key: cord-0818404-pwfn4gma authors: Piche-Renaud, P.-P.; Panetta, L.; Farrar, D. S.; Moore-Hepburn, C.; Drouin, O.; Papenburg, J.; Salvadori, M. I.; Kakkar, F.; Morris, S. K. title: Clinical manifestations and disease severity of SARS-CoV-2 infection among infants in Canada date: 2022-02-04 journal: nan DOI: 10.1101/2022.02.02.22270334 sha: 30af51443d720450219e62ed10a4e7355fb9c1c2 doc_id: 818404 cord_uid: pwfn4gma Importance: There are limited data on outcomes of SARS-CoV-2 infection among infants (<1 year of age). In the absence of approved vaccines for infants, understanding characteristics associated with hospitalization and severe disease from COVID-19 in this age group will help inform clinical management and public health interventions. Objective: The objective of this study was to describe the clinical manifestations, disease severity, and characteristics associated with hospitalization among infants infected with the initial strains of SARS-CoV-2. Design: Prospective study of infants with SARS-CoV-2 from April 8th 2020 to May 31st 2021. Setting: National study using the infrastructure of the Canadian Paediatric Surveillance Program, reporting inpatients and outpatients seen in clinics and emergency departments. Participants: Infants <1 year of age with microbiologically confirmed SARS-CoV-2 infection. Exposure: Infant-level characteristics associated with hospitalization for COVID-19. Main outcomes and Measures: Cases were classified as either: 1) Non-hospitalized patient with SARS-CoV-2 infection; 2) COVID-19-related hospitalization; or 3) non-COVID-19-related hospitalization (e.g., incidentally detected SARS-CoV-2). Case severity was defined as asymptomatic, outpatient care, mild (inpatient care), moderate or severe disease. Multivariable logistic regression was performed to identify characteristics associated with hospitalization. Results: A total of 531 cases were reported, including 332 (62.5%) non-hospitalized and 199 (37.5%) hospitalized infants. Among hospitalized infants, 141 of 199 infants (70.9%) were admitted because of COVID-19-related illness, and 58 (29.1%) were admitted for reasons other than acute COVID-19. Amongst all cases with SARS-CoV-2 infection, the most common presenting symptoms included fever (66.5%), coryza (47.1%), cough (37.3%) and decreased oral intake (25.0%). In our main analysis, infants with a comorbid condition had higher odds of hospitalization compared to infants with no comorbid conditions (aOR=4.53, 2.06-9.97), and infants <1 month had higher odds of hospitalization then infants aged 1-3 months (aOR=3.78, 1.97-7.26). In total, 20 infants (3.8%) met criteria for severe disease. Conclusions and Relevance: We describe one of the largest cohorts of infants with SARS-CoV-2 infection. Overall, severe COVID-19 in this age group is uncommon with most infants having mild disease. Comorbid conditions and younger age were associated with COVID-19-related hospitalization amongst infants. have shown similar risk across pediatric age groups. More specifically, some authors have 1 0 0 suggested that neonates (<28 days of life) 9 ,10 and infants (<1 year-old) may be at higher risk of 1 0 1 severe disease than older children. 1, [11] [12] [13] [14] [15] However, most of these studies have not included data with hospitalization, would inform management and preventive interventions for this specific age 1 0 6 group, including future vaccination strategies. 16, 17 The objective of this study was to describe the between April 2020 and May 2021, and to explore infant characteristics that may be associated aOR of hospitalization for VOC compared to the SARS-CoV-2 ancestor strain was 0.63 (95% CI, 2 9 9 0.27 -1.48). The phase of the pandemic (first, second or third wave) was not associated with an 3 0 0 increased odds of hospitalization in infants. This study describes the clinical manifestations and severity of disease in infants less than one focused only on hospitalized patients with symptomatic disease and may therefore have overestimated the severity of COVID-19 in this age group, this study provides a more complete including a subset of infants seen in outpatient settings. 9 ,24,25 3 1 0 Similar to the results of previous studies, including meta-analyses and systematic reviews on pediatric COVID-19, we report that severe COVID-19 is uncommon in infants, especially when 3 1 2 compared to adults and adolescents. [26] [27] [28] [29] It is thought that the difference in severity from SARS- 3 1 3 CoV-2 infection between age groups relates to distinct immune responses and expression in 3 1 4 receptors of angiotensin-converting enzyme-2 (ACE-2) in younger children. 30 However, 3 1 5 consistent with previous studies, we found that amongst infants, neonates aged <1 month were at 3 1 6 increased risk for hospitalization. 