoryc 393 (37.5) 133 (30.8) 260 (42.2) <.001 
Gastrointestinald 492 (47.0) 188 (43.5) 304 (49.4) .11 
Systemice 646 (61.7) 258 (59.9) 388 (63.0) .36 
Rash or oral changesf 138 (16.2) 62 (16.5) 76 (15.9) .79 
Duration of symptoms at ED presentation, d; median (IQR) 2.0 (0.5–4.0) 2.0 (0.5–4.0) 2.0 (0.5–3.0) .27 
Number of presenting symptoms; median (IQR) 4.0 (2.0–6.0) 4.0 (2.0–6.0) 4.0 (2.0–6.0) .36 
 0 (asymptomatic) 41 (3.9) 8 (1.9) 33 (5.4)  
 1–3 symptoms 410 (39.1) 170 (39.4) 240 (39)  
 4–6 symptoms 353 (33.7) 158 (36.6) 195 (31.7)  
 ≥7 symptoms 244 (23.3) 96 (22.2) 148 (24)  
a

Includes decreased urine output or refusal to drink.

b

Includes rhinorrhea or nasal congestion.

c

Includes chest pain, shortness of breath, sputum production, or wheezing.

d

Includes abdominal pain, anorexia, diarrhea, or vomiting. One participant in the SARS-CoV-2–negative group had missing data.

e

Includes apnea, drowsiness, irritability, or lethargy. One participant in the SARS-CoV-2–positive group had missing data.

f

Includes extremity changes, oral changes, rash to hands or feet, or skin rash. This data were collected from August 2020 onward. Fifty-seven participants in the SARS-CoV-2–positive and 137 in the SARS-CoV-2–negative group had missing data.

g

P values were adjusted for multiple comparisons via the Benjamini-Hochberg method.

At the index ED visit and during the subsequent 14 days, infants with SARS-CoV-2 infections were less likely than test-negative infants to be hospitalized (32.9% vs 44.8%; risk difference −11.9% [95% CI −17.9% to −6.0%]), require ICU admission (1.4% vs 5.0%; risk difference −3.6% [95% CI −5.7% to −1.6%]), or experience severe outcomes (1.4% vs 5.4%; risk difference 4.0% [95% CI −6.1% to −1.9%]; Table 3). SARS-CoV-2–positive infants required fewer intensive interventions (0.5% vs 2.9%, risk difference −2.5% [95% CI −3.9% to −0.98%]), primarily because of fewer infants requiring mechanical ventilation (0.2% vs 2.6%, risk difference −2.4% [95% CI −3.7% to −1.0%]). There were no deaths. Restricting the analysis to hospitalized infants, severe outcomes were also less frequent among those with SARS-CoV-2 infections (4.2% vs 12.0%, risk difference −7.7% [95% CI −12.8% to −2.7%]). Age-stratified outcomes are presented in Supplemental Table 5, and event counts over time are presented in Supplemental Fig 1.

TABLE 3

Clinical Outcomes, Stratified by SARS-CoV-2 Status, n (%)

