The Impact of Obesity on Disease Severity and Outcomes Among Hospitalized Children with COVID-19.

Abstract

Objective: To describe the impact of obesity on disease severity and outcomes of COVID-19 among hospitalized children. Methods: This retrospective cohort study from the SCCM VIRUS registry included all children hospitalized with COVID-19 from 3/2020 to 01/2021. Obesity was defined by CDC Body Mass Index or WHO weight for length criteria. Critical Illness definition adapted from NIH criteria of critical COVID. Multivariate mixed logistic and linear regression was performed to calculate the adjusted odds ratio (aOR) of critical illness and the adjusted impact of obesity on hospital length of stay (LOS). Results: Data from 795 patients (96.4% U.S.) from 45 sites were analyzed, including 251 (31.5%) with obesity and 544 (68.5%) without. A higher proportion of patients with obesity were adolescents, of Hispanic ethnicity and had other comorbidities. Those with obesity were also more likely to be diagnosed with MIS-C (35.7% vs. 28.1%, p= 0.04) and had higher ICU admission rates (57% vs. 44%, p<0.01) with more critical illness (30.3% vs. 18.3%, p<0.01). Obesity had more impact on acute COVID-19 severity than on MIS-C presentation. The aOR for critical illness with obesity was 3.11 (95% CI 1.8, 5.3). Patients with obesity had longer adjusted LOS (exp parameter estimate 1.3 (95% CI 1.1, 1.5) compared to patients without obesity but did not have increased mortality risk due to COVID-19 (2.4% vs. 1.5%, p=0.38). Conclusion: In a large, multi-center cohort, a high proportion of hospitalized children from COVID-19 had obesity as comorbidity. Furthermore, obesity had a significant independent association with critical illness. Introduction Coronavirus disease 2019 (COVID-19), the disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), affects children and adults of all ages. Although children had generally milder symptoms than adults during the global COVID-19 pandemic, some children developed severe disease requiring hospitalization or critical care.1,2 Obesity has been highlighted in the adult literature as an independent risk factor for severity of illness, hospital admissions, and mortality.3,4-6, 7 Among children with COVID-19, a recent meta-analysis describing the effects of comorbidities on disease severity estimated the relative risk of more severe disease as 2.8 (95% CI 1.1, 7.0) in children with obesity. However, this analysis was performed on a small subset of by guest on August 8, 2021 www.aappublications.org/news Downloaded from studies, including fewer than 64 children with obesity and severe disease.8 Young adults with obesity have also been shown to have higher mortality from COVID-19.9 Obesity has been described as a state of chronic inflammation that is often associated with other comorbidities like asthma, diabetes, hypertension, etc.10 This inflammatory state may also affect the host response to SARS-CoV-2 infection adversely and place them at a higher risk of poor outcomes.11 Globally, 41 million children under five years of age are estimated to be affected by obesity or overweight, according to the World Health Organization (WHO).12 The United States (U.S.) is particularly affected by this epidemic, with 18% of U.S. children diagnosed with obesity and 6% with severe obesity.13,14 Elucidating to what degree obesity affects COVID-19 severity in a larger, multi-center cohort of children can help guide prevention, prognostication, and clinical care. This study s primary objective was to describe and compare the clinical presentation, disease course, and outcomes in children with and without obesity requiring hospital admission for the treatment of COVID-19. Our secondary objective was to determine the association between obesity and critical illness with COVID-19. Methods Study design, Population, and Setting This was a retrospective study of patients enrolled in the Viral Respiratory Illness Universal Study (VIRUS) registry). This international VIRUS registry was established by the Society of Critical Care Medicine (SCCM) at the onset of the COVID-19 pandemic15 and now includes >60,000 patients (of all ages) from 306 centers in 28 countries.16 The study protocol was reviewed and approved by the Institutional Review Board at [institution name redacted for review] and all participating centers. The study population included all patients (<18 by guest on August 8, 2021 www.aappublications.org/news Downloaded from years) admitted to the participating hospitals (including those admitted and transferred to the ICU) with SARS-CO-V-2 infection from 03/20 to 01/21. Patients with incidental COVID-19 diagnoses were excluded from the registry. Incidental diagnosis included patients with positive results for SARS-CoV-2 on routine screening or admission diagnosis not related to SARS-CoV2, at the discretion of the site investigators. We further excluded patients who had missing essential demographic data (weight, sex) and incomplete outcome