Individuals with obesity and COVID‐19: A global perspective on the epidemiology and biological relationships

Summary The linkage of individuals with obesity and COVID‐19 is controversial and lacks systematic reviews. After a systematic search of the Chinese and English language literature on COVID‐19, 75 studies were used to conduct a series of meta‐analyses on the relationship of individuals with obesity–COVID‐19 over the full spectrum from risk to mortality. A systematic review of the mechanistic pathways for COVID‐19 and individuals with obesity is presented. Pooled analysis show individuals with obesity were more at risk for COVID‐19 positive, >46.0% higher (OR = 1.46; 95% CI, 1.30–1.65; p < 0.0001); for hospitalization, 113% higher (OR = 2.13; 95% CI, 1.74–2.60; p < 0.0001); for ICU admission, 74% higher (OR = 1.74; 95% CI, 1.46–2.08); and for mortality, 48% increase in deaths (OR = 1.48; 95% CI, 1.22–1.80; p < 0.001). Mechanistic pathways for individuals with obesity are presented in depth for factors linked with COVID‐19 risk, severity and their potential for diminished therapeutic and prophylactic treatments among these individuals. Individuals with obesity are linked with large significant increases in morbidity and mortality from COVID‐19. There are many mechanisms that jointly explain this impact. A major concern is that vaccines will be less effective for the individuals with obesity.


| INTRODUCTION
For persons with coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there appears to be a strong relationship between being an individual with overweight or obesity and the risks of hospitalization and needing treatment in intensive care units (ICUs). Emerging literature suggests that adults with obesity under the age of 60 are more likely to be hospitalized. 1 The COVID-19 pandemic has occurred at a time when the prevalence of individuals with overweight/obesity is increasing in virtually all countries globally. In fact, almost all countries today have a prevalence of individuals with overweight/obesity greater than 20%. [2][3][4] To date, no country has experienced a reduction in the prevalence of individuals with overweight/obesity.
In addition, policy responses for mitigating COVID-19 are creating major economic hardships. The COVID-19 pandemic has brought to all countries the need to restrict movement, implement social distancing and impede economic activities across a broad spectrum of nonessential occupations. These adjustments have caused food system problems, including changes in food consumption and physical activity patterns, and remote telework environments that may exacerbate current trends in the prevalence of individuals with obesity, while another effect will be to increase the proportion food insecure and also those stunted and malnourished. These changes have long-lasting implications beyond the mitigation of the current SARS-CoV-2 spread and may be detrimental to people's health.
The association between individuals with excessive body fat, especially visceral adipose tissue; individuals with obesity; major cardiometabolic problems, ranging from hypertension to cardiovascular disease to type 2 diabetes (T2D); and a number of cancers is strong. [5][6][7][8] The underlying metabolic and inflammatory factors of individuals with obesity also play a considerable role in the manifestation of severe lung diseases. Susceptibility to acute respiratory distress syndrome (ARDS), the primary cause of COVID-19 mortality, is significantly greater among individuals with obesity. 9 Importantly, being an individual with obesity independently increases the risk of influenza morbidity and mortality, 10 most likely through impairments in innate and adaptive immune responses. 11 Potentially the vaccines developed to address COVID-19 will be less effective for individuals with obesity due to a weakened immune response.
In this paper, we first highlight the epidemiological data that provide insight into the relationship between being an individual with overweight/individuals with obesity and COVID-19, undertaking when possible meta-analyses of the published data. We provide an overview of the current understanding of how individuals with obesity affect the immunological and physiological response to SARS-CoV-2.
We follow this with a discussion of the issues of income distribution, food insecurity and the major dietary shifts we are seeing globally. For the latter, we rely on reviews and reports from some key sources of industry sales data, as no solid primary data sources are available. Our discussion includes dietary and activity issues linked with COVID-19 that might exacerbate individuals with obesity and some of the potential policies that can address this issue.