9 ,10,13,15,31 Although a low threshold for admission in infants 3 1 7 aged less than 6 to 12 weeks who present with fever may impact hospitalization rates, a larger 3 1 8 proportion of neonates aged <1 month admitted for COVID-19 have also required respiratory 3 1 9 support compared to older infants, including 5 who required mechanical ventilation. 23 The increased severity of SARS-CoV-2 infection seen in young neonates may relate to their small 3 2 1 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 4, 2022. ; https://doi.org/10.1101/2022.02.02.22270334 doi: medRxiv preprint airways and reduced innate immune responses, especially in the absence of passive immunity 3 2 2 from maternal antibodies against SARS-CoV-2. 32, 33 Several studies and reports have 3 2 3 demonstrated successful placental transmission of SARS-CoV-2 antibodies after maternal 3 2 4 vaccination. [34] [35] [36] Thus, in the absence of any COVID-19 vaccine approved for use in young 3 2 5 infants, an important strategy to protect neonates against severe SARS-CoV-2 may be through 3 2 6 maternal immunization. With multiple jurisdictions reporting lower COVID-19 vaccine coverage 3 2 7 in pregnant women compared to the general population, efforts should be made to optimize their 3 2 8 acceptance and uptake of COVID-19 vaccines. 37,38 3 2 9 Our results also suggest that preterm infants (<37 weeks of gestation) may be at higher risk of 3 3 0 severe COVID-19 compared to term infants. While a multivariable analysis revealed higher odds 3 3 1 of admission in preterm infants, this result was not consistent in our sensitivity analysis on the 3 3 2 data from centres with systematic case reporting. To date, there have been very few data 3 3 3 describing the spectrum of COVID-19 manifestations in infants who are born prematurely. Some 3 3 4 case reports have described severe disease requiring intubation in premature neonates infected 3 3 5 with SARS-CoV-2, whereas others have described an overall mild course. [39] [40] [41] [42] [43] Thus, further 3 3 6 research on the spectrum of illness of SARS-CoV-2 infection in this population is needed. The emergence of new SARS-CoV-2 lineages have raised concerns for differences in 3 3 8 susceptibility and virulence in the pediatric population. 44 In Ontario and Québec, the provinces 3 3 9 from which most of our study subjects have been reported, the third wave of the pandemic that we did not find any significant difference in the proportion of infants admitted for COVID-19 3 4 2 during the third wave of the pandemic, or between SARS-CoV-2 lineages. However, we have All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 4, 2022. ; https://doi.org/10.1101/2022.02.02.22270334 doi: medRxiv preprint cases of the Delta VOC were identified in Québec on April 21, 2021 by using whole genome 3 4 5 sequencing (WGS), as the variant is negative for the detection of N501Y and E484K mutations 3 4 6 (widely used for VOC screening). 16 Since we were unable to obtain data on WGS in our study, 3 4 7 SARS-CoV-2 isolates that were negative for both N501Y and E484K mutations from April 21 st 3 4 8 to May 31 st may have been Delta VOC that were misclassified as wild-type SARS-CoV-2. All 3 4 9 data preceded the Omicron wave of the pandemic. Further data on possible increased 3 5 0 susceptibility and severe outcomes in infants secondary to the Delta and Omicron VOC will be needed. This study is also limited by the voluntary nature of reporting in the CPSP system, and therefore, 3 5 3 we have not captured data on every infant who tested positive for SARS-CoV-2 in Canada, nor 3 5 4 infants who were infected but for whom parents did not seek health care. Under-reporting of 3 5 5 outpatient cases may have also caused an information bias in comparison between hospitalized 3 5 6 and non-hospitalized patients, likely leading to over-estimation of the proportion of infants who 3 5 7 require hospitalization for COVID-19. For cases diagnosed in the first days of life, we were also 3 5 8 unable to differentiate SARS-CoV-2 infection acquired congenitally versus postnatally, and the 3 5 9 possible impact of the method of transmission on disease severity in infants. Although we 3 6 0 described the distribution of cases by population group, we are unable to draw any conclusions 3 6 1 because this variable was reported by physicians, and not by families. Lastly, we were unable to 3 6 2 obtain information on the vaccination status or prior infection of the infants' mothers. Our study has shown that SARS-CoV-2 infection prior to the Omicron wave generally causes 3 6 6 mild illness in infants, but that comorbid conditions and younger age were associated with 3 6 7 