The first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Germany was reported on January 27, 2020 (1, 2), about 2 months after the first pneumonia patient-cases of unknown origin were identified in Wuhan, China (3, 4). Patients with detected SARS-CoV-2 infection have been documented both in hospitals and in family settings (4). The first reports from China indicated mild symptoms in the majority (approximately 4/5) of patients with SARS-CoV-2 infection, about one-fifth were hospitalized, and among them, one-fourth were admitted to intensive care units (ICUs) (3, 5, 6). From China, the SARS-CoV-2 pandemic spread worldwide and affected nearly every country (1, 5, 7, 8). In order to avoid a critical overload of the healthcare system, many countries, like Germany, have implemented lockdown strategies (5, 8, 9). Since the beginning of the COVID-19 pandemic, deaths related to COVID-19 counted more than 5 million people worldwide (10). In particular, the case-fatality rate of COVID-19 patients who have to be treated in ICUs with mechanical ventilation (MV) is very high (2, 5, 9). Studies have shown an association between COVID-19 and cardiovascular disease (CVD) (11, 12). Particularly, preexisting CVD seems to be linked with poor outcomes in patients with COVID-19 (11, 12). Although the predominant clinical manifestation of COVID-19 is pneumonia, COVID-19 infection can also induce CVD such as acute coronary syndrome with myocardial injury, arrhythmia, and venous thromboembolism (VTE) (2, 11, 12). Vascular response to cytokine production of SARS-CoV-2 and interaction between severe acute respiratory syndrome in COVID-19 and angiotensin-converting enzyme 2 receptor might lead to a significant reduction regarding cardiac contractility and result in myocardial dysfunction (12).

Another ongoing pandemic is the increase of obesity worldwide (13, 14). Obesity is a major healthcare concern, not only in high-income countries but even in middle-income and low-income countries, because of its continuous increase in the populations and of its association with chronic diseases, such as CVD, diabetes mellitus (DM), chronic kidney disease (CKD), and some cancer entities (13, 14). In the context of the COVID-19 pandemic, many studies (but not all) identified obesity as a strong risk factor for adverse outcomes in patients with SARS-CoV-2 infection (2, 13, 15–21).

Obesity is accompanied by a well-known chronic inflammatory condition (21). Obesity and its effects on immunity might aggravate disease severity of pneumonia and acute respiratory distress syndrome (ARDS), which are important causes of death due to SARS-CoV-2 infection (21). Adipocytes of the adipose tissue produce and secrete the hormone leptin in proportion to individuals’ body fat mass (21). Increasing levels of circulating plasma leptin are typical for obesity and associated with a leptin-resistant state (21). Leptin, which regulates appetite and immunity, functions in immunity as a cytokine coordinating a host’s innate as well as adaptive responses by promoting the Th1 type of the immune response (21). Leptin is an important factor regarding proliferation and different functions of antigen-presenting cells, T-helper cells, and monocytes, subsequently influencing the pro-inflammatory cytokine secretions by these cells including TNF-a, IL-2, and/or IL-6 (21). Scarcity of leptin levels and leptin resistance correlate with dysregulation of cytokine secretion resulting in autoimmune disorders, inflammatory responses, and especially increased susceptibility towards infections (21, 22). Thus, higher leptin levels and leptin activity in obese individuals contribute to higher mortality rates during SARS-CoV-2 infection (21, 22). In addition, the increased susceptibility to SARS-CoV-2 infection documented in obesity suggests an initial defect in the defense mechanisms, most likely caused by the aforementioned higher systemic metabolic inflammation, which is regulated by NLRP3 inflammasome as a master regulator of metaflammation with a pivotal role in obesity (23–25). NLRP3 inflammasome over-activation contributes to the development of cardiometabolic disorders, while NLRP3 deficiency is accompanied by decreased immune cell activation and, therefore, plays a key role in the immune defense of the host against pathogens, including viruses (23–25). Moreover, increased abdominal visceral adiposity compromises pulmonary function, decreases diaphragmatic excursion, and impairs lung ventilation resulting in reduced oxygen saturated blood levels (22).

The objectives of the present study were to investigate differences in patient characteristics, treatments, and adverse in-hospital events and outcomes of COVID-19 patients with and without obesity as well as the impact of obesity on adverse in-hospital events and outcomes of COVID-19 patients in Germany.

One wave after another of the COVID-19 pandemic has been affecting the citizens and healthcare systems of the countries worldwide. At the end of January 2022, nearly 350 million COVID-19 cases and more than 5.5 million deaths linked with a COVID-19 infection were counted worldwide (10). Regarding risk stratification and better management of these patients with COVID-19 infections, it is of outstanding interest to identify risk factors of adverse outcomes and in-hospital death in hospitalized patients with COVID-19 to initiate adequate treatment, prevent poor outcomes, and save hospital resources to manage pandemic waves without overwhelming regional healthcare systems (2, 5). Several studies identified, among others, obesity is one of these risk factors for higher proneness to SARS-CoV-2 infection and a poorer outcome during COVID-19 infection (2, 10, 12, 14–17).

