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Comorbidities increase COVID‐19 hospitalization in young people with type 1 diabetes

Abstract Objectives We evaluated COVID‐19 outcomes in children and young adults with type 1 diabetes (T1D) to determine if those with comorbidities are more likely to experience severe COVID‐19 compared to those without. Research Design and Methods This cross‐sectional study included questionnaire data on patients <25 years of age with established T1D and laboratory‐confirmed COVID‐19 from 52 sites across the US between April 2020 and October 2021. We examined patient factors and COVID‐19 outcomes between those with and without comorbidities. Multivariate logistic regression analysis examined the odds of hospitalization among groups, adjusting for age, HbA1c, race and ethnicity, insurance type and duration of diabetes. Results Six hundred fifty‐one individuals with T1D and COVID‐19 were analyzed with mean age 15.8 (SD 4.1) years. At least one comorbidity was present in 31%, and more than one in 10%. Obesity and asthma were the most frequently reported comorbidities, present in 19% and 17%, respectively. Hospitalization occurred in 17% of patients and 52% of hospitalized patients required ICU level care. Patients with at least one comorbidity were almost twice as likely to be hospitalized with COVID‐19 than patients with no comorbidities (Odds ratio 2.0, 95% CI: 1.3–3.1). This relationship persisted after adjusting for age, HbA1c, race and ethnicity (minority vs nonminority), insurance type (public vs. private), and duration of diabetes. Conclusions Our findings show that comorbidities increase the risk for hospitalization with COVID‐19 in children and young adults highlighting the need for tailored COVID‐19 prevention and treatment strategies in T1D.

primarily causes lower respiratory tract infections, and clinical manifestations are diverse, ranging from no symptoms to fever, cough, and dyspnea or gastrointestinal symptoms to severe respiratory compromise. Severe COVID-19 has been defined as infection requiring inpatient care for treatment and respiratory support. 1 The few reports on outcomes for children or adults with type 1 diabetes (T1D) are mixed in terms of severity of disease and mortality compared to people without diabetes. [2][3][4][5][6] For adults with type 1 diabetes (T1D), having a co-existing medical diagnosis such as cardiovascular disease, hypertension, or renal disease increases the risk of suffering from severe COVID-19 and adverse outcomes. 4,5,[7][8][9][10][11] However, few published studies examine the relationship between comorbidities and severity of COVID-19 infection in children with T1D.
While most children with COVID-19 either experience mild or no symptoms, severe complications including acute respiratory distress syndrome (ARDS), multisystem inflammatory syndrome (MIS-C) and death can occur. [12][13][14][15][16] A meta-analysis found that children with underlying chronic conditions were at increased risk of severe COVID-19 and mortality. 17 Obesity was the most prevalent diagnosis in this cohort and was independently associated with an increased risk of severe COVID-19. Children with asthma are also suggested to have an increased risk of severe COVID-19. 18 As obesity and asthma have been proposed risk factors for severe COVID-19 in children, it is possible these comorbidities increase the risk of hospitalization for children with T1D who develop COVID-19. We evaluated characteristics and outcomes of  in children, adolescents, and young adults (AYA) with T1D to determine if children and AYA with established T1D and comorbidities are more likely to experience severe COVID-19 compared to those without comorbidities.

| METHODS
The T1D Exchange QI Collaborative, 19 20 The questionnaires collected deidentified data using 33 pre-coded and free text questions, and the complete questionnaire is available in Appendix 1. The coordinating center reviewed questionnaires for possible errors in data entry or incomplete information and performed random data validation for quality assurance. Details of the questionnaire and data from the T1D COVID-19 registry have been previously reported. 12,21-26

| Inclusion criteria
All patients submitted by participating centers with COVID-19 and T1D ages 0-24 years at time of reporting were included in this study.
Emerging adults ages 19-24 years were included in this analysis because many pediatric endocrinology clinics follow patients through this age, and explore how this population is affected by COVID-19.
An individual was entered into the registry as COVID-19 positive if they tested positive by molecular testing (reverse transcriptionpolymerase chain reaction) from nasopharyngeal swabs, throat swabs, sputum, or other bodily fluid testing. We excluded from this analysis any patients that were newly diagnosed with T1D during their COVID-19 illness, and these cases are described separately. 23

| Comorbidities
Participating centers entered comorbidity data for each patient by selecting one or more diagnoses from a pre-populated list. The list included obesity, asthma, cardiovascular disease, other chronic lung disease, hypertension, and celiac disease, among others. There was also an opportunity to add free text or to select none.

