key: cord-0753832-gy3s0t7f
authors: Chambers, Melissa A.; Mecham, Cherisse; Arreola, Elsa Vazquez; Sinha, Madhumita
title: Rise in Pediatric New Onset Diabetes and Diabetic Ketoacidosis During the COVID-19 Pandemic
date: 2022-02-18
journal: Endocr Pract
DOI: 10.1016/j.eprac.2022.02.005
sha: 8cc8a8b76ea365461ab0f037dfcc7513cd9cd6c0
doc_id: 753832
cord_uid: gy3s0t7f

OBJECTIVE: Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces a proinflammatory state that causes hyperglycemia and may precipitate diabetic ketoacidosis (DKA) in patients with known or new-onset diabetes. We examined the trends in new-onset diabetes and DKA prior to and following the onset of the COVID-19 pandemic. METHODS: This single center retrospective observational study included pediatric patients (0-<18 years) hospitalized with new-onset type 1 (T1D) or type 2 (T2D) diabetes pre- (March 1, 2018 - February 29(th), 2020) and post-pandemic onset (March 1(st), 2020 – December 31(st), 2020). Demographic, anthropometrics, laboratory and clinical data, and outcomes were obtained. RESULTS: Among 615 children admitted with new onset diabetes during the entire study period, 401 were admitted pre- and 214 post-pandemic onset. Children admitted with new-onset diabetes in the post-pandemic period were significantly more likely to present with DKA (OR=1.76, 95% CI: 1.24, 2.52) compared to the pre-pandemic phase. Children with DKA post-pandemic, had higher lengths of hospitalization and were significantly more likely to experience severe DKA (OR=2.17, 95% CI: 1.34, 3.52). A higher proportion of children with DKA admitted to the PICU required oxygen support post-pandemic compared to pre-pandemic (8.85% vs 1.92%). Most cases of T2D with DKA occurred following the onset of the pandemic (62.5%) CONCLUSION: A significant rise in T2D cases occurred following the onset of the COVID-19 pandemic with a greater risk for DKA and severe ketoacidosis. Racial disparity was evident with a higher proportion of Black and American Indian children presenting with ketoacidosis following the pandemic onset.

The first reported cases of COVID-19 caused by infection with the severe acute respiratory 48 syndrome coronavirus-2 (SARS-CoV-2) were from Wuhan, China. However, with the rapid 49 global spread of the novel coronavirus infection, the World Health Organization (WHO) 50 declared COVID-19 a pandemic in March 2020. 1 During the early phases of the pandemic, rates 51 of COVID-19 among children were lower, and disease manifestation was less severe, than in 52 adults both in the United States (US) and globally. 2-5 Almost 18 months have elapsed since then, 53 and pediatric cases and hospitalizations are now on the rise in the US likely due to the surge in 54 the highly contagious B.1.617.2 (Delta) variant of the SARS-CoV-2. 6, 7 55

Unlike in the adult population, there is yet no clear evidence that children with known 56 diabetes are at an increased risk from COVID-19 related hospitalization compared to the general 57 pediatric population. 8 However, in a prior study among children with serious COVID-19 58 admitted to forty-six pediatric intensive care units (PICU) across North America, 84% of these 59 critically ill children suffered from underlying comorbidities. 9 Among them, obesity was an 60 important comorbidity, especially in older children, and diabetes was prevalent in 8% of patients 61 in this PICU cohort. 9 Several recent studies have also shown a rise in severity at presentation of 62 prior to the onset of the COVID-19 pandemic (pre-COVID-19 group), and the second group 94 included those patients who were admitted after March 1 st , 2020 following the onset of the 95 COVID-19 pandemic (post-COVID-19 onset group). Although the official declaration of the 96 COVID-19 pandemic by WHO's Director-General occurred on March 11 th 2020, 1 in this study 97

we have included all new-onset diabetes cases presenting on March 1 st , 2020 or later, in the post-98 COVID-19 onset group. To assess temporal trends in cases on new-onset diabetes and DKA, the 99 time periods at presentation were reported in quarterly intervals. 100

On inpatient admission of a new-onset diabetes patient, diabetes type was determined 101 based on standard criteria. 20 A diagnosis of T1D was made if a patient showed the presence of 102 pancreatic islet cell autoantibodies. A patient with a negative Insulinoma-Associated-2 103

Autoantibodies (IA-2A) antibody and glutamic acid decarboxylase 65-kilodalton isoform 104 (GAD65) antibody was suspected as a T2D case. If GAD65 and IA-2 were negative, then 105 additional confirmatory testing was performed in the outpatient setting with testing for Zinc 106

Transporter-8 Autoantibodies (ZnT8A), Insulin Autoantibodies (IAA) and Islet Cell Cytoplasmic 107 Autoantibodies (ICA). A final diagnosis of T2D was made if these antibodies tested negative and 108 clinical phenotype and family history was consistent with T2D. 20 Testing for maturity-onset 109 diabetes of the young (MODY, a form of inherited diabetes caused by impairment of insulin 110 production that is not autoimmune in nature) 21 was performed on a case-by-case basis if clinical 111 (presentation and/or family history) or biochemical evidence suggested possible presence. These 112 children were removed from the data set and are not included in our current analysis. mmol/L) and its severity [mild (venous pH 7.2-7.3), moderate (venous pH 7.1-7.2), and severe 117 DKA (venous pH <7.1)]. 22 The study was approved by the Institutional Review Board. 118

