key: cord-0949299-ls5gychz
authors: Cai, Zixin; Yang, Yan; Zhang, Jingjing
title: Obesity is associated with severe disease and mortality in patients with coronavirus disease 2019 (COVID-19): a meta-analysis
date: 2021-08-04
journal: BMC Public Health
DOI: 10.1186/s12889-021-11546-6
sha: fcd2cd47ed83cdfa23d9cbc34a3ef5cd15361844
doc_id: 949299
cord_uid: ls5gychz

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to global research to predict those who are at greatest risk of developing severe disease and mortality. The aim of this meta-analysis was to determine the associations between obesity and the severity of and mortality due to COVID-19. METHODS: We searched the PubMed, EMBASE, Cochrane Library and Web of Science databases for studies evaluating the associations of obesity with COVID-19. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models. Meta-regression analyses were conducted to estimate regression coefficients. RESULTS: Forty-six studies involving 625,153 patients were included. Compared with nonobese patients, obese patients had a significantly increased risk of infection. (OR 2.73, 95% CI 1.53–4.87; I(2) = 96.8%), hospitalization (OR 1.72, 95% CI 1.55–1.92; I(2) = 47.4%), clinically severe disease (OR 3.81, 95% CI 1.97–7.35; I(2) = 57.4%), mechanical ventilation (OR 1.66, 95% CI 1.42–1.94; I(2) = 41.3%), intensive care unit (ICU) admission (OR 2.25, 95% CI 1.55–3.27; I(2) = 71.5%), and mortality (OR 1.61, 95% CI 1.29–2.01; I(2) = 83.1%). CONCLUSION: Patients with obesity may have a greater risk of infection, hospitalization, clinically severe disease, mechanical ventilation, ICU admission, and mortality due to COVID-19. Therefore, it is important to increase awareness of these associations with obesity in COVID-19 patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-021-11546-6.

On December 31, 2019, the World Health Organization (WHO) was made aware of an outbreak involving several cases of atypical pneumonia. These cases were subsequently identified as being caused by a novel virus belonging to the coronavirus (CoV) family, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] . On January 30, 2020, the WHO declared an international public health emergency due to infections caused by SARS-CoV-2. On February 20, 2020, the WHO officially named the disease caused by SARS-CoV-2 coronavirus disease 2019 [2, 3] . COVID-19 has posed a global health threat, causing an ongoing pandemic in many countries and territories, with approximately 6,287,771 confirmed COVID-19 cases and 379,941 deaths [4] as of June 3, 2020. The number of COVID-19 cases has been rising worldwide, and there is increasing global concern about this outbreak [5] .

WHO global estimates indicate that 39% of adults are overweight and 13% are obese [6] . Obesity is an increasing worldwide health concern and is regarded as a critical risk factor for various infections, postinfection complications and mortality from severe infections [7] . Obesity has been shown to have deleterious effects on host immunity, which is the primary cause of an increased risk of infection, especially severe infection [7, 8] . Obesity has also been shown to affect lung function in multiple ways that are related to mechanical and inflammatory factors, making obese individuals more likely to suffer from respiratory symptoms and progress to respiratory failure [9] .

Accumulating evidence suggests that the group of patients who develop severe COVID-19 may have a higher proportion of obesity than the group with non-severe COVID-19; in some reports, the difference was significant [10] [11] [12] [13] . However, a lack of information regarding the global prevalence of obesity in individuals with COVID-19 remains. Investigating the influence of obesity on COVID-19 is of scientific interest. This investigation aimed to review the relationship between obesity and COVID-19. In doing so, we aim to enhance public awareness of the association between obesity and COVID-19. Furthermore, highlighting the possible associations between obesity and COVID-19 could guide those working to control the COVID-19 pandemic.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data (PRISMA-IPD) statement was followed for the performance and reporting of this meta-analysis [14] . Our metaanalysis focused on the relationships between obesity and the mortality due to and severity of COVID-19.

PubMed, EMBASE, the Cochrane Library and Web of Science were carefully searched from inception to January 2021 for the terms "COVID-19" and "novel coronavirus" combined with the terms "obesity" and "BMI" as index words. Two investigators (ZC and YY) independently reviewed the identified abstracts and selected articles for full review. Disagreements were resolved by a third investigator (JZ). The search strategy is described in a supplementary file (Supplementary File 1).

