Obesity and COVID-19 in Children and Adolescents: Reciprocal Detrimental Influence—Systematic Literature Review and Meta-Analysis

The dramatic lifestyle changes forced by COVID-19-related lockdown promoted weight gain, with a stronger impact on obese subjects, at higher risk of severe infection. The PubMed database was searched to identify original studies assessing: (1) the extent and risk factors of lockdown-induced weight increase; and (2) the impact of obesity on the risk of hospital admission in children and adolescents. A systematic literature review and meta-analyses were performed. Twenty out of 13,986 identified records were included. A significant weight increase was reported in the majority of subjects, with no apparent gender or age differences. It was induced by a higher consumption of hypercaloric/hyperglycemic/junk food and/or the reduction of physical activity, often associated with an altered sleep–wake cycle. On the other hand, obesity increased the risk of hospitalization (OR = 4.38; 95% C.I. 1.46–13.19; p = 0.009; I2 = 96%) as compared to the normal weight population. COVID-19 and obesity represent epidemic conditions with reciprocal detrimental impact. Urgent public health interventions, targeting the various age and social strata, and involving governmental authorities, health care personnel, teachers and families are warranted to increase awareness and actively promote healthy lifestyles to contrast pediatric obesity and its detrimental consequences at a global level.


Introduction
COVID-19, caused by SARS-CoV-2 infection and characterized by acute respiratory syndrome with high morbidity and mortality, was first discovered in Wuhan (China) in December 2019 and rapidly spread all over the world, becoming a pandemic [1,2].
To limit its diffusion, most of the countries adopted unprecedented restriction measures to ensure social distancing, including home quarantines and national closure of schools, working sites and other public places [3]. The generalized lockdown forced the entire population to sudden and drastic lifestyle changes and increased the perceived stress and anxiety associated with the pandemic [3].
Overall, caloric intake significantly increased, while physical activity was drastically reduced. A recent meta-analysis showed significant increases in body weight and BMI during closure among school-age children and adolescents, as well as the increase of obesity and overweight prevalence [4]. Moreover, the sleep-wake cycle was altered, with longer day sleep time and night insomnia, the latter contributing to night eating. Their combination promoted weight increase ("obesogenic environment") in adults and children [5,6].

Results
The database search retrieved 13,986 articles, including 13,845 from the PubMed search, 28 from a bibliographic search of relevant papers, and 113 from hand search. Sixty-seven were excluded as they were duplicates, while 13,752 were excluded because they were not pertinent with the review aims. Of the remaining 167,147 records were excluded because they were not original studies, or did not focus on the topic of interest, i.e., did not evaluate the impact of lockdown on obesity, or did not report the outcome of COVID-19 specifically in children or adolescents.
Finally, 20 articles were considered eligible for full-text evaluation: 14 evaluated the effect of COVID-19 lockdown on obesity (first review aim), while six focused on obesity as a risk factor for hospital/Intensive Care Unit (ICU) admission (second review aim). The PRISMA flowchart, showing the study selection process, is reported in Figure 1.
search, 28 from a bibliographic search of relevant papers, and 113 from hand search. Sixtyseven were excluded as they were duplicates, while 13,752 were excluded because they were not pertinent with the review aims. Of the remaining 167,147 records were excluded because they were not original studies, or did not focus on the topic of interest, i.e., did not evaluate the impact of lockdown on obesity, or did not report the outcome of COVID-19 specifically in children or adolescents.
Finally, 20 articles were considered eligible for full-text evaluation: 14 evaluated the effect of COVID-19 lockdown on obesity (first review aim), while six focused on obesity as a risk factor for hospital/Intensive Care Unit (ICU) admission (second review aim). The PRISMA flowchart, showing the study selection process, is reported in Figure 1.