Demographic and clinical characteristics were summarized as means and standard 120 deviations (SD) or medians and inter-quartile ranges (IQR: Q1-Q3) for non-Gaussian variables. 121

We compared means using the unpaired Student's t test, and medians using the Mann-Whitney 122 test. Categorical variables were summarized using frequency distributions and were compared 123 using the Chi-square test or Fisher's exact method. A multivariable logistic regression model was 124 fit to determine whether time of hospitalization with new-onset diabetes (before or after onset of 125 pandemic) associated with presence or absence of DKA in the whole cohort (children admitted 126 with new-onset diabetes). A separate logistic regression model was fit in patients admitted with 127 new-onset diabetes and DKA to determine whether time of hospitalization associated with 128 presence or absence of severe DKA (venous pH <7.1). Adjusted odds ratio (OR) for presence of 129 DKA and its severity were calculated with 95% confidence intervals from these models. All 130 analyses were performed using SAS. A two-sided p-value <0.05 was considered statistically 131 significant. 132

There were 619 children admitted to our institution with new-onset diabetes, T1D or 135 Table 1 presents descriptive statistics for the whole cohort stratified by admission period (before 146 or after onset of the COVID-19 pandemic). Figure Tables 1 and 2) . 181 Table 2 shows the descriptive statistics for demographic and clinical characteristics for Table 3 Table 4 ) onset of the COVID-19 pandemic 228 was compared. In both time-periods, children with new-onset T2D were significantly older and 229 had higher BMI, and weight for age z-score. Race/ethnicity significantly associated with diabetes was significantly lower for children with T2D than for children with T1D (p=0.0268). There was 232 a significant association between diabetes type and DKA severity after the onset of the pandemic 233 (p=0.0105); the percentages of mild DKA were similar for both types of diabetes, while the 234 percentage of moderate DKA was lower in T1D than in T2D (18% vs 43%), and the percentage 235 of severe DKA was higher in T1D than in T2D (52% vs 27)%. In this retrospective study, we observed an alarming rise in cases of new onset T2D and 249 DKA in a pediatric cohort admitted to a children's hospital in the southwestern US following the 250 outbreak of the COVID-19 pandemic. DKA severity was also higher during the post-pandemic 251 phase. Children with new onset diabetes and DKA admitted for inpatient management following 252 the pandemic onset, presented with more profound acidosis, required vasopressors more frequently, had a higher need for oxygen supplementation, and experienced a significantly longer 254 period of hospitalization compared to the pre-pandemic cohort. The relationship between 255

the SARS-CoV-2 in patients with known diabetes may result in a higher rate of complications 257 and precipitate ketoacidosis that is primarily due to its negative effects on β-cell function. pandemic onset DKA group also exhibited higher adiposity and had higher glycated hemoglobin 280 levels indicating longer exposure to hyperglycemia prior to presentation that could be due to 281

higher baseline obesity prevalence, as well as a delay in seeking care or other factors related to 282 health disparities that is often pervasive in vulnerable populations. With the sudden advent of a 283 catastrophic public health crisis, the COVID-19 global pandemic, we can only speculate that 284 these disparities and health inequities may have been further accentuated that subsequently led to 285 a higher number of children presenting with DKA and severe ketoacidosis. 286

Our study has limitations, this is a single center study, and the study population due to its 

WHO Director-General's opening remarks at the media briefing on COVID-19 -11

Coronavirus Disease 2019 in Children -United States

Epidemiological characteristics of 2143 pediatric patients with 309 2019 coronavirus disease in China

Chinese Pediatric Novel Coronavirus Study Team. SARS-CoV-312 2 infection in children

Coronavirus Infection in Pediatric Emergency Departments 314 (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency 315 Departments in Italy

Trends in COVID-19 Cases

Initial Presentation of Children with Type 348 2 Diabetes during the COVID-19 Pandemic

COVID-19 cases, data, and surveillance: hospitalization and death by race/ethnicity

Association between race and COVID-19 outcomes 355 among 2.6 million children in England

Diabetic Ketoacidosis Among Patients

With Type 1 Diabetes and COVID-19: Data From 52 US Clinical Centers

Racial/Ethnic Minority Youth With Recent-Onset 361 diabetes in children and adolescents

ISPAD Clinical Practice Consensus Guidelines 2018: 371 Diabetic ketoacidosis and the hyperglycemic hyperosmolar state

COVID-19 in people with diabetes: 374 understanding the reasons for worse outcomes

Endocrine and metabolic link 377 to coronavirus infection

SARS-CoV-2 infects human pancreatic β cells and elicits 379 β cell impairment

Incidence trends of type 1 and type 2 381 diabetes among youths

Prevalence of diabetes in U.S. youth in 2009: the 383 SEARCH for Diabetes in Youth Study

Social determinants of health and diabetes: a 385 scientific review