variables (hospital discharge status, hospital length of stay [LOS]). Patients with missing body mass index (BMI) and weight for height percentiles were also excluded. There is possibility of significant overlap between the patients included in this manuscript and those already reported in the literature. Therefore, in keeping with current reporting recommendations, 17 we have provided details of manuscripts that may contain overlapping patients. (SDC A) Measurements Demographic (age, gender, race/ethnicity), clinical characteristics, management, and outcome variables were extracted from the VIRUS REDCap database.18 Race and ethnicity were included in the analysis as a social construct due to their complex relationship with socialeconomic disparities in healthcare access.19 Age was stratified into discrete categories; neonate (≤28 days), infant (28 days to <2 years), child (2 to <12 years), and adolescent (≥12 years).20 BMI percentiles for children ≥ 2 years of age were calculated based on Centers for Disease Control (CDC) SAS codes21; while the weight for length percentiles for children <2 years of age were calculated based on WHO SAS codes.22 Categorization of underweight, normal, overweight, and obese were defined by CDC criteria for ≥ 2 years (< 5th, 5th to <85th, 85th to <95th and ≥95th BMI percentiles respectively),23 and WHO weight for length percentile criteria of by guest on August 8, 2021 www.aappublications.org/news Downloaded from +2 and +3 standard deviations above the median.24 Children, ≥ 2 years of age, with a BMI ≥120% of the BMI 95th percentile, were classified as having severe obesity.21 Presenting signs and symptoms, comorbidities, and COVID-19 related complications were categorized into organ system groups and compared independently and as organ systems. Patients with ≥3 organ system involvement (presenting signs and symptoms in different organ systems), and ≥2 comorbidities were identified. Patients with evidence of other respiratory viral infections were categorized as viral co-infection. Patients with concurrent blood, urine, and bacterial respiratory infections were combined into categories of bacterial co-infection . Diagnosis of Multisystem Inflammatory Syndrome in Children (MIS-C) was made by the individual sites based on the CDC definition25 and was not further adjudicated for this analysis. Outcomes The outcome measures of hospital length of stay (LOS) and mortality were determined at discharge. Critical illness was defined as a composite index of in-hospital mortality and organ support requirements defined as a need for one or more of the following: 1) positive pressure ventilation (invasive or non-invasive), 2) vasoactive – inotropic support, 3) pulmonary vasodilator therapy (inhaled nitric oxide, epoprostenol), 4) extracorporeal life support (ACLS) and/or 5) new renal replacement therapy (Acute Dialysis or Continuous Renal Replacement Therapy [CVVH]). This classification was modified from the National Institute of Health (NIH) definition of critical COVID-19 26 and was previously described by our group.2 Statistical analysis Standard descriptive statistics were performed for continuous and categorical variables and reported as median with Inter Quartile Range (IQR) and number with percentages. The nonparametric Wilcoxon rank-sum test and Chi-square/Fisher’s exact test were used as by guest on August 8, 2021 www.aappublications.org/news Downloaded from appropriate. Multivariable logistic regression was performed to assess the risk factors associated with critical illness for the whole cohort and independently for patients with obesity. The odds ratio and 95% confidence interval (95% CI) were calculated. A mixed logistic regression that included a random effect for the site was used to determine potential risk factors associated with an increased likelihood of critical illness after controlling for the impact of other risk factors. The potential confounders with exposure and critical illness were a priori defined for inclusion in the model. These variables were selected based on the theoretical understanding of their impact on critical illness and hospital length of stay and their interaction with obesity. A Directed Acyclic Graph (DAG) was created to represent the causal relationships using standard terminology and rules as described before. 27,28 (SDC B) Age (adolescent and non-adolescent), race (Black, White and others/unknown), ethnicity (Hispanic, non-Hispanic, other/unknown), sex, and ≥ 2 comorbidities were included in the model. Potential interaction between obesity and age (adolescent versus not) was also assessed. Patients with obesity were separately analyzed with a similar model to identify the association with critical illness in that subset of patients. A multivariable mixed linear regression, with a random intercept for the site, was also performed to assess the association of obesity with hospital LOS after adjusting for confounders (described above with added inclusion of country). Due to non-nor