OutcomeStudy Population, (N = 1048)SARS-CoV-2–Positive, (n = 432)SARS-CoV-2–Negative, (n = 616)Adjusted Pb
Hospitalization 418 (39.9) 142 (32.9) 276 (44.8) .001 
ICU admission 37 (3.5) 6 (1.4) 31 (5.0) .006 
Any severe outcomea 39 (3.7) 6 (1.4) 33 (5.4) .004 
 Cardiovascular 4 (0.4) 1 (0.2) 3 (0.5) .71 
 Infectious disease 3 (0.3) 0 (0) 3 (0.5) .38 
 Neurologic 9 (0.9) 1 (0.2) 8 (1.3) .14 
 Respiratory 6 (0.6) 2 (0.5) 4 (0.7) >.99 
 Intensive intervention/treatment 20 (1.9) 2 (0.5) 18 (2.9) .01 
 Mechanical ventilation 17 (1.6) 1 (0.2) 16 (2.6) .006 
 Inotropic support 4 (0.4) 1 (0.2) 3 (0.5) .71 
 Death 0 (0) 0 (0) 0 (0) N/A 
Any severe outcome among hospitalized infantsa 39 (9.3) 6 (4.2) 33 (12.0) .02 
OutcomeStudy Population, (N = 1048)SARS-CoV-2–Positive, (n = 432)SARS-CoV-2–Negative, (n = 616)Adjusted Pb
Hospitalization 418 (39.9) 142 (32.9) 276 (44.8) .001 
ICU admission 37 (3.5) 6 (1.4) 31 (5.0) .006 
Any severe outcomea 39 (3.7) 6 (1.4) 33 (5.4) .004 
 Cardiovascular 4 (0.4) 1 (0.2) 3 (0.5) .71 
 Infectious disease 3 (0.3) 0 (0) 3 (0.5) .38 
 Neurologic 9 (0.9) 1 (0.2) 8 (1.3) .14 
 Respiratory 6 (0.6) 2 (0.5) 4 (0.7) >.99 
 Intensive intervention/treatment 20 (1.9) 2 (0.5) 18 (2.9) .01 
 Mechanical ventilation 17 (1.6) 1 (0.2) 16 (2.6) .006 
 Inotropic support 4 (0.4) 1 (0.2) 3 (0.5) .71 
 Death 0 (0) 0 (0) 0 (0) N/A 
Any severe outcome among hospitalized infantsa 39 (9.3) 6 (4.2) 33 (12.0) .02 

N/A, not applicable.

a

Composite outcome includes any of the following: Cardiac or cardiovascular (cardiac arrest, cardiac ischemia, congestive heart failure, endocarditis, myocarditis, pericarditis, stroke), infectious (disseminated intravascular coagulation, mastoiditis, sepsis with bacteremia, septic shock, shock syndrome), neurologic (encephalitis, meningitis), respiratory (acute respiratory distress syndrome, empyema, necrotizing or cryptogenic organizing pneumonia, pleural effusion or pneumothorax or pneumomediastinum requiring drainage, respiratory failure), any intensive intervention/treatment (chest drainage, extracorporeal membrane oxygenation, inotropic support, positive pressure ventilation [invasive or noninvasive], renal replacement therapy), or death. One participant in the SARS-CoV-2–positive and 1 in the SARS-CoV-2–negative group had missing data.

b

P values were adjusted for multiple comparisons via the Benjamini-Hochberg method.

In this large, international prospective cohort of infants ≤90 days old tested for SARS-CoV-2, fever, cough, and upper respiratory symptoms were more common among test-positive infants. However, overall symptom profile and number of presenting symptoms were similar between infants with and without SARS-CoV-2 infections. Compared with test-negative infants, those with SARS-CoV-2 infections were hospitalized less frequently and were less likely to be admitted to an ICU or experience severe outcomes within 14 days of their index ED visits. Given the unique management considerations for this vulnerable population, knowledge of SARS-CoV-2 infection status can help inform clinical decision-making for very young infants.

Fever, cough, and upper respiratory symptoms are the most common symptoms among children with acute SARS-CoV-2 infections, with fewer lower airway symptoms.8,20,21  Compared with children with respiratory syncytial virus infections, SARS-CoV-2–infected children are less likely to have lower airway symptoms (eg, wheezing).22,23  However, data characterizing SARS-CoV-2 symptoms among very young infants specifically are limited.13,24,25  Previous studies comparing infants ≤90 days old with and without SARS-CoV-2 infections have found overall similar symptom profiles.13,24  Although we found statistically significant differences in some symptoms between groups, most symptoms and patient characteristics were neither statistically nor clinically significant (eg, ∼60% SARS-CoV-2–positive versus ∼50% SARS-CoV-2–negative infants with upper respiratory symptoms). Further complicating any comparison of symptoms between infants with and without SARS-CoV-2 infections, clinical presentations vary between SARS-CoV-2 variants.16,26  Thus, differentiating young infants with SARS-CoV-2 infections from similar illnesses on the basis of clinical symptoms is unreliable.

Infants with SARS-CoV-2 infections in the current study had a low prevalence of severe outcomes or need for ICU admission (both <1.5%), and none died. Studies in older children suggest that those with SARS-CoV-2 infections experience severe outcomes at comparable or lower frequency than those with respiratory syncytial virus, influenza, and other laboratory-confirmed respiratory viral infections.21 23,27,28  There are few studies reporting on severe outcomes specifically among very young infants with SARS-CoV-2 infections, and results have varied. Some studies have found that neonates with SARS-CoV-2 infections are at increased risk of severe outcomes compared with infants aged 1 to 12 months,5,6,10 12  whereas others have not reported the same findings.13 15  Heterogeneity in previous estimates likely reflects differences in study designs, outcome definitions, and local factors.4  Similar to our findings, a single-center study of infants aged ≤90 days tested in a pediatric ED found that 2% of SARS-CoV-2–positive infants required ICU admission.13  One study reported that 25% of neonates hospitalized with COVID-19 had severe disease, with 8 of 49 (16.3%) requiring ICU admission.11  This is in contrast to our cohort, in which severe outcomes occurred in only 4% of hospitalized infants with SARS-CoV-2 infections, and less frequently than among test-negative infants (∼12%). Unique strengths of our study include its prospective design, large multinational cohort, and the inclusion of SARS-CoV-2 tested but test-negative infants, which permitted comparisons based on SARS-CoV-2 test result status. The lower proportion of SARS-CoV-2–positive infants who experienced severe illness highlights the clinical utility of SARS-CoV-2 testing in guiding further management and prognostication in this unique population.

Several limitations deserve mention. First, this cohort study was conducted over a large time span, and therefore includes participants who were infected with a variety of SARS-CoV-2 strains. As such, symptoms and severity may differ in future waves of COVID-19 as newer SARS-CoV-2 strains emerge and circulate.8,16  Not all infants underwent testing for additional viruses, and viral coinfections among SARS-CoV-2–positive infants could reduce the observed differences in clinical presentations and outcomes between groups. Clinical symptoms were self-reported by parents/caregivers and several of the symptoms recorded are subjective. However, parental reporting of symptoms would not be expected to differ between test-positive and -negative groups. Despite similar clinical presentations among SARS-CoV-2–positive and –negative infants, the possibility of confounding cannot be completely excluded (eg, by country). Because participants were recruited in EDs, the risks of hospitalization and severe outcomes are greater than in the general population,4  although this also would not be expected to differentially impact the study groups. Some young infants may have been hospitalized solely because of their positive SARS-CoV-2 test results, in an abundance of caution, particularly at the start of the pandemic when understanding of the virus and its natural history was limited. Thus, the proportion of infants with SARS-CoV-2 infections hospitalized may be an overestimate.

In this prospective international ED cohort of infants aged ≤90 days tested for SARS-CoV-2, infants with and without SARS-CoV-2 infections had symptom profiles that were difficult to distinguish clinically. Among SARS-CoV-2–positive infants, hospitalization, ICU admission, and severe outcomes were less frequent than test-negative infants. These findings further inform our understanding of the clinical course of SARS-CoV-2 infections among the youngest infants and highlight that they are generally milder than among SARS-CoV-2 test-negative infants with similar illnesses. Thus, viral testing in this population can aid in the assessment of risk of severe outcomes and inform clinical management.

