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Association of Obesity With More Critical Illness in COVID-19

      To the Editor:
      In follow-up to a recent major state-of-the-art review on obesity and outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 19 [COVID-19]),
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.
      we have additional data regarding the relationship of obesity with outcomes in patients with COVID-19. Clearly, obesity and metabolic syndrome affect both innate and adaptive immunity, leading to increased infection severity.
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.
      ,
      • Lavie C.J.
      • Laddu D.
      • Arena R.
      • Ortega F.B.
      • Alpert M.A.
      • Kushner R.F.
      Healthy weight and obesity prevention: JACC Health Promotion Series.
      This association is very important because current statistics indicate that three-fourths of the US population are either overweight or obese by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) criteria, and currently over 42% meet criteria for obesity by a BMI of 30 kg/m2 or greater. More alarmingly, currently over 9% of the US population meet criteria for severe or morbid obesity (class III obesity) by a BMI of 40 kg/m2 or greater.
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.
      ,
      • Lavie C.J.
      • Laddu D.
      • Arena R.
      • Ortega F.B.
      • Alpert M.A.
      • Kushner R.F.
      Healthy weight and obesity prevention: JACC Health Promotion Series.
      Certainly, many other countries across the globe are experiencing marked increases in the prevalence and severity of obesity,
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.
      ,
      • Lavie C.J.
      • Laddu D.
      • Arena R.
      • Ortega F.B.
      • Alpert M.A.
      • Kushner R.F.
      Healthy weight and obesity prevention: JACC Health Promotion Series.
      which may be particularly problematic in COVID-19 and other such pandemics. We performed a rapid review and meta-analysis to evaluate whether obesity is associated with worse outcomes in patients with COVID-19.
      The present study was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We performed a comprehensive search in the MEDLINE and medRxiv.org databases for studies published between January 1, 2019, and May 31, 2020. The following key words were used for the search in different combinations: coronavirus 2019, Covid-19, SARS-CoV2, obesity, body mass index, and outcomes. Studies reporting the relationship between BMI (nonobese vs obese) and outcomes among hospitalized patients with COVID-19 were included for analysis. Three reviewers (A.S., A.G., A.R.) screened the study titles and abstracts for relevance, followed by full manuscript evaluation. The following data were collected from included studies: baseline characteristics, proportion of patients classified by BMI categories (<30 kg/m2 vs >30 kg/m2), and percentage of hospitalized patients. The primary outcome was critical illness (need for intensive care unit [ICU] admission, invasive mechanical ventilation [IMV], or mortality) as defined per individual study protocol. We used Cochrane Review Manager 5.3 (Cochrane Collaboration) for study analysis. Pooled odds ratios and 95% CIs were calculated using random-effects models and the Mantel-Haenszel method. Heterogeneity was assessed using the I2 statistic. The initial search resulted in 266 studies, 13 of which (7196 patients) reported outcomes in patients with COVID-19 based on BMI.
      • Kalligeros M.
      • Shehadeh F.
      • Mylona E.K.
      • et al.
      Association of obesity with disease severity among patients with coronavirus 2019.
      • Qingxian C.
      • Chen F.
      • Fang L.
      • et al.
      Obesity and COVID-19 severity in a designated hospital in Shenzhen, China. SSRN website.
      • Simonnet A.
      • Chetboun M.
      • Poissy J.
      • et al.
      LICORN and the Lille COVID-19 and Obesity Study Group
      High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation.
      • Lighter J.
      • Phillips M.
      • Hochman S.
      • et al.
      Obesity in patients younger than 60 years is a risk factor for Covid-19 hospital admission [published online ahead of print April 9, 2020].
      • Bhatraju P.K.
      • Ghassemieh B.J.
      • Nichols M.
      • et al.
      Covid-19 in critically ill patients in the Seattle region - case series.
      • Petrilli C.M.
      • Jones S.A.
      • Yang J.
      • et al.
      Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. medRxiv website.
      • Goyal P.
      • Choi J.J.
      • Pinheiro L.C.
      • et al.
      Clinical characteristics of Covid-19 in New York City.
      • Hu L.
      • Chen S.
      • Fu Y.
      • et al.
