key: cord-1041754-59ja1ith
authors: Pranata, Raymond; Lim, Michael Anthonius; Yonas, Emir; Vania, Rachel; Lukito, Antonia Anna; Siswanto, Bambang Budi; Meyer, Markus
title: Body Mass Index and Outcome in Patients with COVID-19: A Dose-Response Meta-Analysis
date: 2020-07-29
journal: Diabetes Metab
DOI: 10.1016/j.diabet.2020.07.005
sha: 25fa8a17aa94357d8c2e401e3e5da992c53f6816
doc_id: 1041754
cord_uid: 59ja1ith

Abstract Background There is mounting evidence related to the association between obesity and severity of COVID-19. However, the direct relationship of the increase in the severe COVID-19 risk factors, with an increase in body mass index (BMI), has not yet been evaluated. Aim This meta-analysis aims to evaluate the dose-response relationship between body mass index (BMI) and poor outcome in patients with COVID-19. Methods A systematic literature search was conducted using PubMed, Europe PMC, ProQuest, and the Cochrane Central Database. The primary outcome was composite poor outcome composed of mortality and severity. The secondary outcomes were mortality and severity. Results A total of 34,390 patients from 12 studies were included in this meta-analysis. The meta-analysis demonstrated that obesity was associated with composite poor outcome (OR 1.73 [1.40, 2.14], P <0.001; I2: 55.6%), mortality (OR 1.55 [1.16, 2.06], P =0.003; I2: 74.4%), and severity (OR 1.90 [1.45, 2.48], P <0.001; I2: 5.2%) in patients with COVID-19. A pooled analysis of highest BMI versus reference BMI indicate that a higher BMI in the patients was associated with composite poor outcome (aOR 3.02 [1.82, 5.00], P <0.001; I2: 59.8%), mortality (aOR 2.85 [1.17, 6.92], P =0.002; I2: 79.7%), and severity (aOR 3.08 [1.78, 5.33], P <0.001; I2: 11.7%). The dose-response meta-analysis showed an increased risk of composite poor outcome by aOR of 1.052 [1.028, 1.077], P <0.001 for every 5kg/m2 increase in BMI (P non-linearity <0.001). The curve became steeper with increasing BMI. Conclusion Dose-response meta-analysis demonstrated that increased BMI was associated with increased poor outcome in patients with COVID-19.

As of 2 nd July 2020, the coronavirus disease (COVID-19) has infected 10,533,779 people worldwide, with a death toll of 512,842 [1] . Although a majority of the patients are either asymptomatic or only have a mild, influenza-like illness, a significant proportion develop severe symptoms. However, the factors leading to critical illness in some patients, but not in others, remain unclear. Hence, a detailed investigation of the factors linked to severe COVID-19 is needed, in order to facilitate appropriate resource allocation [2] .

There is mounting evidence of a strong association between obesity and severity of COVID-19 [3] [4] [5] . However, the direct relationship of the increase in the risk factor of severe COVID- 19 , with an increase in body mass index (BMI), has not yet been evaluated. In this systematic review and meta-analysis, we aim to evaluate the association between obesity and poor outcome (mortality and severity) in patients with COVID-19 and explore the doseresponse relationship between BMI and poor outcome in these patients by pooling data from observational studies. We hypothesize that obesity and increase in BMI increases mortality and severity of patients with COVID-19 in a dose-response fashion.

This systematic review and meta-analysis follows the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines.

The following types of articles were included: research articles on adults with COVID-19 with information available regarding obesity (categorical) or BMI, and the clinically validated definition of death, severe illness (WHO-China joint commission), the need for intubation, or J o u r n a l P r e -p r o o f a referral to the intensive care unit (ICU). Only published studies have been included in this systematic review and meta-analysis. We have excluded preprints, abstract-only publications, review articles, letters without primary data, commentaries, case reports/case series < 20 patients, non-English language articles and studies that did not report key exposures or outcomes of interest.

A systematic literature search was conducted using PubMed, Europe PMC, ProQuest, and the Cochrane Central Database with keywords (("SARS-CoV-2" OR "COVID-19" OR "Coronavirus") AND ("Obesity" OR "Overweight" OR "Body Mass Index")) for records published from 1 January 2020 up until 28 Table S1 (see supplementary materials associated with this article on line). Duplicates were removed, and the titles and abstracts of the remaining articles were independently assessed by two authors using the inclusion and exclusion criteria. Both literature searchers are medical doctors with experience in performing systematic reviews and meta-analyses.