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. characteristics associated with severe disease in young infants may inform the clinical his guidance and support, as well as the members and leadership of the Paediatric Inpatient Research Network (PIRN) for cases reported. We thank Lorraine Piché for her assistance at the Montreal Children's Hospital site. Lastly, the authors also wish to thank members of the CPSP All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 4, 2022. ; a t r i c I n f e c t i o u s D i s e a s e s , D e p a r t m e n t o f P e d i a t r i c s , M o n t r e a l C h i l d r e n ' s H o s p i t a l , M o n t r é a l , Q u e . D i v i s i o n o f M i c r o b i o l o g y , D e p a r t m e n t o f C l i n i c a l L a b o r a t o r y M e d i c i n e , M c G i l l U n i v e r s i t y H e a l t h C e n t r e , M o n t r é All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Sanofi Pasteur and AbbVie, and speaker fees from AbbVie and AstraZeneca, all outside of the 3 9 1 submitted work. MS is supported via salary awards from the BC Children's Hospital Foundation, 3 9 2 the Canadian Child Health Clinician Scientist Program and the Michael Smith Foundation for 3 9 3 Health Research. MS has been an investigator on projects funded by GlaxoSmithKline, Merck, 3 9 4 Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his 3 9 5 institute, and he has not received any personal payments. PPPR has been co-investigator on an 3 9 6 investigator-led project funded by Pfizer that is unrelated to this study. RP is a consultant for 3 9 7 Verity Pharmaceuticals. SKM is co-principal investigator on an investigator-led grant from 3 9 8 Pfizer, has served on an ad-hoc advisory boards for Pfizer and Sanofi Pasteur, and has received 3 9 9 speaker fees from GlaxoSmithKline, all unrelated to this study. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 4, 2022. ; https://doi.org/10.1101/2022.02.02.22270334 doi: medRxiv preprint Table 2 . Symptoms, laboratory findings, and clinical syndromes of infants with SARS- 4 1 9 CoV-2 infection All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. A n y r e s p i r a t o r y s u p p o r t r e q u i r e d , n ( % ) ---------2 3 ( 1 6 . 3 ) L o w -f l o w o x y g e n ---------1 5 ( 1 0 . 6 ) H i g h -f l o w n a s a l c a n n u l a ---------5 ( 3 . 5 ) N o n -i n v a s i v e v e n t i l a t i o n ------ All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. C a s e s o c c u r r i n g b e f o r e D e c e m b e r 2 6 , 2 0 2 0 ( i . e . f i r s t c a s e o f c o n f i r m e d A l p h a i n C a n a d a ) w e r e a s s u m e d a s ' n o t a c o n f i r m e d V O C ' . C a s e s w i t h n o V O C s c r e e n i n g a n d o c c u r r i n g o n o r a f t e r D e c e m b e r 2 6 , 2 0 2 0 ( n = 1 1 9 ) w e r e a l s o a s s u m e d a s ' n o t a c o n f i r m e d V O C ' . E x c l u d i n g t h e l a t t e r c a s e s f r o m t h e m u l t i v a r i a b l e a n a l y s i s d i d n o t m e a n i n g f u l l y c h a n g e t h e All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State Clinical Characteristics of Coronavirus Disease 2019 in China SARS-CoV-2-Associated Deaths Among Persons Aged 21 Years -United States COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy. Pediatrics All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance The Lancet Child & Adolescent Health Leung C. The younger the milder clinical course of COVID-19: Even in newborns? Pediatr Allergy Immunol SARS-CoV-2 Infection in Infants Less than 90 Days Old Clinical Characteristics and Disease Severity Among Infants With SARS-CoV-2 Infection in Montreal The differential impact of pediatric COVID-19 between high-income countries and low-and middle-income countries: A systematic review of fatality and ICU admission in children worldwide Coronavirus Disease 2019 in Children -United States Clinical experience with SARS CoV-2 related illness in children -hospital experience in Cape Town, South Africa No reuse allowed without permission. 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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine High antibody levels in cord blood from pregnant women vaccinated against COVID-19 Vaccinations Among Pregnant People ICES COVID-19 Dashboard Two seriously ill neonates born to mothers with COVID-19 pneumonia-a case report Respiratory Failure in an Extremely Premature Neonate with COVID-19 COVID-19 in a premature infant COVID-19 in a 26-week preterm neonate No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted Effect of the new SARS-CoV-2 variant B.1.1.7 on children and young people Estimating the Prevalence and Growth of SARS-CoV-2 Variants in Ontario using Mutation Profiles. Enhanced Epidemiological Summary No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity