Infants Hospitalized for Acute COVID-19: Disease Severity in a Multicenter Cohort Study

doi:10.21203/rs.3.rs-1109292/v1

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Infants Hospitalized for Acute COVID-19: Disease Severity in a Multicenter Cohort Study

https://doi.org/10.21203/rs.3.rs-1109292/v1

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Journal Publication

published 25 Feb, 2022

Read the published version in European Journal of Pediatrics →

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Age is the most important determinant of COVID-19 severity. Infectious disease severity by age is typically J-shaped, with infants and the elderly carrying a high burden of disease. We report on the comparative disease severity between infants and older children in a multicenter retrospective cohort study of children 0 to 17 year old admitted for acute COVID-19 February 2020 through May 2021 in 17 pediatric hospitals. We compare clinical and laboratory characteristics and estimate the association between age group and disease severity using ordinal logistic regression. We found that infants comprised one third of cases, but were admitted for a shorter period (median 3 days IQR 2-5 versus 4 days IQR 2-7), had a lower likelihood to have an increased C-reactive protein and had half the odds of older children of having severe or critical disease (OR 0.50 (95% Confidence Interval 0.32-0.78)).

Conclusion: When compared to older children, there appeared to be a lower threshold to admit infants but their length of stay is shorter and they have a lower odds than older children of progressing to severe or critical disease.

Pediatrics

infants

COVID-19

disease severity

age

-A small proportion of children infected with SARS-CoV-2 require hospitalisation for acute COVID-19 with a subgroup needing specialized intensive care to treat more severe disease.

-For most infectious diseases including viral respiratory tract infections, disease severity by age is J-shaped, with infants having more severe disease compared to older children.

-One third of admitted children for acute COVID-19 during the first 14 months of the pandemic were infants.

-Infants had half the odds of older children of having severe or critical disease.

The distribution of infectious disease severity by age is typically J-shaped [1]. Amongst children, neonates and infants have a high burden of disease [2], particularly with respiratory pathogens, and have the highest hospitalization rates [3]. The objective of this study was to determine whether this is true for coronavirus disease 2019 (COVID-19) in hospitalized children.

Seventeen pediatric hospitals (15 Canadian and one each in Iran and Costa Rica) included children up to 17 years of age, admitted February 1, 2020 through May 31, 2021 with detection of SARS-CoV-2. Patients with incidental SARS-CoV-2 infection or who met World Health Organization (WHO) criteria for multisystem inflammatory syndrome in children (MIS-C)) [4] were excluded as acute COVID-19 was not the reason for admission. Following ethics approval at all sites, data were extracted into REDCap from medical records including demographics, role of SARS-CoV-2 in admission, comorbidities (prematurity, malignancy, asthma, chronic pulmonary, heart or renal disease, obesity, or significant congenital anomalies), antibiotic use, clinical presentation and course.

Cases were defined as mild (ward admission without supplemental oxygen), severe (ward admission with supplemental oxygen) or critical (admission to ICU or death) [5].

Children were divided into infants (up to 11 months of age) versus older children for the primary analysis. For those older than 90 days, only month of birth was recorded, so age was the number of months between the birth and admission month. Sensitivity analyses assessed outcomes i) in three age groups: up to 29 days, 30 days to 11 months and 12 months or older and ii) in infants 0 to 5 months versus 6 to 11 months old.

Descriptive statistics were used to summarize baseline characteristics of patients and comparative statistics was performed applying Kruskal-Wallis and chi square test. Associations between age group and disease severity were examined using ordinal logistic regression in STATA 13 (StataCorp), estimating the odds of mild versus severe or critical disease.

There were 117 (36%) infants and 207 (64%) older children admitted for COVID-19 (Figure 1). Eighty-six infants (74%) had no comorbidities, of which 55 (64%) had mild, 18 (21%) severe and 13 (15%) critical disease, compared to 57 (28%) older children, including 32 (56%) with mild, 13 (23%) with severe and 12 (21%) having critical disease. Of 31 (26%) infants with comorbidities, 15 (48%) had mild, 7 (23%) severe and 9 (29%) critical disease. This contrasted to 150 (72%) older children with comorbidities, with mild, severe and critical disease in 55 (37%), 45 (30%) and 50 (33%), respectively.

Symptoms attributable to COVID-19 were similar in infants versus older children (Table 1). CRP was much more likely to be elevated in older children than in infants (67% versus 15%; p-value<0.0001). Similar proportions received antibiotics (67% of infants versus 60% of older children). Length of stay was shorter in infants (median 3 days IQR 2-5 versus 4 days IQR 2-7) (p-value=0.0043). For infants, the odds of having severe or critical disease was half that of older children (OR 0.50 (95%CI 0.32-0.78)). Compared to older children, the ORs for infants up to 29 days old and 30 days to 11 months were 0.56 (95%CI 0.28- 1.11) and 0.48 (95%CI 0.29-0.79), respectively. There was insufficient evidence for differing disease severity in infants up to 5 months versus 6 to 11 months old (Supplement). Six deaths occurred in children 14 months to 9 years old.

Table 1

Symptoms, peak CRP values and use of antibiotics in hospitalized infants versus older children with a primary diagnosis of acute COVID-19
	Infants N=117	12 months to 17 years of age N=207
Cough	51 (44%)	135 (65%)
Shortness of breath	49 (42%)	125 (60%)
Rhinitis	49 (42%)	60 (29%)
Vomiting	21 (18%)	51 (25%)
Diarrhea	21 (18%)	49 (24%)
Wheezing	15 (13%)	37 (18%)
Rash	5 (4%)	14 (7%)
New-onset seizures	3 (3%)	5 (2%)
Conjunctivitis	0 (0%)	8 (4%)
Splenomegaly	0 (0%)	3 (1%)
Hepatomegaly	0 (0%)	2 (1%)
Fever history Fever documented in hospital Fever prior to admission only No fever Data missing	40/106 (38%) 39/106 (37%) 27/106 (25%) 11/117	90/182 (49%) 53/182 (29%) 39/182 (21%) 25/207
Elevated peak CRP (> 8.0 mg/L)	14/94 (15%)	114/169 (67%)
Antibiotics during admission None Started for possible bacterial pneumonia Started for other possible or proven bacterial infection Data missing	39 (33%) 16 (14%) 61 (52%) 1 (1%)	82 (40%) 75 (36%) 49 (24%) 1 (0.5%)
Legend: CRP – C-reactive protein

Over one-third of children admitted with acute COVID-19 were infants. However, the proportion of infants with severe or critical disease was lower than for older children. As far as we are aware, this is the first study to directly compare the severity of illness in infants versus older children. Previous studies that analyzed the severity in admitted infants reported that only 4 of 34 symptomatic infants up to 90 days of age had severe or critical disease [6] and that only 1 of 14 infants was critically ill [7].

CRP was much more likely to be elevated in older children than in infants (67% versus 15%). CRP is a sensitive marker of inflammation even in neonates [8, 9] so we hypothesize a lower level of measurable inflammation in infants compared to older children admitted with COVID-19, but it may reflect admission of infants with milder disease. Less inflammation might partially explain why infants accounted for only 4% of MIS-C cases in a large series [10].

Limitations are that this study is not population based and investigated children admitted primarily to tertiary care centers. The threshold is presumably lower to admit infants versus older children with a similar severity of illness, especially if they are febrile and less than 90 days old [11]. This may explain why admitted infants in our study had less severe disease than did older children. Insufficient power prevents us to provide evidence for additional and more specific age and other subgroups. Furthermore, when the outcome is common, OR’s calculated cannot be interpreted as risks.

In conclusion, contrary to what is observed in most other infectious diseases [1], SARs-CoV-2 infection is not more severe in infants admitted with acute COVID-19 compared to older children.

CI – confidence interval

COVID-19 – coronavirus disease of 2019

CRP – C-reactive protein

ICU – intensive care unit

IQR – inter-quartile range

MIS-C – multisystem inflammatory disorder in children

OR – odds ratio

WHO – World Health Organization

Funding/Support:

No funding was secured for this study.

Conflict of Interest/Competing Interest:

The authors have no competing interests to declare that are relevant to the content of this article.

Availability of data and material:

The data are not publicly available

Code availability:

The codes are available on request

Authors’ contributions:

Dr Merckx analyzed the data and reviewed and revised the manuscript.

Dr Barton conceptualized and designed the study, collected data and reviewed and revised the manuscript.

Drs Morris, Bitnun, Gill, El Tal, Laxer, Yeh, Yea, Ulloa-Gutierrez, Brenes-Chacon, Yock-Corrales, Ivankovich-Escoto, Soriano-Fallas, Hernandez-de Mezerville, Papenburg, Lefebvre, Nateghian, Aski, Manafi, Dwilow, Bullard, Cooke, Dewan, Restivo, Lopez, Sadarangani, Roberts, Petel, Le Saux, Bowes, Purewal, Lautermilch, Tehseen , Bayliss, Wong, Viel-Thériault, Piche, Top, Leifso , Foo, and Panetta collected data and reviewed and revised the manuscript.

Dr Robinson conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Ethics approval:

This study was performed in line with the principles of the Declaration of Helsinki. Ethics approval was obtained primary at the University of Alberta (Pro00099426) and sequentially from all participating sites.

Consent to participate:

Not applicable

Consent for publication:

Not applicable

Acknowledgements:

The study was made possible thanks to the collaboration of the Paediatric Investigators Collaborative Network on Infections in Canada (PICNIC) and the manuscript was written on behalf of PICNIC.

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MerckxSupplementNov22COVID19infant.docx

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Journal Publication

published 25 Feb, 2022

Read the published version in European Journal of Pediatrics →

Reviews received at journal
19 Dec, 2021
Reviewers invited by journal
19 Dec, 2021
Editor assigned by journal
24 Nov, 2021
First submitted to journal
23 Nov, 2021

You are reading this latest preprint version

Infants Hospitalized for Acute COVID-19: Disease Severity in a Multicenter Cohort Study

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