The inclusion criteria were as follows: (1) patients in the studies had confirmed COVID-19; (2) the body mass index (BMI) values were provided; (3) the comorbidities and severity of disease were provided; and (4) the studies were published in English. The exclusion criteria were as follows: (1) case reports, reviews, letters or nonhuman studies; (2) studies written in a language other than English; and (3) studies with insufficient information. Two investigators (ZC and YY) independently selected studies for inclusion, and disagreements were resolved by a third investigator (JZ).

Data extraction was independently conducted by two authors (ZC and YY) using a standardized data collection form that included the author, year, country, patients, BMI values, and outcomes (infection, hospitalization, severe disease, mechanical ventilation, intensive care unit (ICU) admission, and mortality). The characteristics of these studies are shown in Table 1 .

All analyses and plots were performed and generated using STATA software (version 12.0, STATA Corp, College Station, TX, USA). Forest plots were used to illustrate the association between obesity and COVID-19 in the selected studies. We pooled the data and calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for dichotomous outcomes, including infection, hospitalization, severe disease, mechanical ventilation, ICU admission, and mortality. The results of the included studies were assessed with random-or fixedeffects models. The I 2 statistic was used to assess the magnitude of heterogeneity-25, 50, and 75% represented low, moderate, and high degrees of heterogeneity, respectively. The choice of the appropriate model was based on the results; a fixed-effects model (inverse variance) was used to pool the data if I 2 was < 50%, and a random-effects model (DerSimonian-Laird) was used if I 2 was > 50% [15] . Funnel plots were used to screen for potential publication bias. To determine the robustness of the results, a sensitivity analysis was conducted with sequential elimination of each study from the pool. The threshold of statistical significance was set to 0.05.

Overall, 2874 articles of interest were identified in the initial electronic database searches. A total of 1807 duplicate documents were identified. Of these, 285 full-text articles were considered potentially relevant and further assessed for eligibility. After reviewing the titles and abstracts, 239 articles were excluded because they were not written in English, were case series/reports or reviews, did not contain the full text, or had no reported data. The remaining 46 studies were carefully evaluated in detail; these 46 studies met the inclusion criteria and were finally included (Fig. 1) . Of the included studies, 18 reported mortality, 10 reported ICU admission, 8 reported the development of severe disease, 7 reported mechanical ventilation, 7 reported infections, and 5 reported Table 2 . Definition of severe COVID-19 used in each study was shown in Table 3 . Study design in the included studies were shown in Supplementary Table 1 .

To assess the impact of obesity on viral infection, we included 7 studies [16] [17] [18] [19] [20] [21] [22] with 215,338 subjects. The data indicated that obesity significantly increased the risk of viral infection (OR = 2.73, 95% CI 1.53-4.87; I 2 = 96.8%; Fig. 2 ).

To assess the impact of obesity on the risk of hospitalization, we included 5 studies [23] [24] [25] [26] [27] involving 396,603 subjects. The data indicated that obesity increased the risk of hospitalization (OR = 1.72, 95% CI 1.55-1.92; I 2 = 47.4%; Fig. 3 ).

To assess the impact of obesity on the risk of severe disease, we included 8 studies [10] [11] [12] [28] [29] [30] [31] [32] involving 1839 subjects. The data indicated that obesity was associated with an increased risk of severe disease (OR = 3.81, 95% CI 1.97-7.35; I 2 = 57.4%; Fig. 4 ).

To assess the impact of obesity on mechanical ventilation use, we included 7 studies [33] [34] [35] [36] [37] [38] [39] involving 2088 subjects. The data indicated that obesity was associated with the use of mechanical ventilation (OR = 1.66, 95% CI 1.42-1.94; I 2 = 41.3%; Fig. 5 ).

To assess the impact of obesity on the risk of ICU admission, we included 10 studies [33, [35] [36] [37] [40] [41] [42] [43] [44] [45] involving 3652 subjects. The data indicated that obesity was closely associated with the risk of ICU admission (OR = 2.25, 95% CI 1.55-3.27; I 2 = 71.5%; Fig. 6 ).

To assess the impact of obesity on the risk of mortality, we included 18 studies [23, 33, 35, 36, 39, 44, [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] involving 29,305 subjects. The data indicated that obesity was significantly associated with the risk of mortality (OR = 1.61, 95% CI 1.29-2.01; I 2 = 83.1%; Fig. 7 ). Univariate meta-regression analysis of possible confounders of COVID-19 outcomes in patients with and without obesity was shown in Table 4 .

We found no potential publication bias in the studies included in the meta-analysis (Fig. 8) . The sensitivity analysis suggested that our results are stable and reliable (Fig. 9 ).

We conducted this meta-analysis to determine whether obesity is a predictor of the COVID-19 severity of and mortality. In the present review, we included 46 articles involving 625,153 patients. Obese patients had a significantly increased risk of infection, hospitalization, severe disease mechanical ventilation, ICU admission, and mortality relative to patients of normal weight. Mechanisms underlying the association of obesity with the severity of and mortality due to COVID-19

The first mechanism underlying the investigated associations involves adipose tissue (AT). Obesity, usually defined as a BMI > 30 kg/m 2 , is characterized by visceral AT expansion and inflammation [58] . Adipocytes secrete a plenty of factors and hormones that affect many organ systems, including the lungs. Underlying mechanisms of obesity on the severity of COVID-19 may involve abnormalities in the production of adipokines by AT, for example, leptin and adiponectin [59, 60] . Leptin as a cytokine can have pro-inflammatory functions that influences both innate and adaptive immune responses by stimulating the production (interleukin (IL)-2 and tumour necrosis factor-alpha (TNF-α)) and suppressing the secretion of IL-4 and IL-5 [61] . In contrast, adiponectin is adipokine that exerts anti-inflammatory actions that inhibits (TNF-α, IL-6, and nuclear factor-κB) and induces (IL-10 and IL-1 receptor antagonist) [61] . Leptin concentrations are increased, whereas adiponectin levels are decreased in obesity [62, 63] . The imbalance between leptin and adiponectin may result in the development of dysregulated immune response [64] . The second mechanism involves angiotensin-converting enzyme-2 (ACE-2), COVID-19 utilizes the host ACE2 for binding and entry into host cells. The ACE2 expression is highest in AT. The increase of AT in obese patients increases the expression level of ACE2, which may increase their susceptibility to COVID-19 [65] .

Third, impaired lung function and higher level of proinflammatory Cytokines may collaborate to promote the development of respiratory viral infections in patients with obesity. Obesity reduces thoracic wall compliance, resulting in a reduction in functional residual capacity and favor the development of atelectasis [9, 66] .

Finally, obesity results in physiological lung alterations, such as decreased functional residual capacity and hypoxemia [67] . In addition, obstructive sleep apnoea hypopnea syndrome (OSAHS) increases adverse outcomes of COVID-19 [68] . The etiology of OSAHS is complex, and obesity is one of the main causes of the syndrome. OSAHS is related to obesity. About 60-90% of patients with OSAHS are overweight [69] , and the incidence rates of OSAHS in the obese patients is near twice that in normal-weight patients [70] .

All of the above mechanisms can reasonably explain how obesity increases COVID-19 severity and mortality.

Obesity is a clinical predictor of adverse outcomes in COVID-19 patients; therefore, improved intensive care guidelines for patients with elevated BMI are strongly recommended. Individuals with obesity is an important risk factor for COVID-19, including infection, hospitalization, severe disease, mechanical ventilation, ICU admission, and death. Patients with obesity may require special monitoring. Therefore, obesity patients with COVID-19 require special attention. Additionally, Obesity aggravates adverse outcomes in COVID-19 patients, and the occurrence of COVID-19 also leads to an increase in obesity. The public control of the COVID-19 outbreak is mainly about controlling human contact, which affects people's behavior to a certain extent and contributes to obesity [71] . Isolation susceptibility to incidence of mental illness [72] . Experiencing loneliness can lead to cut down on physical activity [73] . Regular physical activity is important for maintaining body weight. And as economic conditions decline, people turn to cheaper foods, which tend to be higher in calories [74] . While more and more people are cooking at home, food stored is likely to be processed to extend its shelf life. Processed foods are associated with more fat, carbohydrate and calorie intake, which is more likely to lead to weight gain than a healthy diet [75] . Preventing obesity is important. Losing weight usually involves increasing physical activity and limiting caloric intake. It is said that individuals complete ≥300 min/ week of physical activity for weight maintenance [76] .

People implemented a variety of weight loss strategies, including eating less, increasing physical activity, skipping meals, or taking weight-loss pills or diuretics [77] . Among those trying to lose weight, reducing calorie intake is the most common way [78, 79] .

One study found that use of metformin was significantly associated with a reduction in COVID-19 mortality [80] . Several reasons might explain this finding. First, metformin reduces the binding of the SARS-CoV-2 to the receptor [81] . Second, metformin inhibits the mTOR signaling pathway, thus reducing SARS-CoV-2 infectivity and COVID-19 mortality [80] . Third, metformin can the inflammatory response [82] . Additionally, metformin reduces the risk of adverse outcomes in COVID-19 patients by reducing BMI and body weight [83] .

Due to the extensive spread of COVID-19, enforced confinement has influenced the lives of individuals in many ways, including working behaviours, psychological factors, sedentary activities, and other harmful effects on life habits [84] . Because of increased stress and boredom, people tend to overeat, resulting in the consumption of additional energy/calories and an increased craving for food [85] . In this regard, COVID-19 has contributed to the occurrence of obesity.

To the best of our knowledge, this is the first metaanalysis to comprehensively assess obesity and COVID-19 outcomes (infection, hospitalization, severe disease, mechanical ventilation, ICU admission, and mortality). Obesity is a risk factor and predictor of serious disease and is a factor in the need for advanced medical care for COVID-19 patients. Basic research is needed to determine the causal relationship between obesity and adverse outcomes of COVID-19. This study has some limitations. First, some indicators, such as the risk of infection, ICU admission, and mortality, had greater degrees of heterogeneity, and subgroup analyses cannot be performed due to the small number of studies on each indicator. However, the trends were consistent across nearly all forest plots. In addition, many of the included articles did not give specific BMI values, and it is not clear how much a specific unit increase in BMI can increase the severity and mortality rate of COVID-19. Third, because this meta-analysis includes data from 

The online version contains supplementary material available at https://doi. org/10.1186/s12889-021-11546-6.

Additional file 1. Full electronic search performed in multiple international databases.

Additional file 2: Table S1 . Study design.

Acknowledgments I am grateful to my department leaders for their great encouragement, support and help to this project.

Authors' contributions JZ coordinated the study. ZC, YY, and JZ conceived the study, contributed to the study design, literature search, figure generation, statistical analysis, outcome synthesis and paper drafting and editing. All authors edited and approved the final version of the manuscript.

This work was supported by grants from the National Natural Science Foundation of China (82070807, 91749118, 81770775, 81730022), the Planned Science and Technology Project of Hunan Province (2017RS3015) and

National key research and development program (2019YFA0801903, 2018YFC2000100).

The datasets used and/or analyzed during the current meta-analysis are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate Not applicable, as this is a meta-analysis of previously published papers.

Not applicable. 

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

Coronavirus disease 2019 (COVID-19): a perspective from China

Strategies for selecting/switching chemotherapy and supportive care treatments during COVID-19 outbreak

Rapidly increasing cumulative incidence of coronavirus disease (COVID-19) in the European Union/European economic area and the United Kingdom

A randomised controlled study shows supplementation of overweight and obese adults with lactobacilli and bifidobacteria reduces bodyweight and improves well-being

Obesity and type 2 diabetes mellitus drive immune dysfunction, infection development, and sepsis mortality

Association between obesity and vulnerability and serologic response to influenza vaccination in older adults

The effect of obesity on lung function

Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children's Hospital in

Letter to the editor: obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease

Clinical findings of patients with coronavirus disease 2019 in Jiangsu province, China: a retrospective, multi-center study

Association of higher body mass index (BMI) with severe coronavirus disease 2019 (COVID-19) in younger patients

The PRISMA statement: a guideline for systematic reviews and meta-analyses

The effect of statins on microalbuminuria, proteinuria, progression of kidney function, and all-cause mortality in patients with non-end stage chronic kidney disease: a metaanalysis

Obesity is the comorbidity more strongly associated for Covid-19 in Mexico. A case-control study

Predicting Mortality Due to SARS-CoV-2: A Mechanistic Score Relating Obesity and Diabetes to COVID-19 Outcomes in Mexico

Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of general practitioners research and surveillance Centre primary care network: a cross-sectional study

Implications of obesity for the Management of Severe Coronavirus Disease 2019 pneumonia

Clinical and chest radiography features determine patient outcomes in young and middle-aged adults with COVID-19

COVID-19 infection in kidney transplant recipients: disease incidence and clinical outcomes

Epidemiology of coronavirus disease 2019 in pregnancy: risk factors and associations with adverse maternal and neonatal outcomes

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

Characteristics associated with hospitalization among patients with COVID-19 -metropolitan

Lifestyle Risk Factors for Cardiovascular Disease in Relation to COVID-19 Hospitalization: A Community-Based Cohort Study

