Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is a novel coronavirus that causes coronavirus disease 2019 (COVID-19). The virus first emerged in Wuhan (China) in December 2019 and rapidly spread worldwide (1). On March 11, 2020, COVID-19 was declared a pandemic by the World Health Organization. In most cases, the infection course is asymptomatic or mild, but symptoms progress in some patients, leading to respiratory failure and death (2, 3). Risk factors associated with disease severity and/or mortality include advanced age, male sex, socioeconomic deprivation, non-white ethnicity, and the presence of comorbidities such as hypertension, diabetes, and pre-existing respiratory or cardiovascular disease (4–9).

Obesity is defined as a body mass index (BMI) ≥ 30kg/m² (10). It is a debilitating condition associated with a range of disorders such as type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease, and cancer (11). Several of the cardiometabolic complications of obesity are risk factors for poor COVID-19 outcomes (12). Some reports also implicate obesity itself as a risk factor for severe COVID-19, with an increased risk of hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and/or death (13–17). Several explanations have been proposed, including the presence of obesity-associated comorbidities, restrictive pulmonary function due to increased visceral and thoracic fat mass, low-grade systemic inflammation, and immune dysfunction (18–20). However, given the confounding links between obesity and other COVID-19 risk factors, it is currently unknown whether excess body weight is an independent risk factor for a poor COVID-19 outcome. Therefore, we evaluated the associations between overweight (defined as BMI 25-29.9 kg/m²) or obesity and the clinical course and outcomes in patients hospitalized with COVID-19 during the first wave in the Netherlands.

Data from this retrospective multicenter cohort study of hospitalized COVID-19 patients during the first wave of the pandemic in the Netherlands demonstrates that patients who are overweight or have obesity do not have an increased probability of in-hospital mortality nor an extended length of hospital stay as compared to normal-weight patients. However, both patients with overweight and obesity have an increased probability of developing ARDS and AKI during admission for COVID-19.

It is important to note that in this cohort the prevalence of overweight and obesity was 40.9% and 30.1%, respectively; while in the Dutch population in 2019 the prevalence of overweight and obesity amongst those aged 65-75 years (i.e., the age range in our cohort) was 42.5 and 17.7%, respectively (23). This indicates that patients with obesity were overrepresented in our cohort of hospitalized COVID-19 patients. This finding is in line with previous reports describing the increased probability of hospitalization for COVID-19 in patients with obesity (13, 24). Two possible explanations for this observation are that: i) obese individuals may be more prone to infection with SARS-CoV-2 (due to increased risk of exposure; time spent indoors; contact with healthcare professionals; immunological, or other factors), or ii) individuals with obesity and COVID-19 may be at higher risk of severe COVID-19 disease requiring hospital admission. Obese individuals have an altered immune system with chronic low-grade inflammation (25), and previous studies have implicated obesity to negatively impact immune function and response to viral infections and vaccines (26–28). Additionally, increased visceral adiposity has been linked to an elevated risk for adverse outcomes in septic ICU patients (29). Moreover, once admitted, the overweight and obese groups in our cohort had increased probability of ARDS and AKI; a finding that is consistent with previous reports (30). However, despite this, we found no increased probability of overall in-hospital complications or death in COVID-19 patients who are overweight or have obesity.

These observations are important for clinicians because they indicate that the presence of overweight or obesity per se should not influence important clinical decisions during in-hospital COVID-19 care, including decisions regarding ICU admission or the initiation of mechanical ventilation.

Our observation that overweight and obesity are not independent factors for in-hospital mortality may seem contrary to previous reports and popular media coverage (31–33), but several possible explanations are available. Firstly, obesity disproportionally impacts the lower socioeconomic classes (34, 35); in countries where income affects healthcare availability, this may confound COVID-19 outcomes in obese individuals (36), whereas both emergency care and the care for chronic conditions (including the cardiometabolic complications of obesity) are widely accessible, independent of socioeconomic status, in the Netherlands. Secondly, the median BMI of the obese group was 33.1 kg/m², with only 44 patients classified as severely obese (i.e., BMI ≥ 40 kg/m²). In other cohorts, in-hospital mortality was increased in patients with severe obesity (BMI ≥ 35 kg/m²), but not in patients who had overweight or class 1 obesity (BMI 25-34.9 kg/m²) (33, 37, 38). A recent large multicenter study found that increased risk of death was limited to class 3 obesity (BMI ≥ 40 kg/m²) (39). Additionally, a meta-analysis confirmed this non-linear relationship between BMI and poor outcome in patients with COVID-19, in which the association became increasingly stronger from BMI 30-35 kg/m² onwards (40). Thirdly, as described previously increased visceral adipose tissue is associated with adverse outcomes in ICU patients (29). More recent studies have corroborated this finding in patients with COVID-19 (41–43). In our cohort anthropomorphic data on body composition was not available. Measuring visceral adiposity with computed tomography scans to assess the risk for adverse outcomes in patients admitted with COVID-19 would not be feasible in the clinical practice. However, waist circumference and waist-to-hip ratio are simple and inexpensive methods to measure abdominal obesity and have proven to predict obesity-related health risks and mortality (44, 45). It would be interesting for future studies to add the measurement of waist circumference and/or waist-to-hip ratio as a supplement to BMI to predict adverse events and mortality in patients hospitalized with COVID-19. Lastly, patients who are overweight or have obesity may be at increased risk of severe COVID-19, requiring hospital admission, with similar outcomes once they are admitted; this would still make overweight/obesity a risk factor for COVID-19 related morbidity/mortality from a population point of view.

We found several group differences in specific complications during admission. Patients who were overweight or had obesity more frequently developed ARDS and, on average, patients who were overweight required longer mechanical ventilation. Notably, prolonged mechanical ventilation was not observed in patients with obesity. The data on mechanical ventilation shows a large interquartile range which could explain the need for a larger sample size to reach statistical significance. Two possible explanations for the increased ARDS probability in the overweight and obese group are: i) reduced lung volume and compliance due to the presence of adipose tissue around the rib cage, abdomen, and within the visceral cavities (46, 47), which impairs alveolar gas exchange (48, 49), and ii) increased airway hyperresponsiveness due to the chronic inflammatory state (50–53). It is important to note that even though patients with overweight and obesity more often developed ARDS they did not have a higher mortality rate. This observation has more frequently been described and is also referred to as ‘the obesity paradox’ (54). Several studies, including two large meta-analysis, have reported that obesity was associated with an increased risk of ARDS; however, lower risk of mortality (54–57). The underlying mechanisms of ‘ the obesity paradox’ remain unclear. A possible explanation could be an altered inflammatory response. Animal studies have shown that obese rodents with acute lung injury (ALI) had an anti-inflammatory phenotype which, after acute infection, could protect the lungs from further damage due to severe inflammation (58, 59). Additionally, lower circulating pro-inflammatory cytokines have been reported in humans with obesity and ALI (60). Next, patients who were overweight or had obesity also more often developed AKI requiring dialysis. Several factors such as age, diabetes, hypertension and baseline serum creatinine concentrations are associated with an increased risk for AKI in patients with COVID-19 (61). In this cohort, there was a higher prevalence of hypertension and diabetes in patients with overweight and obesity which could affect the renal function in these groups (62, 63). However, our analysis corrected for these factors and baseline creatinine concentrations did not differ between the groups. Nevertheless, obesity is known to be an independent risk factor for developing kidney disease (64, 65). The pathophysiology behind an increased risk of kidney disease in obesity is not completely understood, but factors such as peripheral insulin resistance, pro-inflammatory state, glomerular hyperfiltration, and dyslipidemia could increase the risk for AKI during illness (66–68). Moreover, in patients admitted to the ICU an increased BMI has previously been described to be an independent risk factor for developing AKI (69, 70). A finding which more recently has also been reported in patients with COVID-19 (71).

This retrospective study has several strengths and limitations. It describes a large cohort of hospitalized COVID-19 patients in the Netherlands, with relatively large normal-weight, overweight, and obese groups; it is a multicenter study, spanning both academic and general hospitals throughout the Netherlands; and the CovidPredict database records detailed individual patient data on pre-existing conditions, signs and symptoms at the time of hospital admission as well as events occurring during the hospital stay.

The first and most important limitation is that 46.3% of admitted patients in the original dataset had missing BMI data; given our primary outcome, these patients had to be excluded from all analyses. One may hypothesize that BMI is selectively registered in severely ill patients, thereby introducing bias. We performed several missing data analyses ( Supplemental Materials S2 , S3 ) to gain insight into the missing data. These analyses showed some minor and, in our opinion, clinically irrelevant differences between groups. Even though we do not think that these slight differences are likely to meaningfully impact our results on mortality outcome, a possible selection bias on registering BMI cannot be excluded. Secondly, we were unable to correct for socioeconomic status and ethnicity; factors associated with COVID-19 prevalence and mortality (72, 73). Thirdly, a small number of patients was discharged to another hospital (3.0%) after which they were lost to follow-up. Fourthly, during the first wave of the pandemic, there was no nationwide protocol on the treatment of COVID-19, which led to differences in treatment strategies between the participating hospitals. During the first wave in the Netherlands, the two most prescribed medications were hydroxychloroquine and remdesivir (74). More recent insights suggest that both have little-to-no effect on the need for mechanical ventilation, length of hospital stay, or overall mortality (75). Therefore, we do not believe that heterogeneity in therapeutic strategies introduced any bias. Fifthly, our data merely represents patients admitted to the hospital. Hence, we cannot exclude a bias introduced by hospital admission policies per se. Sixthly, patients with severe comorbidities may have had a non-ICU admission policy; introducing a bias in the main outcomes. Therefore, ICU admission rates were reported as descriptive data only. Finally, we stress that these data only apply to hospitalized patients with COVID-19.

In conclusion, during the first wave of the pandemic in the Netherlands, patients with obesity were overrepresented amongst hospitalized patients with COVID-19. Overweight and obesity were associated with the development of ARDS and AKI, but not with in-hospital mortality nor with the duration of hospital stay.

The datasets presented in this article are not readily available as they contain clinical information. Aggregated data can be obtained based upon reasonable request from the senior author.

The study protocol was reviewed by the medical ethics committees of the Amsterdam University Medical Centers (Amsterdam UMC; 20.131). Given the exceptional circumstances related to the COVID-19 crisis and in accordance with national guidelines and European privacy law, the need for informed consent was waived, and an opt-out procedure was communicated by press release. One of the participating centers (Maastricht University Medical Centre) did collect written informed consent from all their patients.

MB organized the database. JS, SO, and MS contributed to the conception and design of the study. JS, SO, and AŞ performed the statistical analysis. JS and SO wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

This work was supported by a grant from the Corona Research Foundation Amsterdam UMC.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.