Two independent authors abstracted data using standardized forms and obtained information on first author, year, study design, age, gender, diabetes mellitus, hypertension, cardiovascular diseases, mortality, severe COVID-19, the need for intubation, and a need for J o u r n a l P r e -p r o o f referral to the ICU. Selection of data was based on potential variables that may affect the relationship between obesity and the outcome.

Exposure in this study was obesity was defined as BMI ≥ 30 kg/m 2 , BMI ≥ 28 kg/m 2 is acceptable for Asian studies. The primary outcome was composite poor outcome composed of mortality and severity. Secondary outcomes were mortality and severity. Severity was defined as severe COVID-19 as per the WHO-China Joint Mission on COVID-19, the need for intubation, or referral to the ICU [6] . To reduce the influence of confounders, adjusted odds ratios (ORs) were used for effect estimate obtained with the pooling method, whenever possible. Risk of bias/quality of studies were assessed using the Newcastle-Ottawa Scale (NOS) by two independent authors and discrepancies were resolved through discussion.

We used STATA 16.0 (StataCorp LLC, Texas, US) to perform meta-analysis. The prevalence of obesity across the studies were pooled using random-effects meta-analysis of proportion.

ORs were reported for the effect estimate, along with its 95% confidence intervals (CIs).

Adjusted ORs (aORs) were pooled for meta-analysis of obesity and poor outcome; if only dichotomous variables were present, we converted them into OR. The aORs were pooled for analysis stratified by BMI and the adjusted hazard ratios (HRs) were converted into adjusted ORs for the analysis. The unadjusted outcomes were excluded. Random-effects model was used for the analyses, regardless of heterogeneity. Two-tailed P-values were used, with the statistical significance set at < 0.05. Inter-study heterogeneity was assessed using Cochran's Q test and I 2 statistic; I 2 values > 50% and P-value < 0.10 indicated statistically significant heterogeneity. A dose response meta-analysis was then performed for studies that have at least three quantitative classifications. A two-stage random-effects dose-response meta-J o u r n a l P r e -p r o o f analysis was performed using generalized least-squares regression trend estimation based on logaORs across BMI intervals. The potential for a non-linear relationship based on aORs of each quantitative BMI was examined using restricted cubic splines with three-knots model. The restricted maximum likelihood method in a multivariate random-effects metaanalysis was used to combine the effect estimates. Wald-type test was used to assess nonlinearity by testing regression coefficient of the second spline. A subgroup analysis was performed for individual components of the composite poor outcome (mortality and severity). The sensitivity analysis was performed by excluding studies with a BMI cut-off other than >30 kg/m 2 for obesity analysis. A leave-one-out sensitivity analysis was performed to test the statistical robustness of the analysis. To assess the risk of publication bias, funnel-plot analysis and Begg's test were performed.

Our initial search yielded 1498 records, of which 1234 remained after the removal of duplicates. After a screening of the titles and abstracts of these records, 25 potential articles were found. Their full-texts were assessed and 13 were excluded due to the following reasons: 1) no data on outcome of interest/BMI analysis was not stratified, no data on obesity or specific BMI cut-off point (n=11), 2) pregnancy (n=1), and 3) only in pediatric patients (n=1). The remaining 12 studies were included in the systematic review and metaanalysis [ Figure 1 ] [3, 4, 14, 15, 5, [7] [8] [9] [10] [11] [12] [13] . There were a total of 34390 patients from these 12 studies. The baseline characteristics of the included studies is given in Tables I & II 

The prevalence of obesity in this meta-analysis was 31% (21-42%), with the values being 42% (38-45%) for North America, 24% (9-39%) for Europe, and 6% (4-8%) for Asia.

This meta-analysis demonstrated that obesity was associated with composite poor outcome 

The pooled analysis of highest BMI versus reference BMI of each of the studies showed that a higher BMI was associated with composite poor outcome (aOR 3.02 [1.82, 5.00], P < 0.001; I 2 : 59.8%, pheterogeneity = 0.021) [ Figure 3A ]. The subgroup analysis showed that a higher BMI 

Meta-regression analysis showed that the association between obesity and composite poor outcome did not vary with the prevalence of male (P = 0.250), hypertension (P = 0.669), diabetes (p=0.599), and the continent in which the study was conducted (P = 0.919).