      Risk factors associated with clinical outcomes in 323 COVID-19 hospitalized patients in Wuhan, China [published online ahead of print May 3, 2020].
      • Argenziano M.G.
      • Bruce S.L.
      • Slater C.L.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      • Hajifathalian K.
      • Kumar S.
      • Newberry C.
      • et al.
      Obesity is associated with worse outcomes in COVID-19: analysis of early data from New York City [published online ahead of print May 29, 2020].
      • Busetto L.
      • Bettini S.
      • Fabris R.
      • et al.
      Obesity and COVID-19: an Italian snapshot [published online ahead of print May 28, 2020].
      • Caussy C.
      • Pattou F.
      • Wallet F.
      • et al.
      COVID Outcomes HCL Consortium and Lille COVID–Obesity Study Group. Prevalence of obesity among adult inpatients with COVID-19 in France.
      • Palaiodimos L.
      • Kokkinidis D.G.
      • Li W.
      • et al.
      Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.
      Critical illness was defined as the need for ICU care or IMV or a composite of ICU care, IMV, hospice, or death. Pooled analysis revealed that obesity was associated with increased odds of critical illness among patients hospitalized with COVID-19 (odds ratio, 1.39; 95% CI, 1.21-1.60) (Figure). Low heterogeneity was evident across studies (I2=19%) (Figure).
      Figure thumbnail gr1
      FigureForest plot comparing the odds of critical illness between obese (body mass index >30 kg/m2) vs nonobese (body mass index <30 kg/m2) patients hospitalized with coronavirus disease 19 infection. M-H = Mantel-Haenszel test.
      In this rapid review and meta-analysis, obesity was associated with a 39% increased risk of critical illness, defined by individual study protocol as ICU admission, need for IMV, or hospice admission or death. Considering the very high prevalence of obesity among adults in the United States and worldwide, and even severe obesity approaching nearly a tenth in US adults, this increased critical illness is a worrisome sign.
      • Lavie C.J.
      • Laddu D.
      • Arena R.
      • Ortega F.B.
      • Alpert M.A.
      • Kushner R.F.
      Healthy weight and obesity prevention: JACC Health Promotion Series.
      Patients with obesity also have more endothelial dysfunction, as well as respiratory and renal diseases that could worsen COVID-19 outcomes. However, probably most importantly, COVID-19 coronavirus attaches to the angiotensin-converting enzyme 2 receptors in the lungs and organs.
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.
      Obese patients have insulin resistance and activation of the renin-angiotensin-aldosterone system.
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.
      The presence of angiotensin-converting enzyme 2 may enable the entry of SARS-CoV-2 into adipocytes, which makes adipose tissue an important viral reservoir.
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.
      Therefore, adipose tissue, which is more abundant in obesity, might also be infected by SARS-CoV-2 and allow spread to other organs, thus explaining the more severe COVID-19 disease in obesity.
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.
      The prevention of obesity in the first place, and especially its progression to more severe forms, is desperately needed for future pandemics, as well as for the primary and secondary prevention of diabetes mellitus and cardiovascular disease.
      • Lavie C.J.
      • Laddu D.
      • Arena R.
      • Ortega F.B.
      • Alpert M.A.
      • Kushner R.F.
      Healthy weight and obesity prevention: JACC Health Promotion Series.
      In this COVID-19 pandemic, clinicians should recognize the marked increased risks associated with obesity, and these patients need more aggressive triage and treatment.
      Our study has several limitations. Because patient-level data were not available, the results in our study were not adjusted to baseline patient characteristics. Several studies analyzing the relationship between obesity and clinical outcomes have reported results after adjusting for different confounders. Because of differences in the variables used to adjust results in these studies, we have not performed the pooled analysis of those adjusted confidence intervals and odds ratios. Further, the studies did not have long-term follow-up data and most patients were still hospitalized without a definite outcome (ie, mortality), and thus caution should be exercised before extrapolation of our results to long-term outcomes.
      Despite these study limitations, however, our data of a 39% increase in worse outcomes associated with obesity strongly supports the recent article in Mayo Clinic Proceedings.
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Mehra M.R.
      • Henry B.M.
      • Lippi G.
      Obesity and outcomes in COVID-19: when an epidemic and pandemic collide.

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