We thank the PERN COVID-19 study team: Fahd A. Ahmad, MD, MScI; Lilliam Ambroggio, PhD, MPH; Usha R. Avva, MD; Sarah M. Becker, MD; Isabel Beneyto Ferre, MD; Kelly R. Bergmann, DO, MS; Maala Bhatt, MD; Meredith L. Borland, MD; Kristen A. Breslin, MD; Carmen Campos, MD; Kerry Caperell, MD, MS, MBA; Pradip P. Chaudhari, MD; Jonathan C. Cherry, MD; Shu-Ling Chong, MPH; Andrew C. Dixon, MD; Stuart R. Dalziel, MBChB, FRACP, PhD; Michelle Eckerle, MD; Yaron Finkelstein, MD; Iker Gangoiti, MD; Michael A. Gardiner, MD; April J. Kam, MD; Nirupama Kannikeswaran, MD; Kelly Kim, BSc; Terry P. Klassen, MD, MSc; Maria Y. Kwok, MD, MPH; Maren M. Lunoe, MD; Richard Malley, MD; Santiago Mintegi, MD, PhD; Claudia R. Morris, MD; Andrea K. Morrison, MD, MS; Nidhya Navanandan, MD; Jasmine R. Nebhrajani, MD; Mark I. Neuman, MD, MPH; Laura Palumbo, MD; Viviana Pavlicich, MD; Amy C. Plint, MD; Naveen Poonai, MD; Pedro B. Rino, MD; Alexander J. Rogers, MD; Marina I. Salvadori, MD; Laura F. Sartori, MD, MPH; Nipam P. Shah, MD, MBBS, MPH; Norma-Jean Simon, MPH; Muhammad Wassem, MD; Adriana Yock-Corrales, MD. We also thank the PERC COVID-19 study team: Darcy Beer, MD; Simon Berthelot, MD, MSc; Jason Emsley, MD; Gabrielle Freire, MD; Jocelyn Gravel, MD; April Kam, MD; Ahmed Mater, MD; Anne Moffatt, MD; Naveen Poonai, MD; Robert Porter, MD, MSc; Roger Zemek, MD.

Dr Burstein assisted in study conceptualization and design, data collection, analysis, and interpretation, and drafted and critically revised the manuscript; Dr Sabhaney assisted in data collection, analysis, and interpretation, and reviewed and critically revised the manuscript for important intellectual content; Drs Florin, Kuppermann, and Freedman assisted in study conceptualization and design, data collection, analysis, and interpretation, reviewed and critically revised the manuscript, and secured funding for the parent study; Dr Xie assisted in data collection and analysis, and reviewed and critically revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by grants from the Canadian Institutes of Health Research (operating grant: Coronavirus disease 2019, clinical management), the Public Health Agency of Canada, the Alberta Health Service, University of Calgary, Clinical Research Fund, the Alberta Children’s Hospital Research Institute, the COVID-19 Research Accelerator Funding Track Program at the University of California, Davis. Dr Burstein is the recipient of a career award from the Quebec Health Research Fund. Dr Florin is supported by grants from Cincinnati Children’s Hospital Medical Center Division of Emergency Medicine Small Grant Program. Dr Freedman is supported by the Alberta Children’s Hospital Foundation Professorship in Child Health and Wellness. Dr Kuppermann is supported by the Bo Tomas Brofeldt endowed professorship from the University of California, Davis, School of Medicine. The other authors received no additional funding.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.