The funnel-plot analysis qualitatively showed an asymmetrical shape [ Figure 5 ], indicating the possibility of publication bias for the association between obesity and composite poor outcome. Begg's test for small-study effects showed no indication of small-study effects (P = 0.053). Funnel-plot analysis and begg's test was not performed for body mass index and composite poor outcome because the number of studies were < 10.

Our meta-analysis showed that obesity was associated with composite poor outcome, mortality, and severity of COVID-19. The dose-response meta-analysis showed that the risk for composite poor outcome increased by OR of 5% for every 5 kg/mg 2 increase in BMI; the relationship departed from linearity and became steeper from 30-35 kg/mg 2 onwards. To the best of the authors' knowledge, this is the first meta-analysis to evaluate the doseresponse relationship of BMI and its' effect on COVID-19 prognosis.

The association between obesity and composite poor outcome has a moderate-high heterogeneity, this heterogeneity persists despite the removal of studies without BMI cut- [19] . Class 3 obesity is frequently called "severe" or "extreme" obesity and it may, along with several other medical conditions, increase the risk of severe COVID-19 [20] [21] [22] [23] [24] .

When compared to individuals with normal BMI, subjects with obesity have a greater risk of hypertension, dyslipidemia, insulin resistance, type 2 diabetes mellitus (T2DM), cardiovascular disease and cerebrovascular disease, all of which are recognized as comorbidities for poor outcomes in COVID-19 patients [21, 22, 24, 25] . Excess BMI has been shown to increase susceptibility to infections, and obesity itself is an independent risk factor for severe COVID-19 [26, 27] . In fact, individuals with obesity are found to have reduced protection from influenza vaccination and are at risk of contracting infections, respiratory J o u r n a l P r e -p r o o f infections in particular [26, 28] . People with excessive BMI and/or having comorbid conditions generally have low-grade chronic inflammation that makes them susceptible to infections with poorer outcomes [29] [30] [31] . Obesity causes systemic inflammation and adversely affects innate and adaptive immunity in a manner similar to immunosenescence or immune system aging [32] .

Low-grade inflammation in overweight and individuals with obesity is characterized by the dysfunction and hypoxia of adipocyte, which leads to an increased release of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α), and the recruitment of immune cells including macrophages, B-cells, and T-cells. This results in a cycle of auto-regenerating inflammation leading to a cytokine storm, which is one of the fundamental pathomechanisms of severe COVID-19 and can lead to acute respiratory distress syndrome or even multi-organ failure (MOF), affecting kidney and liver. It exhibits a phenomenon of immune hyperactivation very similar to cytokine-release syndrome [31] .

In COVID-19 patients, the virus may either invade organs directly or enter the cells through angiotensin-converting enzyme 2 (ACE2) receptor. [33] In addition, viral invasion may generate huge amounts of cytokines, which is also thought to be involved in the pathophysiology of MOF. [34] The combination of virus-induced and obesity-driven hyperinflammation could further exacerbate the inflammation in COVID-19 patients and lead to worse prognosis, including mortality [21] [22] [23] [24] .

and high leptin (a pro-inflammatory adipokine) concentrations. This unfavorable hormonal state negatively influences immune function and may play a role in the development of J o u r n a l P r e -p r o o f obesity-related complications [29] . Another concern among subjects with obesity is the lack of physical activity. Aging, physical inactivity, obesity and metabolic syndrome are shown to contribute to weakened immune and viral defense systems [32] .

Reduced physical activity, irrespective of insulin resistance, disrupts the immune response against pathogenic agents. The presence of antigen may not be adequately managed due to diminished macrophage activation and the inhibition of release of pro-inflammatory cytokines upon its stimulation. These defects in the immune response cause prolonged shedding of the virus, which increases the possibility of its transmission to others.

Furthermore, the obese microenvironment leads to diminished production of interferons, which enables greater viral RNA replication. This may eventually result in the emergence of novel more virulent virus strains. In addition, BMI correlates positively with infectious virus in exhaled breath [29] .

