COVID-19-related school closing aggravate obesity and glucose intolerance in pediatric patients with obesity

It is important to pay attention to the indirect effects of the social distancing implemented to prevent the spread of coronavirus disease 2019 (COVID-19) pandemic on children and adolescent health. The aim of the present study was to explore impacts of a reduction in physical activity caused by COVID-19 outbreak in pediatric patients diagnosed with obesity. This study conducted between pre-school closing and school closing period and 90 patients aged between 6- and 18-year-old were included. Comparing the variables between pre-school closing period and school closing period in patients suffering from obesity revealed significant differences in variables related to metabolism such as body weight z-score, body mass index z-score, liver enzymes and lipid profile. We further evaluated the metabolic factors related to obesity. When comparing patients with or without nonalcoholic fatty liver disease (NAFLD), only hemoglobin A1c (HbA1c) was the only difference between the two time points (p < 0.05). We found that reduced physical activity due to school closing during COVID-19 pandemic exacerbated obesity among children and adolescents and negatively affects the HbA1C increase in NAFLD patients compared to non-NAFLD patients.


Materials and methods
Patients and data collection. This study was a retrospective observational study conducted at the Department of Pediatrics of Samsung Medical Center between December 2019 and May 2020. The subjects were pediatric patients with obesity who attended school between aged 6 and 18, and visited the outpatient clinic at least twice before and during school closing period due to COVID-19 outbreak. During the study period, subjects were all at their homes because their school program was suspended due to COVID-19 outbreak. It was assumed that pre-school closing was from December 2019 to February 2020 and school closing was from March 2020 to May 2020. Patients were identified through a search of our electronic medical records system. In the database search, we identified 179 school-aged patients diagnosed with obesity and the number of patients visited outpatient clinic at least twice before and after social distancing was 127. Then, 37 patients were excluded because of alternative etiologies for elevated liver enzymes, and 90 patients were eligible for analysis finally (Fig. 1).
Demographic and clinical data including sex, age, body weight, height, and BMI were collected before and after school closing. BMI was calculated as weight/height 2 (kg/m 2 ). Z-scores for body weight and BMI were calculated based on the 2017 Korean National Growth Charts for children and adolescents 18 . Data at each visit to the outpatient clinic were collected retrospectively from electronic charts and laboratory results, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, uric acid, cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and HbA1c. We compared data between pre-school closing and during school closing and also according to the presence of NAFLD.
Definitions. Obesity was defined as a BMI above the 95th percentile in children and adolescents in accordance with the Committee on Pediatric Obesity of the Korean Society of Pediatric Gastroenterology Hepatology and Nutrition 19 . NAFLD was diagnosed by excluding alternative etiologies for elevated ALT and/or hepatic steatosis, such as medication (amiodarone, glucocorticoids, L-asparaginase, valproic acid) and the presence of coexisting chronic liver disease including Wilson's disease, type 1 diabetes mellitus, hepatitis B, and hepatitis C 20 . It is important to note that not all pediatric patients with obesity and chronic elevated liver enzymes are classified as NAFLD. The gold standard for establishing a NAFLD diagnosis is liver biopsy; however, there are the serious limitations to liver biopsy in pediatric patients in the real-world setting. Therefore, NAFLD was diagnosed based on three conditions; elevated ALT (> 50U/L in boys, > 44 U/L in girls) 21 , increased brightness of the liver parenchyma compared to the kidney in liver ultrasonography conducted by one pediatric radiology specialist 20 , and excluding other etiologies for hepatic steatosis as described above 22 .  tile range (IQR) or mean with standard deviation and for categorical variables with frequency and percentages. The analysis of variance (ANOVA) test was used to compare continuous variables while the chi-square test was used for discrete variables. We used paired t-tests to evaluate the significance of changes from pre-school closing to school closing period. In addition, we tested the significance of differences between patients with and without NAFLD in response to changes using independent two-sample t-tests. Statistical significance was defined as p < 0.05. Statistical analyses were performed using Rex (Version 3.0.3, RexSoft Inc., Seoul, Korea).

Ethics declarations. This study was approved by the Institutional Review Board of the Samsung Medical
Center and was conducted in accordance with the Declaration of Helsinki 23 . All patients and parents and/or legal guardian of subjects who are under 18 provided written informed consent. We confirmed that all methods were performed in accordance with the approved guidelines and regulations. We reported and presented data according to the STROBE statement.

Results
Baseline characteristics. During the period from December 2019 to May 2020, a total of 90 pediatric patients with obesity visited the clinic at least two times between the pre-school closing and during school closing period. Table 1 shows descriptive characteristics of subjects at baseline. The mean age of patients at preschool closing was 12.2 ± 3.4 years and 70 patients (77.8%) were male. The median interval between first visit of outpatient clinic (pre-school closing) and second visit (during school closing) was 4.3 months. Mean body weight z-score was 2.0 and mean BMI z-score was 1.9. At baseline, 53 (58.9%) subjects had NAFLD, 10 (11.1%) had type 2 diabetes mellitus, and 14 (15.6%) had dyslipidemia. In addition, statin usage was observed in 13 subjects (14.4%), metformin usage was in 10 subjects (11.1%), and insulin usage was in 1 subject (1.1%), which was maintained during the study period. Other baseline demographics and clinical characteristics, as well as data collected at diagnosis, are summarized in Table 1.
Comparison of variables between pre-school closing and during school closing in patients with obesity. We investigated the changes in growth in weight, height, and BMI and other laboratory results  Fig. 2A). There were no statistically significant differences between the two time points in mean blood pressure (MBP), uric acid, HDL, and HbA1c. Detailed comparison results are presented in Table 2.  (Table 3). Other detailed comparison results are presented in Table 3.

