key: cord-0770379-j4ju9fte authors: Malik, Preeti; Patel, Urvish; Patel, Karan; Martin, Mehwish; Shah, Chail; Mehta, Deep; Malik, Faizan Ahmad; Sharma, Ashish title: Obesity a predictor of outcomes of COVID‐19 hospitalized patients‐ A systematic Review and Meta‐Analysis date: 2020-09-25 journal: J Med Virol DOI: 10.1002/jmv.26555 sha: e2dc7f100829d029aac1f9eb15fa5df9916649ff doc_id: 770379 cord_uid: j4ju9fte BACKGROUND: COVID‐19 pandemic is a global health crisis. Very few studies have reported association between obesity and severity of COVID‐19. In this meta‐analysis, we assessed the association of obesity and outcomes in COVID‐19 hospitalized patients. METHODS: Data from observational studies describing the obesity or body mass index (BMI) and outcomes of COVID‐19 hospitalized patients from December 1, 2019, to August 15, 2020, was extracted following PRISMA guidelines with a consensus of two independent reviewers. Adverse outcomes defined as intensive care units (ICU), oxygen saturation <90%, invasive mechanical ventilation (IMV), severe disease and in‐hospital mortality. The odds ratio (OR) and 95% confidence interval (95%CI) were obtained and forest plots were created using random‐effects models. RESULTS: A total of 10 studies with 10,233 confirmed COVID‐19 patients were included. The overall prevalence of obesity in our study was 33.9% (3473/10,233). In meta‐analysis, COVID‐19 patient with obesity had higher odds of poor outcomes compared to better outcomes with a pooled OR of 1.88 (95%CI:1.25–2.80; p=0.002), with 86% heterogeneity between studies (p<0.00001). CONCLUSION: Our study suggests a significant association between obesity and COVID‐19 severity and poor outcomes. Our results findings may have important suggestions for the clinical management and future research of obesity and COVID‐19. This article is protected by copyright. All rights reserved. As of August 20, 2020, a total of 23 million coronavirus disease 2019 (COVID- 19) cases have been reported, leading to 814,797 deaths worldwide 1 . This pandemic has posed a Accepted Article greater risk to population and healthcare. Research studies have shown that not only affects the respiratory system but affects multiple organs of the body [2] [3] [4] [5] . In addition, certain groups of people, including the elderly and immunocompromised, have been identified as most susceptible to the virus, especially those with underlying diseases like diabetes, hypertension, cardiovascular disease etc. 6 . Researchers across the globe have been exploring predictors of severity of COVID-19 cases to identify and stratify them accordingly. More recent studies are focusing on identifying other high-risk patients helping in their early management 7 . According to recent trends observed in the United states from 1999-2000 through 2017-2018, the age-adjusted prevalence of obesity increased from 30.5% to 42.4% 8 . Obesity, a subclinical inflammatory state caused by an excess of inflammatory cells in adipose tissue, is known to be a risk factor for various disease states 9, 10 . The majority of people who had high mortality due to COVID-19 have suffered from other comorbidities, the most prevalent being cardiovascular disease, hypertension, and respiratory diseases, all of these are also strongly associated with obesity [11] [12] [13] . A lot of our current knowledge about the relationship between obesity and COVID-19 has come from previous evidences, showing that morbidly obese patients had increased risk of hospitalization, mechanical ventilation and mortality during the H1N1 pandemic and seasonal influenza 14-16 . In addition, it has been noted that influenza A, along with several other pathogens, uses adipose tissue as a viral reservoir 17 . Obese patients, along with a weakened immune system may provide a virus with a larger replication region. A few recent articles have begun to explore the relationship between obesity and COVID-19, but are limited in sample size and geographical locations. Hence, the aim of This article is protected by copyright. All rights reserved. Article our meta-analysis is to assess the effect of obesity on outcomes in the COVID-19 hospitalizations. The aim of the study is to evaluate the association between obesity and outcomes in confirmed COVID-19 positive hospitalized patients. COVID-19 confirmation was evaluated by combined findings of RT-PCR, serology, symptoms, and MRI chest in majority of those studies. Obesity defined as body mass index (BMI) >=25 or 28 or 30 or confirmed obesity comorbidity in individual studies. Composite poor outcomes were defined by intensive care unit (ICU) admission, oxygen saturation<90%, invasive mechanical ventilation (IMV) utilization, severe disease, and in-hospital mortality. A systematic search was conducted on published studies using PRISMA guidelines 18 Article studies, non-English literature, non-full text, and animal studies were excluded. Flow diagram of the literature search and study selection process is described in Figure 1 . Abstracts were reviewed, and articles were retrieved and reviewed for availability of data on Obesity or BMI and outcomes of COVID-19 patients. Studies which gave details on outcomes were selected for quantitative analysis. PM and UP independently screened all identified studies and assessed full-texts to decide eligibility. Any disagreement was resolved through consensus. From the included studies, we extracted the following variables higher BMI, Obesity and outcomes. Details on binary outcomes like ICU vs. non-ICU admission, severe vs nonsevere disease, IMV vs no-IMV use, oxygen saturation <90% vs >90%, in-hospital mortality vs discharged alive and survivors were collected using prespecified data collection forms by two authors (PM and UP) with a common consensus. We have presented the study characteristics like the first author's last name, publication month and year, country of origin, sample size, study design mean or median age, sex, outcomes and definition of obesity assessed in that individual study Table 1 . This article is protected by copyright. All rights reserved. Centre, The Cochrane Collaboration, Copenhagen, Denmark). The Maentel-Haenszel formula was used to calculate dichotomous variables to obtain odds ratios (ORs) along with its 95% confidence intervals (95%CI) to describe the relationship of obesity and outcomes of COVID-19 patients in each study. Random-effects models were used regardless of heterogeneity to estimate the combined effect and its precision, to give a This article is protected by copyright. All rights reserved. Article more conservative estimate of the ORs and 95%CI. p<0.05 was considered significant. The I 2 statistic was used to assess statistical heterogeneity and value >75% was considered significant heterogeneity. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included studies 20 (Supplemental file 1.2) . Sensitivity analysis was performed to assess the effect of publication bias and heterogeneity by excluding outlying studies on the funnel plot. In This article is protected by copyright. All rights reserved. Our meta-analysis found 37.6% prevalence of pre-existing obesity in COVID-19 patients with poor outcomes. Another main finding of our meta-analysis was, COVID-19 patients with pre-existing obesity had 1.88-folds higher risk of having worse outcomes. Our results fall in line with previous studies that have documented an above normal BMI as a potential risk factor for the coronavirus 7, 10 . Although the reasons behind the relationship between obesity and COVID-19 still remain unclear, there have been several studies that have proposed various underlying mechanisms that may provide us with some insight 7, 9, 21 . One plausible theory is that, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the ACE2 receptor in the cellular membrane and once inside a host cell it slows down angiotensin II metabolism leading to an increased expression of angiotensin II. Angiotensin II leads to pulmonary vasoconstriction and acute lung injuries, two of the prominent symptoms of COVID-19. Since obese patients have more adipose tissue, they have more ACE2 receptors providing the virus with more entry points into a host cell. In addition, obesity is strongly associated with Type 2 diabetes (T2DM) which also leads to an increase in ACE2 receptors. In people with T2DM, angiotensin II levels are positively correlated with body weight. As a result, if an obese patient with a comorbid of T2DM becomes infected with the SARS-CoV-2, their previously high angiotensin II levels will further elevate leading to greater This article is protected by copyright. All rights reserved. In the RAS pathway, a precursor protein Agt is secreted from various tissues (including adipose tissue) and then is cleaved twice by the enzymes renin and ACE resulting in the production of angiotensin II. Another mechanism is, in obese people there is both overexpression of Agt and an overactivation of the RAS system in adipose tissue resulting in an increased production of angiotensin II 21 . This coupled with the increase of angiotensin II due to COVID-19 may lead to poorer outcomes for obese patients. Furthermore, obesity has been known to compromise the adaptive and innate immune system responses. In obesity there is reduced macrophage activation, increased proinflammatory cytokine production, and impaired B and T cell activation 9 . As a result, an obese patient is not only more susceptible to being infected with SARS-CoV-2 but also cannot fight the infection leading to increased morbidity in COVID-19 infections. Moreover, obesity not only causes a wide array of organ and immune system dysfunction, but also makes it more difficult to evaluate and treat patients in a clinical setting. Because COVID-19 causes severe respiratory complications including acute respiratory distress syndrome (ARDS), many patients who contract the virus may need mechanical ventilation. Ventilating obese patients is quite challenging due to decreased diaphragmatic excursion, decreased expiratory reserve volume, and decreased lung functional capacity 7 . Besides, many hospitals are not well equipped to easily evaluate and treat obese patients. There is increasing prevalence of obesity in the US population 8 and 8/10 studies in our meta-analysis were conducted in US population. However, this high prevalence of obesity is really important to be considered worldwide since the association of obesity and severity of COVID-19 has been reported and it is a major public health problem This article is protected by copyright. All rights reserved. Article worldwide and so is the SARS-CoV-2 infection. Considering our results and severity of COVID-19 and the proposed mechanisms and pathology in the literature, it is suggested that patients with obesity are at higher risk of COVID-19 and poor outcomes. Hence, there is need for increased surveillance, priority on early detection and testing, and aggressive therapy for patients with obesity and COVID-19 infections. The main limitation of this meta-analysis is the heterogeneity of the included studies. All the studies are retrospective studies due to the lack of data from prospective studies and randomized trials. Furthermore, the different definitions of the severity of the COVID-19 disease and discrepancy in the cut off values for the BMI and different diagnostic criteria for obesity might be explanations for the heterogeneity. Another limitation is that, the studies included in our analysis have not performed multivariate analysis to find association between obesity and severity of COVID-19 adjusting for diabetes and/or hypertension and/or cardiovascular disease. Despite these limitations, our meta-analysis of 10,233 confirmed COVID-19 patients suggests that obesity plays a significant role in the progression of COVID-19. This may help in early triage of high-risk patients and prevent the complications associated with poor outcomes by early and aggressive management of such patients. Our meta-analysis suggests that obesity is significantly associated with poor outcomes in COVID-19 patients. Obesity has added additional burden on both the patient and healthcare, resulting in an overall poorer prognosis. Additionally, obesity negatively Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area Comorbidity and its Impact on Patients with COVID-19 Epidemiological and Clinical Characteristics of 6635 COVID-19 Patients: a Pooled Analysis. 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Influenza Other Respir Viruses Hospitalized patients with 2009 H1N1 influenza infection: the Mayo Clinic experience Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group Article impacts the body in many ways from weakening the immune system to over activating various pathways resulting in an overall increased morbidity. More studies on obesity and COVID-19 should be designed in order to evaluate the effect of the obesity epidemic on coronavirus pandemic.