A higher BMI is associated with poor pulmonary function, including lower respiratory reserve volume, functional capacity, and respiratory system compliance. In patients with metabolic syndrome or those who have increased abdominal circumference, decreased lung function is further compromised in supine position due to reduced diaphragmatic excursion, causing additional difficulties in ventilation [35] . Patients with severe obesity and full expression of the obstructive sleep apnea phenotype receive less benefit from non-invasive positive pressure ventilation, and require medical management of its comorbid conditions. These patients have increased risk of cardiovascular diseases, cancer, and all-cause mortality and frequently present with exaggerated pro-inflammatory profile [26] . In addition, chronic low-grade inflammation and impaired fibrinolysis put subjects with obesity at the risk of thrombosis, which appears to be a causative factor of worsening lung damage J o u r n a l P r e -p r o o f and death in COVID-19 patients. This is in agreement with several current protocols and recommendations that endorse the use of heparin, an anticoagulant, for the treatment for COVID-19 patients [31, 36] .

Another medical condition commonly presented in subjects with obesity is metabolic associated fatty liver disease (MAFLD), defined by the presence of hepatic steatosis in addition to one of the following conditions-overweight/obesity, T2DM, or metabolic dysregulation. In such patients, IL-6 concentration independently predicted liver inflammation, which could synergistically promote more severe COVID-19. Moreover, gut dysbiosis in obesity is another significant factor potentially linked with the development of severe forms of COVID-19 [31] . Furthermore, vitamin D deficiency or insufficiency is another common finding in obesity which can disrupt immune function and increase the risk of systemic infections [37] .

Individuals with obesity are generally a high-risk and complicated group of patients to treat for COVID-19, often requiring longer hospitalization and comprehensive management of its comorbidities and complications [31] . Because of prolonged viral shedding, subjects with obesity are also required to be quarantined longer than those who have normal BMI [29] . It is clear that an increase in BMI is significantly correlated with composite poor outcome in COVID-19, however, the impact of body composition (fat/fat-free muscle) on the outcome for COVID-19 patients needs to be investigated further. Table III summarizes the possible mechanisms of the association between obesity and poor prognosis in patients with COVID-19. The perception of weight gain during lockdown was observed in half of the respondents in an Italian survey [38] , although it was not an objective measurement, it may indicate a potential rise for obesity. These may increase the number of individuals at risk for developing severe COVID-19. An increase in the obesity prevalence along with other diseases may also lead to a surge in non-communicable diseases post pandemic [39] . Hence, physical activity and healthy eating habits should be encouraged during the pandemic [40] [41] [42] .

This meta-analysis has several limitations. Firstly, although the analysis for BMI only pooled adjusted OR/HR, there might be other confounders that might not be accounted for in their study. Secondly, the majority of the studies were retrospective which is less reliable compared to prospective studies. Thirdly, we did not include articles published in foreign languages, which may limit epidemiological data from non-English speaking countries.

In conclusion, obesity was associated with an increase in poor outcome for COVID-19

patients. The dose-response meta-analysis demonstrated that increased BMI was associated Ethics Approval : Not applicable.

Supplementary materials (Table S1 and S2) associated with this article can be found at http://www.scincedirect.com at doi . . . Palaiodimos 2020 Mechanism Explanation A higher risk of developing comorbidities A greater risk of hypertension, dyslipidemia, insulin resistance, T2DM, cardiovascular disease and cerebrovascular disease, all of which are known as comorbidities for poor outcomes in COVID-19 Impaired immunity Dysfunction in innate and adaptive immunity increases the susceptibility to contract infections, particularly respiratory infections. Proinflammation state Low-grade, systemic, chronic inflammation that is characterized by adipocyte dysfunction and hypoxia, which leads to an increased release of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, CRP, and TNF-α, and the recruitment of immune cells including macrophages, B-cells, and T-cells. This results in a cycle of auto-regenerating inflammation leading to a cytokine storm, which is one of the main pathomechanisms of severe COVID-19 and serious complications. Virus-induced hyperinflammation SARS-CoV-2 may enter human cells or organs through ACE2 receptor and consequently generate huge amount of cytokines. The combination of virus-induced and obesity-driven hyperinflammation could further exacerbate the inflammation in COVID-19 and lead to worse prognosis, including mortality. Unvaforable hormonal state Low adiponectin (an anti-inflammatory adipokine) and high leptin (a pro-inflammatory adipokine) concentrations negatively affects immune function.