Thus, in the present study, we attempted to analyze the impact of obesity on adverse in-hospital events in all hospitalized COVID-19 patients in Germany during the year 2020.

The main results of the study can be summarized as follows:

In accordance with the literature (18, 28), our study results demonstrated that COVID-19 inpatients with obesity were younger than those without. Despite younger age, obese patients were affected with an unfavorable comorbidity profile, including CVD risk factors and CVD, and also lung diseases and CKD, similarly to other studies (13, 15, 16, 22, 28–31).

Our study results highlighted that the majority of COVID-19 patients suffered from pneumonia as their respiratory manifestation of COVID-19, whereby pneumonia and ARDS were more prevalent in obese than in non-obese COVID-19 patients. Regardless of the pathophysiological effects of acute respiratory failure (ARF) and ARDS, obese patients are characterized by multiple alterations in respiratory mechanics. The compliance of the respiratory system is influenced by the external compression due to the weight of fat tissue resulting in an impaired functional residual capacity (FRC) (32–34). The obesity hypoventilation syndrome is a well-known problem in severe obesity also outside COVID-19 infection and ICU treatment and is associated with an increase regarding the need for ventilator support and organ damage (35, 36).

Regarding the setting of respiratory parameters, the identification of optimal positive end-expiratory pressure (PEEP) in COVID-19 pneumonia and associated ARDS has especially been widely discussed since the beginning of the pandemic (37). Current consensus recommendations are provided on the basis of the ARDS network table to detect adequate PEEP (38). Since these recommendations for PEEP settings were derived from experiences in the standard population of patients predominantly with normal weight, it has to be suggested that obese patients might be ventilated with significantly higher PEEP values in order to overcome external compression of the respiratory system. Therefore, alternative approaches are needed to identify the optimal individualized PEEP in obese COVID-19 patients, such as electric impedance tomography or transpulmonary pressure measurement (39). In this context, too low PEEP values can result in negative end-expiratory trans-pulmonary pressure levels accompanied with elevated risk regarding the occurrence of atelectasis, impaired gas exchange, and cyclic lung collapse followed by pulmonary inflammation and ARF (40, 41).

Some other cornerstones in the up-to-date treatment of ARDS in COVID-19 patients, such as prone positioning, are also harder to achieve in obese patients. Prone positioning in obese patients requires more staff (nurses, respiratory therapists (RTs), and physicians) to provide it safely. Nevertheless, prone positioning could in severe obesity be harmful, and its implementation in the individual ICU treatment could sometimes be impossible if not provided by a skilled team (42–44).

In addition to the changes in respiratory mechanics, recent studies have indicated that the occurrence, disease severity of COVID-19 patients, and the attributed adverse outcomes of COVID-19 patients are directly associated with the weakened immune system in obese individuals by chronic inflammation due to adipose tissue and by dysregulation of pro-inflammatory cytokines (13, 15, 45). Therefore, it has to be hypothesized that acute inflammation arising from acute COVID-19 infection may amplify existing chronic inflammation secondary to obesity and might lead to a more severe disease status as well as poorer outcomes (15).

Our study results corroborate the aforementioned physiological effects of obesity, demonstrating that obese COVID-19 patients in Germany revealed more severe disease status and were treated more often in ICUs and with a higher rate of MV, dialysis, and ECMO. This more aggressive treatment approach might be attributed to lower patient age and the higher number of obese COVID-19 patients who were treated at larger urban hospitals with more invasive capacities. However, it has been previously reported that obese patients have a higher demand for more aggressive treatments in the context of acute and critical care medicine including especially invasive treatment approaches (46–50).