Hospitalization and mortality among black patients and white patients with Covid-19

Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in new York City: prospective cohort study

Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis

Clinical features and outcomes of 105 hospitalized patients with COVID-19 in

Obesity and COVID-19 severity in a designated Hospital in Shenzhen

Risk factors associated with clinical outcomes in 323 COVID-19 hospitalized patients in Wuhan, China

Obesity as a potential predictor of disease severity in young COVID-19 patients: a retrospective study

Impact of chronic liver disease on outcomes of hospitalized patients with COVID-19: a multicentre United States experience

Neck circumference as reliable predictor of mechanical ventilation support in adult inpatients with COVID-19: A multicentric prospective evaluation

Obesity is associated with worse outcomes in COVID-19: analysis of early Data from new York City

Obesity and COVID-19: an Italian snapshot. Obesity (Silver Spring)

Association of Obesity with Disease Severity Among Patients with Coronavirus Disease

High prevalence of obesity in severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation

The impact of obesity on COVID-19 complications: a retrospective cohort study

Clinical and epidemiological characteristics of patients diagnosed with COVID-19 in a tertiary care center in Mexico City: a prospective cohort study

Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in metropolitan Detroit

Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series

Selective CD8 cell reduction by SARS-CoV-2 is associated with a worse prognosis and systemic inflammation in COVID-19 patients

How important is obesity as a risk factor for respiratory failure, intensive care admission and death in hospitalised COVID-19 patients? Results from a single Italian Centre

Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center

Obesity is associated with increased risk for mortality among hospitalized patients with COVID-19. Obesity (Silver Spring)

Exposure to air pollution and COVID-19 mortality in the United States: A nationwide cross-sectional study

Risk factors for mortality in patients with coronavirus disease 2019 (COVID-19) in Bolivia: an analysis of the first 107 confirmed cases

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

Severe obesity as an independent risk factor for COVID-19 mortality in hospitalized patients younger than 50. Obesity (Silver Spring)

30-day mortality in patients hospitalized with COVID-19 during the first wave of the Italian epidemic: a prospective cohort study

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study

Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher inhospital mortality

Clinical characteristics and prognosis of 244 cardiovascular patients suffering from coronavirus disease in Wuhan

COVID-19 in elderly kidney transplant recipients

COVID-19-associated critical illness-report of the first 300 patients admitted to intensive care units at a new York City medical center

Risk factors for coronavirus disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: a French nationwide cohort study

CACOVID-19)

Obesity-induced changes in adipose tissue microenvironment and their impact on cardiovascular disease

Functional Role of Dietary Intervention to Improve the Outcome of COVID-19: A Hypothesis of Work

Contrasting effects of Adipokines on the cytokine production by primary human bronchial epithelial cells: inhibitory effects of adiponectin

Leptin, adiponectin and pulmonary diseases

Do genome-wide association scans provide additional information on the variation of plasma adiponectin concentrations?

Increased cardiovascular risk markers in obesity are associated with body adiposity: role of leptin

Influenza and obesity: its odd relationship and the lessons for COVID-19 pandemic

Risk of COVID-19 for patients with obesity

ARDS in obese patients: specificities and management

Environmental perturbations: obesity

Obstructive sleep apnea (OSA) and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: a systematic review and meta-analysis

Obesity and obstructive sleep apnea

Interactions between obesity and obstructive sleep apnea: implications for treatment

How adolescents use social media to cope with feelings of loneliness and anxiety during COVID-19 lockdown

Are patients suffering from severe obesity getting a raw Deal during COVID-19 pandemic?

Loneliness predicts reduced physical activity: cross-sectional & longitudinal analyses

The cost of US foods as related to their nutritive value

Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake

AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines and the Obesity Society

Helping patients lose weight--what works?

Attempting to lose weight: specific practices among U.S. adults

Health-related quality of life and weight loss practices among overweight and obese US adults, 2003 behavioral risk factor surveillance system

Metformin in COVID-19: a possible role beyond diabetes

COVID-19 and diabetes: is metformin a friend or foe?

Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations

Role of metformin in overweight and obese people without diabetes: a systematic review and network meta-analysis

Anxiety and Stress during COVID-19: Associations with Changes in Physical Activity, Sleep, Tobacco and Alcohol Use in Australian Adults

Eaten up by boredom: consuming food to escape awareness of the bored self

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations

All authors declare that there is no conflict of interest.Received: 4 October 2020 Accepted: 23 July 2021