Comparison of variable differences between patients with and without NAFLD.
We also compared incremental change (delta value) in each variable at the two time points of pre-school closing and during school closing according to the presence of NAFLD. The delta values were calculated by subtracting the value of the pre-school closing from the value of the school closing period. Comparison of the delta values between patients with or without NAFLD revealed significant difference in only HbA1c levels at  There were no other significant differences between the two time points in the NAFLD and non-NAFLD groups (Table 4 and Fig. 2B).

Discussion
To date, most studies have described the relationship between life style behaviors affected by COVID-19 and weight gain based on questionnaires, however there is scarce data about children and adolescents [24][25][26][27][28][29] . As far as we know, this is the first study to objectively investigate the indirect impact of COVID-19 pandemic on metabolic problems in pediatric patients with obesity using laboratory results. In this study, the results show that COVID-19 pandemic has had a substantial negative impact on the health in pediatric patients with obesity and its comorbidities regardless of infection status of COVID-19. As a result of the current situation in which almost all people, even children and adolescents, are confined to their homes, physical activity drastically declined while dietary habits remained unchanged or failed to offset physical inactivity. We show that reduced physical activity caused by school closing in COVID-19 pandemic era could lead to a rapid decline in metabolic homeostasis. Notably, during the school closing period, there were remarkable increases in Table 3. Comparison of variables according to the presence of NAFLD between pre-school closing and during school closing period. BMI body mass index, NAFLD non-alcoholic fatty liver disease, AST aspartate transferase, ALT alanine transferase, HDL high-density lipoprotein, LDL low-density lipoprotein, HbA1c hemoglobin A1c.

Pre-school closing
School closing

NAFLD (n = 53) Non-NAFLD (n = 37) p value NAFLD (n = 53) Non-NAFLD (n = 37) p value
Age ( Table 4. Comparison of difference in each variable at pre-school closing and during school closing according to the presence of NAFLD. delta, △ Subtracting the value of the pre-social distancing from the value of the social distancing period, BMI body mass index, NAFLD non-alcoholic fatty liver disease, MAP mean arterial pressure, AST aspartate transferase, ALT alanine transferase, HDL high-density lipoprotein, LDL low-density lipoprotein, HbA1c hemoglobin A1c.  www.nature.com/scientificreports/ body weight, BMI, and laboratory results related to metabolic disease, such as AST, ALT, triglyceride, and LDL, which were statistically significant (p < 0.05).
In results according to the presence of NAFLD, NAFLD group had significantly higher MBP and HbA1c levels relative to non-NAFLD group during school closing period, which is consistent with other existing studies that reported children affected by obesity and NAFLD had a higher cardiovascular and metabolic risk, including hypertension 30,31 . In Table 2, HbA1c did not seem to change between before and during school closing; however, when subgroup analysis was performed with or without NAFLD, difference of HbA1c was significantly confirmed between the two time points (Table 3). Furthermore, in accordance with previous studies, children with NAFLD were more susceptible to increases in HbA1c than non-NAFLD pediatric patients caused by reduced physical activity during COVID-19 pandemic (p < 0.05) 16 . In other words, NAFLD may be an important predisposing factor in pediatric patients with obesity for the development of glucose intolerance, especially in environments with reduced physical activity 16,32 .
These observations not only recommend that patients with obesity do physical activities such as home training to the extent possible during school closing, but also emphasize that family members and pediatricians should pay attention to the lifestyle of pediatric patients with obesity. Although further studies in post-school closing are needed, aggravated obesity and other metabolic diseases during out-of-school circumstances may not be easily reversible and might contribute to excess adiposity and cardiometabolic or non-cardiometabolic comorbidities, which can persist into adulthood 2,19,33 .
Previous research has demonstrated that children gained significantly more body weight and showed increased BMI during out-of-school periods 5,6,[8][9][10][11][12] . Some studies have suggested that individual weight gain during the holiday period was quite variable; however, this period is more important especially for those who have already been diagnosed with obesity 9,11 . Our findings are consistent with those of recent studies and indicate that out-of-school circumstances, such as school closing caused by COVID-19 outbreak, contribute to childhood and adolescent obesity and its comorbidities caused by low physical activity level.
The strength of this study is that body weight, BMI, and laboratory results associated with metabolic disease were objectively compared between two time points, pre-school closing and during school closing. On the other hand, our study has some limitations. First, as a retrospective study, it has certain limitations compared to a prospective design. However, all patients attended an outpatient clinic at least two times between pre-school closing and school closing periods and the extraction of objective clinical and biochemical results from the medical records was possible. Second, the lack of information about subject diet and exercise time is a limitation; however, such information is subjective, thus eliminating potential bias was possible in this study. Third, selection bias may have been introduced as patients who had not visited twice between the two time points were excluded from this study. Therefore, further well-designed prospective post-social distancing studies are required to address these limitations.
In conclusion, we found that reduced physical activity due to social distancing during COVID-19 pandemic exacerbated obesity among school-aged children and adolescents and negatively affects the HbA1C increase in NAFLD patients compared to non-NAFLD patients. These results lend support to the fact that physical activity is important in the prevention and treatment of obesity. Therefore, physicians should pay attention to life style modification as well as pharmacotherapy and surgery in pediatric patients with obesity. Moreover, physicians should carefully monitor the development of glucose intolerance in pediatric NAFLD patients during physical inactivity periods caused by school closing during COVID-19 pandemic.