Despite these strong efforts in therapy, obesity in COVID-19 was independently associated with increased in-hospital case-fatality rate and MACCE rate as well as VTE events in our study in accordance with others (10, 12, 14–17). Although the unadjusted comparison between obese and non-obese COVID-19 patients revealed that obese COVID-19 patients had a 1.1% lower in-hospital case-fatality rate (16.9% vs. 18.0%) in comparison to non-obese COVID-19 patients, the adjusted logistic regressions revealed a negative effect of obesity on the case-fatality rate. The multivariate logistic regression models (regarding the outcome in-hospital case fatality) demonstrated eminently an association of obesity in COVID-19 patients with increased in-hospital case fatality independently of age, sex, cancer, heart failure, coronary artery disease, peripheral artery disease, chronic obstructive pulmonary disease, essential arterial hypertension, hyperlipidemia, renal insufficiency (GFR < 60 ml/min/1,73 m²), DM, and atrial fibrillation/flutter. For a more precise and in-depth comparison, we performed logistic regression models to analyze the impact of obesity on the case-fatality rate of COVID-19 patients in each decade of life. The age-dependent analysis demonstrated an independent association of obesity with increased case-fatality rate in the 3rd, 4th, 5th, 6th, and 7th decades of life in COVID-19 patients, while obesity did not affect case-fatality rates of older patients significantly and independently. Remarkably, the effect of obesity on the case-fatality rate was larger in COVID-19 patients in the 3rd and 4th decades of life. Since most hospitalized COVID-19 patients were older, it is not surprising that the univariate logistic regressions failed in the overall study sample without age-adjustment or age-dependent analysis to demonstrate an increased in-hospital case fatality in the unadjusted comparisons and was only evident in the adjusted and age-dependent analyses.

Gao et al. highlighted in accordance with our results that even below the threshold for obesity, a BMI higher than 23 kg/m² was associated with an increased risk of severe COVID-19 outcomes, particularly in patients younger than 40 years (13, 16). Also in line with these observations, the study of Mohammad et al. identified obesity as a major risk factor for adverse outcomes in patients with COVID-19 (15). In a large Swedish cohort of ICU patients with COVID-19, a high BMI was associated with an increased risk of death and prolonged length of in-hospital stay as well (18). Tartof et al. reported in a retrospective study that obesity plays an important role in risk for death from COVID-19, especially in male and younger patients (17). In addition, a large Korean study revealed a non-linear (U-shaped) relationship between BMI and fatal illness, meaning that especially patients with underweight as well as having a BMI ≥25 kg/m² had a higher risk of fatal COVID-19 disease (28). Also an analysis of the Premier Healthcare data of the United States (March–December 2020) showed that obesity was a risk factor for MV, hospitalization, and death predominantly among adults aged <65 years (51).

Based on nationally representative data on demographics and the cardiometabolic conditions of the patients, O’Hearn et al. estimated that nearly 2/3 (63.5%) of COVID-19 hospitalizations among the adult citizens of the United States were attributable to four cardiometabolic conditions: obesity, DM, arterial hypertension, and heart failure. Within this group, obesity (30.2%) and arterial hypertension (26.2%) were linked to most COVID-19 hospitalizations (52). The large epidemiology study of Popkin et al. reported an increase of COVID-19 patients’ hospitalizations, ICU admissions, and deaths in nearly 400,000 COVID-19 patients with obesity worldwide (53). In contrast to some of the studies, our study results demonstrated that particularly severe obesity affected in-hospital case fatality and MACCE rate independently and significantly, while mild obesity and moderate obesity were not independently associated with these outcomes. In addition, as aforementioned, the impact of obesity was age-dependent.

In one previous publication of our research group, we observed a temporal trend regarding hospitalizations and in-hospital case-fatality rate of all hospitalized patients with COVID-19 infection in Germany 2020 (2). In line with the time trend of all admitted COVID-19 patients in Germany, the highest monthly numbers of hospitalizations of COVID-19 patients with obesity were observed during October to December 2020 and in the 7th and 8th age decades of life. Remarkably, the case-fatality rate was higher in the months with increased numbers of admitted COVID-19 patients, which might be interpreted as a surrogate of overloading of the healthcare system, and increased exponentially with age (2, 5, 8, 9).

Several pathophysiological mechanisms of obesity as a risk factor driving severe COVID-19 illness have been suggested (19): first, the adipose tissue has more angiotensin-converting enzyme-2 receptors, which is the site for the coronavirus entry into the cells, than does the lung tissue, so the excess adipose tissue could serve as a reservoir for the coronavirus (29, 30). Also an excess of abdominal fat and weight impairs adequate ventilation and increases the risk for infection (including expansion of the COVID-19 infection but also secondary infections) (19, 31), which might explain higher rates of pneumonia and ARDS of obese patients in our study. Certainly, central or abdominal obesity or visceral adipose tissue may carry a particularly “heavy” risk in COVID-19. Ventilating obese patients via mask ventilation or intubation is more difficult not least because of an increased thoracic mass accompanied by a need for higher positive end-expiratory and peak pressures to maintain proper oxygenation and an increased risk of barotrauma (such as alveolar injury/rupture and pneumothorax) (19, 31). Since our study detected a decrease regarding the necessity of ICU admissions and MV over the months of the year 2020, this could be interpreted as a learning curve of the treating physicians regarding the use of invasive treatments in obese COVID-19 patients. As mentioned, the effect of a weakened immune system in obese individuals by chronic inflammation due to adipose tissue and by dysregulation of pro-inflammatory cytokines might predispose obese COVID-19 patients to more severe infections (13, 15, 19, 45). Last but not least, social factors may contribute to poor outcomes, including loneliness, and might be followed by a higher frequency of depressive syndromes (19). In addition, because the focus is on the healthcare system and the physicians working with the COVID-19 pandemic, other prevalent acute or chronic diseases that carry an increased risk for adverse outcomes in patients with COVID-19 infection and severe COVID-19 complications might be overlooked, be considered to be unimportant at this time, or be unnoticed (19). National lockdown measures with stay-at-home orders for longer periods favored sedentary lifestyle with distinctly reduced physical activity (PA) and exacerbated unhealthy dietary habits resulting in increased prevalence of obesity during the pandemic along with the psychological effects of social isolation (5, 8, 9, 19, 54). Nevertheless, the proportion of COVID-19 cases with severe obesity did not change over the months ( Figure 3A ), indicating only a slow shift regarding more severe obesity.

