key: cord-0944861-yu0e5tm9
authors: Kristensen, Nickolai M.; Gribsholt, Sigrid B.; Andersen, Anton L.; Richelsen, Bjørn; Bruun, Jens M.
title: Obesity augments the disease burden in COVID‐19: Updated data from an umbrella review
date: 2022-02-08
journal: Clin Obes
DOI: 10.1111/cob.12508
sha: 583d763fc37d343afcc6d5e02dcf383de1f8b414
doc_id: 944861
cord_uid: yu0e5tm9

The ongoing coronavirus disease 2019 (COVID‐19) pandemic calls for identification of risk factors, which may help to identify people at enhanced risk for severe disease outcomes to improve treatment and, if possible, establish prophylactic measures. This study aimed to determine whether individuals with obesity compared to individuals with normal weight have an increased risk for severe COVID‐19. We conducted a systematic literature search of PubMed, Embase and Cochrane Library and critically reviewed the secondary literature using AMSTAR‐2. We explored 27 studies. Findings indicate that individuals with obesity (body mass index ≥ 30 kg/m(2)), as compared to individuals without obesity, experience an increased risk for hospitalization (odds ratio [OR]: 1.40–2.45), admission to the intensive care unit (OR: 1.30–2.32), invasive mechanical ventilation (OR: 1.47–2.63), and the composite outcome ‘severe outcome’ (OR or risk ratio: 1.62–4.31). We found diverging results concerning death to COVID‐19, but data trended towards increased mortality. Comparing individuals with obesity to individuals without obesity, findings suggested younger individuals (<60 years) experience a higher risk of severe disease compared to older individuals (≥60 years). Obesity augments the severity of COVID‐19 including a tendency to increased mortality and, thus, contributes to an increased disease burden, especially among younger individuals.

the infection, up to 20% of infected individuals may not develop any kind of symptoms through the course of the infection. 6 Most of the symptomatic individuals will experience a mild or moderate course of disease consisting of fever, cough, fatigue and even anosmia and ageusia. 5 However, as many as 20% of patients may develop severe or critical disease resulting in requirement of oxygen support and hospital care or even admission to ICU to prevent and handle feared complications such as acute respiratory distress syndrome, sepsis, thromboembolism and even multiorgan failure. 5 As the WHO estimates that nearly 2 billion individuals experience overweight or obesity (650 million with obesity) 7 it is important to clarify whether these individuals should be considered at increased risk of developing severe COVID- 19 . In addition, it may be of interest to investigate if an age-dependent risk exists as a previous report has demonstrated that BMI among hospitalized individuals was negatively correlated with age (r 2 = .051; p = .0002), 8 suggesting that the severity of in younger individuals with obesity might be augmented.

This ubiquitous crisis demanding a worldwide attention has resulted in the production of an enormous number of scientific publications. To explore the possible link between obesity and COVID-19 severity, it is necessary to continuously critically review and discuss the available literature. Hence, a systematic appraisal of the study quality of the available systematic reviews on the association between obesity and risk of severe a COVID-19 outcome and a discussion of their conclusions is needed.

We hypothesize that obesity is an independent risk factor for the development of severe illness following SARS-CoV-2 infection. This paper seeks to give an updated answer on the following Population, Intervention, Comparison, Outcome (PICO) 9 question: In individuals infected with a SARS-CoV-2 (P), does obesity (I) compared to normal weight (C) affect outcomes such as hospitalization, ICU admission, need for IMV or mortality (O)? 3 | METHODS

We performed a systematic literature search of PubMed, Embase and Cochrane Library using the search strings as presented in Table S1 . To be included, the studies must fulfil the following criteria:

(1) Publication type of systematic review with or without metaanalysis of SARS-CoV-2-positive individuals; (2) risk assessments of the continuous variable, BMI, or the dichotomous variable, obesity (BMI ≥ 27.5 kg/m 2 for Asian individuals; BMI ≥ 30 kg/m 2 for non-Asian individuals 10 ), regarding COVID-19 severity either as hospitalization, ICU admission, need of IMV, mortality, or any representative measurement of severe (blood oxygen saturation < 90%, respiratory rate > 30/min, signs of severe respiratory distress 5 ) or critical (requirement of life sustaining treatment or acute respiratory distress 5 ) disease outcome; (3) the included study must have been through a proper peer-review process.

After the removal of duplicates, studies were screened by title and abstract and excluded if found ineligible, e.g., improper publication type such as editorials, commentaries, primary studies, or secondary literature without investigations included by the aforementioned inclusion criteria. We evaluated the remaining studies for final inclusion in accordance with the inclusion criteria by full-text reading. The literature selection process is shown in Figure 1 .

To assess the quality of each included study this project used the appraisal tool 'A MeaSurement Tool to Assess systematic Reviews-2' (AMSTAR-2). 11 The instrument consists of 16 questions of which 7 are considered critical. By applying these questions to each study, it is possible to qualitatively rate the overall confidence in the results of the review as either 'critically low' (more than one critical flaw), 'low' (one critical flaw), 'moderate' (more than one noncritical weakness) or 'high' (no or one noncritical weakness). We excluded studies rated as 'critically low' for qualitative synthesis. Two authors (A.A. and N.K.)

independently performed the quality assessment, and any differences were solved through discussion.

Using the standardized data extraction tool in accordance with the guidelines for umbrella reviews by the Joanna Briggs Institute 12 One of the authors (N.K.) extracted the following data from the literature:

Author, date of publication, study objectives, sources searched, search details, types and number of studies included, total number of participants, appraisal instrument used, and summary of findings, including heterogeneity.

The initial literature search yielded 347 potential publications. After removing duplicates, screening titles and abstracts 163 articles remained and were evaluated in detail prior to potential inclusion. This led to exclusion of further 101 articles with reasons specified in Figure 1 . After full-text reading we excluded 25 articles and using the AMSTAR-2 quality assessment tool we excluded further 10 studies which led to the inclusion of 27 systematic reviews in this paper's qualitative deductions. The 27 systematic reviews included a total of 260 unique primary studies. 

Using the AMSTAR-2 appraisal tool to judge the methodological quality, 25 14,17-21,24-26,28,30,32,33,35,37,41-50 

The results of the included systematic reviews are presented in Table 1 and visually summarized in Table 2. Tables S4 and S5 and Figures S1 and S2 presents subgroup analyses regarding IMV and mortality, respectively. A total of five different outcomes (hospitalization, ICU, IMV, 'severe outcome' and mortality) were assessed across the 27 studies.

Eight studies examined the role of obesity in relation to hospitalization. 14, 17, 19, 24, 27, 30, 35, 39 Seven studies provided a metaanalysis, 14, 17, 19, 24, 27, 30, 35 Obesity is proposed as a likely risk factor for experiencing poor outcome in patients with This is synthesized as the prevalence of chronic diseases including obesity is higher in individuals requiring hospitalization especially those younger than 60 years old with obesity; of these hospitalized patients the ones admitted to the ICU significantly presents a higher BMI Finally, patients with obesity and other concurrent chronic diseases (e.g., NALFD, diabetes, cardiovascular diseases, asthma, hypertension) seem to experience higher rates of hospitalization, IMV as well as mortality 

Eleven studies focused on the need for IMV in relation to SARS-CoV-2 infected individuals with obesity. 14, 17, 19, 20, 24, 25, 27, 30, 33, 35, 38 All studies except one provided a meta-analysis 38 Figure 2C ).

Only two studies presented heterogeneity of high value 25, 30 (50% ≤ I 2 < 75% 51 ) whilst the rest were characterized as either moderate 14,24,33 (25% ≤ I 2 < 50% 51 ) or low 27 (0% < I 2 < 25% 51 ) if heterogeneity was described at all. 20, 35 Zhang et al. 17 did not provide any estimate of heterogeneity. These levels of heterogeneity for the IMV-meta-analysis represent the lowest for all the five outcomes (hospitalization, ICU, IMV, 'severe outcome' and mortality) describing COVID-19 severity (Table 1) .

Four studies further quantified the relationship between an elevated BMI and the increased OR for IMV. 20 

The most detrimental outcome of COVID-19 is death. Twenty-one studies reported on the association between death in relation to SARS-CoV-2 infection and obesity and/or overweight. [13] [14] [15] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] 32, 34, 37, 39 Fourteen studies found an association between mortality in relation to COVID-19 [13] [14] [15] 18, 21, 22, 24, [26] [27] [28] 30, 32, 34, 39 and overweight and/or obesity versus BMI < 25 kg/m 2 without obesity, and seven studies found no such association. 17, 19, 20, 23, 25, 29, 37 Twelve of the 13 studies provided a meta-analysis with ORs or RRs ranging between 1.14 27 to 3.34 28 when comparing individuals with obesity to individuals without obesity ( Figure 4 ).

Comparing individuals with a BMI ≥25 kg/m 2 to individuals with a BMI <25 kg/m 2 , Seidu et al. 34 found an RR of 3.52 (95% CI:

1.32-9.42).

Despite nonsignificant ORs reported by seven studies 17, 19, 20, 23, 25, 29, 37 it should be noted that only two studies 17, 25 reported an OR < 1.0 and the study by Zhou et al. 37 Du et al. 28 COVID-19, however, possibly due to the lack of power, the association between obesity and death due to COVID-19 was found nonsignificant (p = .08). In comparison, the primary study by Gao et al. 55 utilizing data from more than 6.9 million patients reported a 4% increase in mortality for each increment in BMI above 23 kg/m 2 . Few studies provided a stratified analysis on the association between disease progression and age. 23, 25, 34, 38, 39 Of these, three found disease progression to be greatest among the younger (<60 years) individuals 25, 38, 39 when comparing individuals with obesity to individuals without obesity, whilst another study reported the strongest association among the older (≥60 years) individuals, 34 and a fifth study did not find any significant associations when stratifying individuals by age. 23 Despite the secondary literature reporting diverging results concerning the role of obesity in relation to disease severity and age, primary studies with great n numbers (i.e., >100.000) may provide evidence for an increased risk associated with overweight or obesity.

The primary study by Kompaniyets et al. 59 estimates in their meta-analysis. Maybe this discrepancy in relation to age and disease severity can be explained merely by differences in the adjustments in the meta-analyses.

Regarding the risk of IMV, Kompaniyets et al. 59 found no differences between the different age groups suggesting that the primary contributor to the risk of IMV might be the mechanical compression of lungs forced by a high bodyweight. 60, 61 It should be noted that once exposed to IMV, BMI might not be associated to death due to This was demonstrated in a prospective multicentre study, 63 reporting BMI >40 kg/m 2 to be associated with increased mortality following SARS-CoV-2 infection and ICU admission (OR: Schwarzbach et al. 64 re-evaluated the primary studies and reported pooled effect estimates stratified for studied geographical region. In support of our findings, they also reported an increased risk of severe COVID-19 outcomes when exposed to obesity compared to normal weight, however, methodological differences among the primary studies hindered the comparability resulting in some of the effect estimates to be based on only few primary studies.

In total, we identified 27 systematic reviews which included increased airway resistance 61 and decreasing various lung volumes. 40 The obesity-induced extraordinary load to the respiratory system on top of a possible exposition to enhanced viral load during secondary viremia and impaired immune response may contribute to individuals with obesity experiencing a more severe course of disease than individuals without obesity.

This paper has several limitations. First, by exploiting previously published systematic reviews this umbrella review was influenced by a considerable amount of overlapping data resulting in somewhat concordant findings among the systematic reviews. Hereby, we could not Second, is the lack of comparability among primary studies, hence secondary studies as well, observed as levels of I 2 ( Table 1 ). The high levels of heterogeneity were listed as the reason for the two qualitative studies to refrain from quantitative deductions. 38, 39 Third, no study restricted the group of reference to individuals with normal weight only. The most commonly used comparator group was individuals without obesity (BMI <30 kg/m 2 for non-Asian individuals and BMI <28 kg/m 2 for Asian individuals 10 ). This group of reference also included individuals with underweight (i.e., BMI < 18.5 kg/m 2 ) which diminished the reported associations as individuals with underweight previously has been reported to experience a worse prognosis following SARS-CoV-2 infection compared to individuals with normal weight. 55, 59, 69 Therefore, we could not use individuals with normal weight as comparator as stated in the PICO question. Future studies should exclude underweight individuals when assessing the role of obesity in relation to COVID-19 outcomes.

Lastly, the study quality among the systematic reviews varied greatly according to AMSTAR-2. The key limitation was the lack of a prespecified protocol before conducting the study 17, 18, 20, 21, [24] [25] [26] 28, 30, 32, 35, [41] [42] [43] [44] [45] 47, 48, 50 (Item no. 2). This, however, might be considered as a downside but was probably and understandably due to the urgent need to understand and manoeuvre the COVID-19 pandemic. Table S3 shows the full results of the AMSTAR-2 appraisal.

In conclusion, this updated umbrella review provides an overview of the available secondary literature summarizing that individuals with obesity compared to individuals without obesity experience an increased risk of COVID-19 severity measured as hospitalization, ICU admission, need for IMV, as well as the composite outcome 'severe outcome'. Overall, the data also seem to trend towards obesity acting as an individual risk factor for death due to COVID-19. In addition, obesity might affect the COVID-19 disease course in a dose-response manner with an incremental effect particularly seen among individuals younger than 60 years compared to individuals ≥60 years.

The authors declare no conflict of interests. 

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