CI

confidence interval

COVID-19

coronavirus disease 2019

ED

emergency department

IQR

interquartile range

PERC

Pediatric Emergency Research Canada

PERN

Pediatric Emergency Research Network

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

1
American Academy of Pediatrics and the Children’s Hospital Association
.
Children and COVID-19: state data report
.
2
Shekerdemian
LS
,
Mahmood
NR
,
Wolfe
KK
, et al
International COVID-19 PICU Collaborative
.
Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units
.
JAMA Pediatr
.
2020
;
174
(
9
):
868
873
3
Liguoro
I
,
Pilotto
C
,
Bonanni
M
, et al
.
SARS-COV-2 infection in children and newborns: a systematic review
.
Eur J Pediatr
.
2020
;
179
(
7
):
1029
1046
4
Sumner
MW
,
Kanngiesser
A
,
Lotfali-Khani
K
, et al
.
Severe outcomes associated with SARS-CoV-2 infection in children: a systematic review and meta-analysis
.
Front Pediatr
.
2022
;
10
:
916655
5
Götzinger
F
,
Santiago-García
B
,
Noguera-Julián
A
, et al
ptbnet COVID-19 Study Group
.
COVID-19 in children and adolescents in Europe: a multinational, multicenter cohort study
.
Lancet Child Adolesc Health
.
2020
;
4
(
9
):
653
661
6
Ward
JL
,
Harwood
R
,
Smith
C
, et al
.
Risk factors for PICU admission and death among children and young people hospitalized with COVID-19 and PIMS-TS in England during the first pandemic year
.
Nat Med
.
2022
;
28
(
1
):
193
200
7
Harwood
R
,
Yan
H
,
Talawila Da Camara
N
, et al
.
Which children and young people are at higher risk of severe disease and death after hospitalization with SARS-CoV-2 infection in children and young people: a systematic review and individual patient meta-analysis
.
EClinicalMedicine
.
2022
;
44
:
101287
8
Zhu
Y
,
Almeida
FJ
,
Baillie
JK
, et al
International Severe Acute Respiratory and Emerging Infection Consortium Comprehensive Clinical Characterization Collaboration (ISARIC4C) investigators
;
Pediatric Active Enhanced Disease Surveillance (PAEDS) Network group
.
International pediatric COVID-19 severity over the course of the pandemic
.
JAMA Pediatr
.
2023
;
177
(
10
):
1073
1084
9
Pantell
RH
,
Roberts
KB
,
Adams
WG
, et al
Subcommittee on Febrile Infants
.
Evaluation and management of well-appearing febrile infants 8 to 60 days old
.
Pediatrics
.
2021
;
148
(
2
):
e2021052228
10
Farrar
DS
,
Drouin
O
,
Moore Hepburn
C
, et al
.
Risk factors for severe COVID-19 in hospitalized children in Canada: a national prospective study from March 2020–May 2021
.
Lancet Reg Health Am
.
2022
;
15
:
100337
11
Piché-Renaud
PP
,
Panetta
L
,
Farrar
DS
, et al
Canadian Paediatric Surveillance Program COVID-19 Study Team
.
Clinical manifestations and disease severity of SARS-CoV-2 infection among infants in Canada
.
PLoS One
.
2022
;
17
(
8
):
e0272648
12
Leung
C
.
The younger the milder clinical course of COVID-19: even in newborns?
Pediatr Allergy Immunol
.
2021
;
32
(
2
):
358
362
13
Benenson-Weinberg
T
,
Gross
I
,
Bamberger
Z
, et al
.
Severe acute respiratory syndrome coronavirus 2 in infants younger than 90 days presenting to the pediatric emergency department: clinical characteristics and risk of serious bacterial infection
.
Pediatr Emerg Care
.
2023
;
39
(
12
):
929
933
14
Spoulou
V
,
Noni
M
,
Koukou
D
,
Kossyvakis
A
,
Michos
A
.
Clinical characteristics of COVID-19 in neonates and young infants
.
Eur J Pediatr
.
2021
;
180
(
9
):
3041
3045
