key: cord-0883214-rkthl8g2
authors: Huang, Huei‐Kai; Bukhari, Khulood; Peng, Carol Chiung‐Hui; Hung, Duan‐Pei; Shih, Ming‐Chieh; Chang, Rachel Huai‐En; Lin, Shu‐Man; Munir, Kashif M.; Tu, Yu‐Kang
title: The J‐shaped relationship between body mass index and mortality in patients with COVID‐19: A dose‐response meta‐analysis
date: 2021-04-14
journal: Diabetes Obes Metab
DOI: 10.1111/dom.14382
sha: 4363d2f8f0becc5060f64b3fc8bbe3e6ffa08a7f
doc_id: 883214
cord_uid: rkthl8g2

nan

studies using the Newcastle-Ottawa Scale. 8 Discrepancies were resolved via discussion among the study team.

We first conducted a meta-analysis for the difference in the risk of mortality between the highest and the lowest category of BMI using a DerSimonian and Laird random-effects model (the high vs. low meta-analysis). 9 We then conducted the random-effects doseresponse meta-analysis to estimate the linear and nonlinear trends in the association between BMI and mortality. 10 The linear trend was estimated by using the generalized least squares model described by Greenland and Longnecker. 11 We used the two-stage approach to estimating the nonlinear trend by first fitting a restricted cubic splines model with knots at the 10th, 50th and 90th percentiles for each study and then undertaking a multivariate meta-analysis for the model variables. 12 The Wald test was used to test for nonlinearity by comparing the model fit between the linear and nonlinear models. When the BMI level was presented as a range, the dose was assigned using the midpoint of the upper and lower boundaries; for the open-ended highest and lowest BMI categories, the width between the boundaries was assumed to be equal to that of the adjacent category. RRs for mortality with 95% confidence intervals (CIs) were used to report the outcome. For the dose-response meta-analysis, a sensitivity analysis was conducted by pooling only studies specifically evaluating underweight patients (BMI < 18.5 kg/m 2 ). We assessed heterogeneity among studies with I 2 statistics. The heterogeneity was considered low, moderate and high for I 2 < 50%, 50% to 75%, and > 75%, respectively. 13 Potential publication bias was assessed using funnel plots, Egger's test and Begg's test. 14,15 A leave-one-out sensitivity analysis was performed to evaluate the influence of each study on the overall pooled estimate. All statistical tests were two-sided, with the significance level set at 5%. Statistical analyses were conducted using Stata acceptable quality, with a Newcastle-Ottawa Scale score of ≥7 points (Table S1 ).

In the high versus low meta-analysis, we found that COVID-19

patients with a high BMI had an increased risk of mortality (pooled RR 1.33, 95% CI 1.15-1.53; P < 0.001), with moderate heterogeneity (I 2 = 54.2%; Figure S2 ). There was no evidence of publication bias according to Egger's test (P = 0.270), Begg's test (P = 0.260), or the funnel plot ( Figure S3) . The leave-one-out sensitivity analysis demonstrated that the pooled RR was robust ( Figure S4 ).

In the dose-response meta-analysis, a positive dose-response relationship between BMI and mortality was found based on the linear model. The mortality of patients with COVID-19 increased by 1.6% for each 1-kg/m 2 increase in BMI (pooled RR 1.016, 95% CI 1.008-1.025), with high heterogeneity (I 2 = 75.9%). However, a significant nonlinear relationship between BMI and mortality was observed (Wald test: P non-linearity < 0.001). We demonstrated a J-shaped curve, indicating that both underweight and obese patients had a higher mortality than those with normal weight ( Figure 1A) . A BMI of approx- between-study heterogeneity (I 2 = 62.3%). In the sensitivity analysis of the 13 studies with data on underweight patients, the J-shaped relationship between BMI and mortality remained unchanged, and the nonlinear fit was significantly better than the linear fit ( Figure 1B) , further supporting the robustness of our findings.

To our knowledge, this is the first dose-response meta-analysis to demonstrate a J-curved relationship between BMI and COVID-19 mortality, indicating that both underweight and obese COVID-19

patients had a higher mortality risk than patients with normal weight.

Our findings are supported by previous studies which suggested a more severe respiratory virus infection or respiratory mortality in both underweight and obese patients. [43] [44] [45] We found that overweight patients (BMI 25-30 kg/m 2 ) seemed to have the lowest COVID-19 mortality risk, which was compatible with some previous evidence evaluating all-cause mortality in the general population. 46 However, the observed association between overweight and lower mortality may be subject to the problems of reverse causation and confounding by smoking or other confounders discussed previously in the literature. 47 50 The differences in obesity rates may explain some of the variations in the COVID-19 mortality rates among countries. 51 Owing to these limitations, more high-quality studies from different countries and ethnic groups are necessary to validate our findings.

KEYWORDS body mass index, COVID-19, meta-analysis, mortality, obesity, underweight

We thank Stella Seal, MLS, from Johns Hopkins University, for her expertise with the database search.

The authors received no specific funding for this study.

Author contributions were as follows. Study conception and design:

Huei 

None declared.

The peer review history for this article is available at https://publons. com/publon/10.1111/dom.14382.

The data that support the findings of this study are available from the corresponding author upon reasonable request. 

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