Obesity predisposes patients to develop a VTE event, which was reported by Karbhel et al., who demonstrated a strong association between increasing BMI and higher VTE rate (55). The authors outlined that the relative risk of unprovoked pulmonary embolism (PE) increased by approximately 8% per 1 kg/m² higher BMI and approached an approximately 6-fold elevated risk among individuals with a BMI ≥ 35 kg/m² (55, 56). This finding was supported by the results of the present study, revealing a 1.7-fold risk for VTE in obese vs. non-obese patients. VTE is a potentially life-threatening complication, and hospitalized COVID-19 patients frequently have macrovascular and microvascular thrombosis and inflammation, which are associated with a poor clinical outcome (57, 58). Interestingly, the number of VTE events in obese COVID-19 patients decreased over time but remained unchanged with age. This is an important finding, since the risk of VTE events increased in the general population, substantially with age (27, 59–61). Besides the challenges in dosing anticoagulants in critical ill overweight patients, it should be suggested that some VTE events might be overlooked since not all COVID-19 patients were examined by CT with angiography and PE might be fatal in COVID-19 patients before PE is diagnosed (62).

Based on our findings, we recommend that COVID-19 patients with obesity should be closely monitored when hospitalized (18). The awareness regarding VTE events is important in obese patients; these events or delays in the diagnosis of these life-threatening complications should not be overlooked (27, 59, 62). When clinicians develop healthcare plans for COVID-19 patients, they should consider the risk of poor outcomes, especially in patients with severe obesity (51). In addition, these considerations should be included in the promotion of COVID-19 prevention strategies and healthcare planning (51, 63, 64). Maintaining a healthy weight is therefore important not only to prevent chronic cardiometabolic diseases but also regarding better individual outcomes of COVID-19 patients (28, 63, 65, 66). Thus, public health efforts directed towards a healthy diet and an increase in PA are crucial in both children and adults (19, 63, 64, 66–70). A body of evidence suggests that the nutritional status of COVID-19 patients is directly associated with the severity of the SARS-CoV-2 disease (71–73). Although no single diet or food item has been proven to prevent COVID-19 infections, some key dietary components comprising vitamins C and D, omega-3 fatty acids, and zinc might have positive anti-inflammatory effects similar to the Mediterranean diet and might enhance the health of COVID-19 patients (71–73). In addition, the protective role of nutraceuticals such as quercetin and resveratrol in patients with obesity or cancer has to be considered and emphasized for regularization of the hypersecretion of interleukins and cytokines in order to improve the immune function and reduce the risk of ARDS and inflammation (73, 74). International efforts are needed to prevent obesity, particularly its progression to more severe degrees, and to improve PA, exercise, and fitness, as well as overall healthy living, for this and future pandemics (29, 31, 63–70).

Obesity independently affected case fatality, MACCE, VTE, and other adverse in-hospital events of COVID-19 patients. Obesity should be taken into account regarding COVID-19 prevention strategies, risk stratification, and adequate healthcare planning. Maintaining a healthy weight is important not only to prevent chronic cardiometabolic diseases but also for better individual outcomes during COVID-19 infection.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

Conceptualization: KK and LH. Writing—original draft: KK. Writing—review and editing: KK, IS, VHS, VS, CE-K, CL, TM, and LH. Data curation: KK and LH. All authors discussed the results and contributed to the final manuscript.

TM is PI of the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. CE-K reports having received fees from Amarin Germany, Amgen GmbH, Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, MSD Sharp & Dohme, Novartis Pharma, Pfizer Pharma GmbH, and Sanofi-Aventis GmbH. LH received lecture/consultant fees from MSD and Actelion, outside the submitted work.

The remaining 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.