The lack of physical activity disrupts the immune response against pathogenic agents, while aging, obesity, and metabolic syndrome are shown to contribute to weakened immune and viral defense systems. Prolonged viral shedding

The defects in the immune response cause prolonged shedding of the virus, which delays recovery from COVID-19 (a longer period of hospitalization or quarantine) while increasing the possibility of its transmission to others.

Obese microenvironment leads to diminished production of interferons, which enables greater viral RNA replication. This may eventually result in the emergence of novel more virulent virus strains. Poor lung function Lower respiratory reserve volume, functional capacity, and respiratory system compliance, coupled with reduced diaphragmatic excursion (in individuals with metabolic syndrome or increased abdominal circumference) when lying supine contributes to decreased lung function and cause additional difficulties in ventilation.

J o u r n a l P r e -p r o o f 32 OSA Interference in ventilation occurs in OSA, which is also a major source of cardiovascular morbidity and mortality. Individuals with full expression of the OSA phenotype receive less benefit from non-invasive positive pressure ventilation, and require medical management of its comorbid conditions. Thrombosis Impaired fibrinolysis, complemented by low-grade inflammation, put obese individuals at the risk of thrombosis, which appears to be a causative factor of worsening lung damage and death in COVID-19.

It is defined by the presence of hepatic steatosis in addition to one of the following conditions: overweight/obesity, T2DM, or metabolic dysregulation. In this condition, IL-6 concentration independently predicted liver inflammation, which could synergistically promote more severe COVID-19. 

World Health Organization. Coronavirus disease (COVID-19) Situation Report -164

Lymphopenia in severe coronavirus disease-2019 (COVID-19): systematic review and meta-analysis

Morbid Obesity as an Independent Risk Factor for COVID-19 Mortality in Hospitalized Patients Younger than 50

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

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

Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)

Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Hospitalized Patients in Wuhan, China

Factors Associated With Intubation and Prolonged Intubation in Hospitalized Patients With COVID-19

Association of Obesity with Disease Severity among Patients with COVID-19

Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission

Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease

High prevalence of obesity in severe acute respiratory syndrome coronavirus

requiring invasive mechanical ventilation

Clinical Features and Outcomes of 105 Hospitalized patients with COVID-19 in

Obesity and COVID-19 Severity in a Designated Hospital in Shenzhen

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

Obesity surgery mortality risk score: proposal for a clinically useful score to predict mortality risk in patients undergoing gastric bypass

Validation of the Obesity Surgery Mortality Risk Score in a Multicenter Study Proves It Stratifies Mortality Risk in Patients Undergoing Gastric Bypass for Morbid Obesity

Validation of Obesity Surgery Mortality Risk Score in patients undergoing gastric bypass in a Canadian center

Groups at Higher Risk for Severe Illness

Hypertension is associated with increased mortality and severity of disease in COVID-19 pneumonia: A systematic review, meta-analysis and meta-regression

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia -A systematic review, meta-analysis, and meta-regression

Effect of chronic obstructive pulmonary disease and smoking on the outcome of COVID-19

Impact of Cerebrovascular and Cardiovascular Diseases on Mortality and Severity of COVID-19 -Systematic Review, Meta-analysis, and Meta-regression

Elevated N-terminal pro-brain natriuretic peptide is associated with increased mortality in patients with COVID-19: systematic review and meta-analysis

Obesity and severe COVID-19 disease: a strong association

COVID-19 and obesity

COVID 19 and the Patient with Obesity -The Editors Speak Out

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

Does high cardiorespiratory fitness confer some protection against pro-inflammatory responses after infection by SARS-CoV-2?

Obesity: The "Achilles heel" for COVID-19?

Coronavirus Disease-2019: A tocsin to our aging, unfit, corpulent, and immunodeficient society

The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis

Multiorgan Failure With Emphasis on Acute Kidney Injury and Severity of COVID-19: Systematic Review and Meta-Analysis

Obesity and its Implications for COVID-19 Mortality

C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a metaanalysis

Considerations for Obesity, Vitamin D, and Physical Activity Amid the COVID-19 Pandemic

Eating habits and lifestyle changes during COVID-19 lockdown: an Italian survey

A wave of non-communicable diseases following the COVID-19 pandemic

Physical activity recommendations during the coronavirus disease-2019 virus outbreak

An international physical activity and public health research agenda to inform coronavirus disease-19 policies and practices

Sports activities during any pandemic lockdown

If there is no information based on such grouping, data for overall sample is presented instead