15
Funk
AL
,
Florin
TA
,
Kuppermann
N
, et al
Pediatric Emergency Research Network-COVID-19 Study Team
.
Outcomes of SARS-CoV-2–positive youths tested in emergency departments: the global PERN–COVID-19 study
.
JAMA Netw Open
.
2022
;
5
(
1
):
e2142322
16
Sumner
MW
,
Xie
J
,
Zemek
R
, et al
Pediatric Emergency Research Canada (PERC) COVID Study Group
.
Comparison of symptoms associated with SARS-CoV-2 variants among children in Canada
.
JAMA Netw Open
.
2023
;
6
(
3
):
e232328
17
Sumner
MW
,
Florin
TA
,
Kuppermann
N
,
Xie
J
,
Tancredi
DJ
,
Freedman
SB
.
Pediatric Emergency Research Network PERN, Pediatric Emergency Research Canada PERC–COVID-19 study teams
.
Liver transaminase concentrations in children with acute SARS-CoV-2 infection
.
Clin Biochem
.
2023
;
118
:
110588
18
von Elm
E
,
Altman
DG
,
Egger
M
,
Pocock
SJ
,
Gøtzsche
PC
,
Vandenbroucke
JP
;
STROBE Initiative
.
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies
.
PLoS Med
.
2007
;
4
(
10
):
e296
19
Benjamini
Y
,
Hochberg
Y
.
Controlling the false discovery rate: a practical and powerful approach to multiple testing
.
J R Stat Soc B
.
1995
;
57
(
1
):
289
300
20
Viner
RM
,
Ward
JL
,
Hudson
LD
, et al
.
Systematic review of reviews of symptoms and signs of COVID-19 in children and adolescents
. [Published online ahead of print December 17, 2020]
Arch Dis Child
.
2020
.10.1136/archdischild-2020-320972
21
Yu
B
,
Chen
HH
,
Hu
XF
,
Mai
RZ
,
He
HY
.
Comparison of laboratory parameters, clinical symptoms and clinical outcomes of COVID-19 and influenza in pediatric patients: a systematic review and meta-analysis
.
World J Clin Cases
.
2022
;
10
(
29
):
10516
10528
22
Fedorczak
A
,
Zielińska
N
,
Nosek-Wasilewska
P
, et al
.
Comparison of COVID-19 and RSV infection courses in infants and children under 36 months Hospitalized in pediatric department in fall and winter season 2021/2022
.
J Clin Med
.
2022
;
11
(
23
):
7088
23
Nunziata
F
,
Salomone
S
,
Catzola
A
, et al
.
Clinical presentation and severity of SARS-CoV-2 infection compared to respiratory syncytial virus and other viral respiratory infections in children less than 2 years of age
.
Viruses
.
2023
;
15
(
3
):
717
24
Leibowitz
J
,
Krief
W
,
Barone
S
, et al
.
Comparison of clinical and epidemiologic characteristics of young febrile infants with and without severe acute respiratory syndrome coronavirus-2 infection
.
J Pediatr
.
2021
;
229
:
41
47.e1
25
Mark
EG
,
Golden
WC
,
Gilmore
MM
, et al
.
Community-onset severe acute respiratory syndrome coronavirus 2 infection in young infants: a systematic review
.
J Pediatr
.
2021
;
228
:
94
100.e3
26
Bahl
A
,
Mielke
N
,
Johnson
S
,
Desai
A
,
Qu
L
.
Severe COVID-19 outcomes in pediatrics: an observational cohort analysis comparing alpha, delta, and omicron variants
.
Lancet Reg Health Am
.
2023
;
18
:
100405
27
Meyer
M
,
Ruebsteck
E
,
Eifinger
F
, et al
.
Morbidity of respiratory syncytial virus (RSV) infections: RSV compared with severe acute respiratory syndrome coronavirus 2 infections in children aged 0–4 years in Cologne, Germany
.
J Infect Dis
.
2022
;
226
(
12
):
2050
2053
28
Song
X
,
Delaney
M
,
Shah
RK
,
Campos
JM
,
Wessel
DL
,
DeBiasi
RL
.
Common seasonal respiratory viral infections in children before and during the coronavirus disease 2019 (COVID-19) pandemic
.
Infect Control Hosp Epidemiol
.
2022
;
43
(
10
):
1454
1458

Supplementary data