| Primary outcome
The primary outcome was hospitalization during COVID-19 illness in individuals with known T1D as a marker of severe COVID-19. 1 As a binary outcome, hospitalization was defined as admission to general inpatient care or an intensive care unit as the highest level of care received during COVID-19 illness. Non-hospitalization was defined as receiving care in a clinic, urgent care, or emergency department setting or receiving care at home.

| Additional covariates
Patient-specific information was collected on additional variables of interest that included sociodemographic information (age, sex, and health insurance type), and diabetes characteristics (most recent HbA1c, duration of T1D, use of continuous glucose monitoring [CGM] or insulin pump). Race and ethnicity were also collected as a social construct rather than genetic or biological categories. Adverse outcomes collected included diabetic ketoacidosis (DKA), severe hypoglycemia, death, and an option to write in others.

| Statistical analyses
Descriptive statistics were used to describe the study population and summarize study data. Patient outcomes, comorbidities, and demographics were analyzed as categorical variables when appropriate. Race and ethnicity information were collected in the questionnaire as a categorical variable with potential responses including: Non-Hispanic White, Non-Hispanic Black, Asian, Hispanic, more than one race, other, or unknown per US Census criteria. 27 The race and ethnicity variable for this analysis was constructed with 4 groups: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Hispanic, and other. Health insurance type was classified as either public, private, or unknown. Duration of diabetes was collected as a categorical variable with potential responses including: less than 1 year, 1-5 years, or greater than 5 years. Use of an insulin pump and use of CGM were also analyzed as binary (yes/no) variables. The use of both an insulin pump and CGM in the same patient was analyzed separately. Patient age and last reported HbA1c value were collected and analyzed as continuous variables.
Continuous variables were analyzed using mean (SD) or median (IQR) as appropriate based on data distribution. Categorical variables were shown as the percentage of patients. p-values were calculated using the Fisher exact or chi-square tests to examine the association between the categorical variables.  Asthma affects 7% of children in the US and disproportionately affects racial and ethnic minority groups and those living in poverty. 32,33 Asthma-related morbidity and mortality also disproportionately impact NHB Americans. 34 Asthma was the second most prevalent comorbidity in this population of children, adolescents, and young adults with T1D, and it was the only independent comorbidity found to be a risk factor for hospitalization. Asthma was disproportionately present in NHB patients and those with public health insurance. When adjusted for race, ethnicity and insurance type, asthma did not maintain its significance as a risk factor for hospitalization. As this relationship between asthma and severity of COVID-19 seems to be modified by other factors, more work is needed to understand the factors underlying these social constructs influence this association.
Like studies of children hospitalized with COVID-19 who do not have diabetes, this study found obesity as the most prevalent underlying medical condition in this cohort with T1D. 13,35,36 Childhood obesity is becoming increasingly prevalent in the US, now estimated to affect nearly one in every five children and is disproportionately affecting NHB and Hispanic children. 37 In youth with T1D, most recent estimates from the T1D Exchange 38 show obesity and overweight affecting more than one in three adolescents with T1D (13.1% and 22.9%, respectively). 39 Obesity is well recognized as a risk factor for severe COVID-19 in adults, and given the rising prevalence in children, understanding how obesity impacts severity of COVID-19 illness in children is imperative. 7 Obesity was not an independent risk factor for severe COVID-19 in this study, and further case-control studies would help elucidate the effect of obesity on COVID-19 disease course in youth with T1D.
Celiac disease is more common individuals with type 1 diabetes compared those without, and has been associated with an increased susceptibility to bacterial and viral infections, and some reports have identified worse outcomes for these infections. [40][41][42] Similar to a large population-based study from Sweden, 43 this analysis found no association between Celiac disease and COVID-19 severity in this population.
Limitations of this study include its cross-sectional nature.
While we cannot identify any causation between comorbidities and severity of COVID-19 disease in young people with T1D, the demonstrated relationships do allow identification of high-risk groups.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

ETHICS STATEMENT
A central review board, the Western IRB, deemed the study as exempt. Participating sites also obtained local institutional review board approvals as appropriate.