Impact of COVID-19 Lockdown on Weight and Lifestyle in Children and Adolescents
Relevant data of the 14 studies focusing on the impact of COVID-19 lockdown on changes in weight and lifestyle in children and adolescents are summarized in Table 1.
Three (21.4%) studies reported 'changes in eating habits' associated with lockdown that consisted of a significant increase of the intake of fresh fruit, vegetables, dairy products, pasta, sweets (especially at breakfast) and snacks in the study by Androutsos et al. [21], and of pasta, bread and pizza according to Cipolla et al. [24], and in the decrease of vegetable/fruit intake in the study of Maltoni et al. [29]. Valenzise et al. [31] reported an overall increase in BMI during lockdown, although not significant, associated with an overall increase in the number of daily meals, especially in children with parents with elementary school diploma vs. high school diploma (6 ± 0.7 vs. 4.4 ± 1.3; p = 0.019).
Six (42.9%) studies reported a reduction of physical activity [21,24,26,28,29,31], together with an increase in video-gaming [24], while two (14.3%) focused on the impact of COVID-19 lockdown on sleep hygiene and demonstrated an overall increase of sleep hours [21,26]. Azoulay et al. [22] reported the positive effect on body composition associated with engagement in physical activity during the lock-down, although data on lifestyle changes (type and prevalence) were not reported.
According to Brooks et al. [23] and Hu et al. [25], children aged 8-12-years old and 6-11-years old, respectively, had a more marked increase in weight gain than adolescents. Moreover, four studies reported a higher weight increase in boys than in girls in [23,25,29,30], likely related to a more significant increase of sedentary behavior, electronic gaming and screen time, especially in younger children.
Pre-existing weight excess/obesity [23], lower socioeconomic position, a lack of health insurance/Medicaid, Black and Hispanic ethnicity increased the risk of weight increase [22,23]. In the study by Hu et al. [25], no significant differences in BMI increase associated with lockdown were detected in children living in urban and rural areas.

Figure 2.
Meta-analysis assessing the risk of hospitalization/admission to Intensive Care Units in obese children/adolescents as compared to normal weight peers. Studies are listed in alphabetical order [36][37][38].

Discussion
The aims of the present systematic literature review and meta-analysis were to assess in children and adolescents the impact of COVID-19 lockdown in promoting weight gain and obesity, on one hand, and the risk of developing severe COVID-19 disease, with consequent admission to hospital/ICU, associated with overweight/obesity on the other hand.
COVID-19 and pediatric obesity can be approached as "syndemic conditions". This notion, conceived by the medical anthropologist Merrill Singer in the 1990s, goes beyond comorbidities as it identifies conditions characterized by biological and social interactions that increase a person's susceptibility to harm or worsen health outcomes, so are important for prognosis, treatment and health policy. As the same author explained, a "syndemic approach" provides a very different orientation to clinical medicine and public health as an integrated approach to understanding and treating diseases can be significantly more successful than simply controlling epidemic disease or treating individual patients [41]. In 2020, Horton suggested applying the term 'syndemic' to COVID-19 for its clustering and interactions with pre-existing conditions, and the influence of larger political, economic and social factors [42].

Discussion
The aims of the present systematic literature review and meta-analysis were to assess in children and adolescents the impact of COVID-19 lockdown in promoting weight gain and obesity, on one hand, and the risk of developing severe COVID-19 disease, with consequent admission to hospital/ICU, associated with overweight/obesity on the other hand.
COVID-19 and pediatric obesity can be approached as "syndemic conditions". This notion, conceived by the medical anthropologist Merrill Singer in the 1990s, goes beyond comorbidities as it identifies conditions characterized by biological and social interactions that increase a person's susceptibility to harm or worsen health outcomes, so are important for prognosis, treatment and health policy. As the same author explained, a "syndemic approach" provides a very different orientation to clinical medicine and public health as an integrated approach to understanding and treating diseases can be significantly more successful than simply controlling epidemic disease or treating individual patients [41]. In 2020, Horton suggested applying the term 'syndemic' to COVID-19 for its clustering and interactions with pre-existing conditions, and the influence of larger political, economic and social factors [42].

Impact of COVID-19 Lockdown on Weight and Lifestyle Changes in Children and Adolescents
Data analysis clearly demonstrated the detrimental impact of COVID-19 lockdown on children and adolescents' body weight and BMI, children with pre-existing overweight/obesity being more at risk of gaining weight.
Obesity is a chronic disease resulting from the interaction of genetic, environmental, and psychosocial factors leading to the predominance of caloric intake over expenditure.
Based on the standardized growth charts of the Centers for Disease Control and Prevention [43], youths are defined as 'overweight' for body weight in the 85th-94th centile, 'obese' in the 95th-98th centile, and 'severely obese' if >99th centile. Even before the COVID-19 pandemic, pediatric weight excess was considered a worrisome epidemic condition affecting over 337 million children globally, with more than 124 million cases of obesity and severe obesity, worsening over the time, with rates varying with age, ethnicity, location, and social determinants [7]. The associated health and social burden depend on the several physical and psychological co-morbidities, characterized by early onset and lifetime duration, with an overall poor patient quality of life and significant social costs [44][45][46].
Weight gain seems to be explained primarily by the increase of sedentary life, secondary to the longer time spent at home sitting and screen time for homeschooling and recreational activities (i.e., video games, computers/tablets, and television), in the absence of a structured environment on weekdays, to the detriment of compulsory physical activity at school and extracurricular physical activity in dedicated recreational spaces and outdoors [21,26,27,29,32,39]. This phenomenon appeared to be more prevalent among younger children with respect to adolescents, and in boys as compared to females [23,25,29,30]. As demonstrated by previous studies, the abrupt cessation of exercise and prolonged inactivity promote several other adverse health changes, including insulin resistance, muscle atrophy and bone loss [47].
Change in dietary habits towards unhealthy patterns and lifestyles characterized by an overall increase of ingested calories, secondary to a higher number of meals per day [31], a more abundant breakfast [21], and the consumption of hypercaloric food at the various meals (i.e., sweets, snacks, carbohydrates, junk food [21,24,29]), significantly contributed to weight increase during COVID-19 lockdown.
Some studies also reported the alteration of sleep-wake cycles during the lockdown periodpredisposing to night eating [26,27,32] and altering the hormone circadian rhythms- [48,49] and the overall increase of sleep time, reducing hours dedicated to physical activity and, thus, further contributing to the sedentary lifestyle [21,26].
Finally, the high levels of stress, fear and anxiety experienced by children and adolescents during COVID-19 pandemic could have contributed to weight increase during the lockdown [26,28]. Previous studies had demonstrated the complex relationship between stress, mental health, and obesity [50]. First, stress can cause weight gain by stimulating chronic cortisol secretion [51,52]. Second, prolonged stress periods can lead to depression with consequent isolation, home stay, sedentary behavior, and unhealthy nutrition, overall contributing to weight increase and obesity, that are, in turn, responsible for social stigma, stress and isolation [50]. Factors promoting stress and anxiety in children and adolescents were self-experienced but also parent-transmitted and included poor knowledge (especially at the beginning of the pandemic) of SARS-CoV-2 mechanisms of transmission, potentially severe outcomes of infection, and absence of efficacious treatments, social isolation, drastic changes in family dynamics and exacerbation of dysfunctional aspects, economic difficulties secondary to job loss/unemployment and difficulties in the use of technology necessary for home schooling and working [53,54].
Interestingly, the significant increase of body weight and BMI reported by the various studies occurred in a very short period, confirming previous observations on higher weight gain during summer vacations than during the school year, thus reinforcing the importance of school in obesity prevention through structured routine with meals, physical activity and a routine that promotes an adequate sleep schedule [55,56]. Forced school closure during the COVID-19 pandemic had a greater impact because of the previously mentioned associated psychological aspects impairing mental health and well-being, and the detrimental effect on academic progression [50].
The highest weight/BMI increase was observed in children with pre-existing overweight/obesity, of Hispanic and African American ethnicity, and in those living unfavorable socioeconomic conditions, therefore, most vulnerable to unhealthy lifestyle, food insecurity, family and social stress (i.e., lower parental psychological and educational support, and higher financial concerns/limitations), and with difficult access to academic resources and healthcare services [22,23,50].

Impact of Overweight/Obesity on the Severity and Outcome of COVID-19 Disease
Our study clearly pointed out a significant increase in the risk of severe COVID-19 disease and, consequently, of hospital/ICU admission in youths with overweight/obesity as compared with normoweight pairs [35,36,40,57].
The prevalence and severity of COVID-19 disease in children is significantly lower than in adults. It seems that, because of their immune systems' immaturity, younger individuals are less likely to develop severe disease than adults and are more often asymptomatic. Most of the cases occurred in children aged 5-10 years old, and the prevalence in males was slightly higher than in females [58,59].
Around 3% developed critical conditions and few died. Racial/ethnic minorities and low-income populations, as well as children with comorbidities (i.e., chronic cardiac, respiratory, kidney, oncological, immunological, and hematological diseases, especially if associated with immunosuppression; diabetes and obesity) presented a significantly higher risk of infection and adverse disease outcome [60,61].
It should be underlined that obesity appeared to be the most significant independent risk factor, even in the mildest cases, in agreement with data from the adult population [12,14,16,61]. Several altered mechanisms, related to obesity itself and to its comorbidities, are involved. These include: (1) altered respiratory physiology, secondary to the pressure exerted by abdominal adiposity on the lungs, and the defective lung mesenchymal stem cells, responsible for ineffective tissue repair processes and immune response, with an overall increased risk of pulmonary infections, asthma, and obstructive apneas; (2) insulin resistance and hyperinsulinemia, because of which, in situations of intense metabolic activity, like during the response to SARS-CoV-2 infection, beta cells, already working at their limit, were not able to increase insulin secretion and can also be damaged by the virus [62,63]. Moreover, they contribute to the onset of other metabolic and cardiovascular alterations; including (3) dyslipidemia (low HDL-and increased LDL-cholesterol levels contribute to endothelial dysfunction and atherosclerosis); (4) hypertension with consequent left ventricular hypertrophy; (5) non-alcoholic steatohepatitis; and (6) hyperuricemia [62,63]. Finally, insulin resistance increases the (7) oxidative stress and, together with visceral adiposity, endothelium damage and micronutrients deficiencies (i.e., vitamin D, C, A, E and B12, iron and folate, with anti-oxidative action) lead to (8) chronic inflammation, excessive and dysregulated inflammatory response, and increased coagulation activity [62,63].

Study Strengths and Limitations
The main strengths of this work are: (1) the 'syndemic' approach to pediatric obesity and COVID-19 disease, according to which their reciprocal influence has been evaluated by dedicated analyses in the same study; (2) the accurate study search-through the initial application of a purposely-created highly sensitive string to identify as many pertinent articles as possible, so reducing the risk of missing important data-and selection; (3) the inclusion of studies focusing only on children and adolescents, thus discarding those including adults together with youths, thus increasing the specificity of the study.
On the other hand, the study presents some important limitations. First, the limited number and heterogeneity of the studies, in terms of sample size, gender distribution, ethnicity, study design and parameters used for the assessment of study variables, outcomes and confounders could be only partially limited by the accurate selection made. Most of the studies were cross sectional and some were based on parent interviews, thus limiting the validity of collected data because of intrinsic study limitations. Moreover, some population samples may be overlapping. Finally, the majority of the studies considered absolute weight increase and/or BMI, while only few reported weight and BMI percentiles, which are fundamental to assessing the presence and degree of weight excess in children and adolescents.

Conclusions
The COVID-19 pandemic had a huge impact on the health and well-being of children and adolescents. Lockdown measures affected healthy lifestyle behaviors through the modification of dietary habits, the reduction of physical activity and the alteration of sleep patterns, and also increased the levels of stress and anxiety, overall promoting weight gain and obesity. Moreover, pediatric overweight/obesity-already representing an alarming epidemic of increasing proportions, with detrimental effects on physical and mental health before COVID-19, has been demonstrated to be the most important independent risk factor for the development of severe SARS-CoV-2 infections in youths, requiring admission to hospital/ICUs. Urgent measures aimed at supporting children and their families through counseling and active implementation of services for the promotion of healthy lifestyle in the different settings as well as medical care at all population levels are mandatory to limit the outburst of pediatric obesity. Finally, active population surveillance, as well as structured prospective studies focusing on physical and psychological aspects, are warranted to assess the real impact of COVID-19 disease and related containment measures on youth health and wellbeing in the long-term, and, consequently, promote targeted, more efficacious Public Health interventions.