| BACKGROUND: THE GLOBAL PREVALENCE OF INDIVIDUALS WITH OVERWEIGHT AND OBESITY
The prevalence of individuals with overweight/obesity is at an all-time high and is increasing across the globe. This is true not only in higher income countries but also in low-and middle-income countries with high levels of undernutrition leading to the double burden of malnutrition. 4,12 Few low-and middle-income countries have a prevalence of individuals with overweight/obesity less than 20% among their adult populations. Figure 1 shows a map of the world in the 1990s and the late 2010s.
A large proportion of the populations in higher income countries are overweight or obese. As Figure 1 shows, few higher income countries have adult populations with a prevalence of overweight/obese less than 70%. This prevalence is not declining in any country. In higher income countries, the prevalence of individuals with overweight/obesity was already high in the 1990s, and it has continued to increase. In fact, larger portions of their populations have become individuals with morbid obesity with body mass indexes (BMIs) over 35-40 kg m −2 . In low-and middle-income countries outside of Latin America and a number of small islands, the growth in individuals with overweight/obesity has occurred primarily in the past several decades from 1990 to 2020 which we and many others have documented. 2,3,[13][14][15][16] Further, evidence shows that >70% of the individuals with overweight/obesity live in low-or middle-income countries, and as country economies grow, the burden of individuals with obesity shifts to the poor. [17][18][19] In the Middle East and Latin America, the prevalence of rates of individuals with obesity are among the highest in the world.
Two related factors are equally important. First, we are finding that much of the BMI increase accompanies an increase in central adiposity proxied by waist circumference at all ages compared with the amount of such adiposity one or two decades earlier. [20][21][22] Second, across the globe, the economically poor are more prone to develop obesity than are the rich. [17][18][19]23 F I G U R E 1 Prevalence of overweight and obesity based on 1990s and late 2010s weight and height data

| EPIDEMIOLOGICAL RELATIONSHIPS: INDIVIDUALS WITH OVERWEIGHT AND OBESITY AND COVID-19
This review study is exempted from IRB review, and there was no public or patient involvement.

| Literature retrieval
We examined PubMed, Google Scholar, MedRxiv, BioRxiv, Wanfang (for Chinese literature) and other literature search engines (e.g., China National Knowledge Infrastructure Data and ICNARC) to systematically review all publications in Chinese or English that include data on COVID-19 and BMI or individuals with obesity. We briefly reviewed the abstracts and results and located 75 publications available by 15 July 2020 that presented data on the BMIs or BMI categories of diagnosed COVID-19 patients. We excluded literature in other languages, as we read Chinese and English only. All of our authors performed the literature searches and reviews.

| Study characteristics
We found 1733 studies, 75 of which provided data we could use in this review ( Figure 2). All were conducted between January and June 2020, including five case-control studies, 33 retrospective or prospective cohort studies and 37 observational cross-sectional studies.
Sample sizes varied from 24 to 109 367 diagnosed patients in more than 10 countries in Asia, Europe and North and South America. In total, we included 399 461 diagnosed patients in this study, about 55% of whom were male. Table S2 presents detailed demographic data from the studies we used, including a few studies that had inadequate data for use in the meta-analysis. We used STATA (version 16, College Station, TX) to perform all random-effects meta-analysis and used residual maximum likelihood to fit all models. 24

| Being an individual with obesity and the risk of COVID-19
We identified 20 studies that assessed the association between individuals with obesity and COVID-19, all but two of which showed that individuals with obesity significantly increase the risk of COVID-19 (Table S3). [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] One study in Denmark showed that the prevalence of overweight and individuals with obesity was lower in SARS-CoV-2 positive cases than SARS-CoV-2 test-negative individuals (8.6% vs. 9.9%). 44 The results may be biased because body weight status was determined at hospital discharge. A study used U.K. Biobank data CI, 1.46-2.65; p < 0.0001), adjusted for age, sex, ethnicity and socioeconomic deprivation as measured by unemployment, assets and household density. 32 The authors tested only a small portion of individuals (0.5%) for COVID-19, a key limitation of this study. A better way to calculate OR for this study is to compare the odds between subjects who tested positive and those who tested negative. Our pooled data analysis showed that the odds of individuals with obesity being COVID-19 positive were 46.0% (OR = 1.46; 95% CI, 1.30-1.65; p < 0.0001) higher than those of individuals who were not obese ( Figure 3).

| Being an individual with obesity and COVID-19 illness severity
Being an individual with obesity increases the odds of COVID-19 patients being hospitalized. Among diagnosed COVID-19 patients, the prevalence of individuals with obesity in hospitalized patients was much higher than that in nonhospitalized patients. For example, a report that included 5700 patients with obesity in New York City 45 showed that 41.7% of COVID-19 hospitalized patients were individuals with obesity, whereas the average prevalence of individuals with obesity in New York City was 22.0%. 46 Many studies reported COVID-19 hospitalizations, but only a few reported the relationship between individuals with obesity and hospitalization. We identified 19 studies that examined the relationship and included them in this analysis. 1,28,38,40,44,[47][48][49][50][51][52][53][54][55][56][57][58] Table S4 presents the results 1,45,47,48,59,60 ; all showed a significantly higher prevalence of individuals with obesity among hospitalized patients than among patients not hospitalized or the general population.
All studies reported that among those diagnosed, patients with obesity were more likely to be admitted to ICUs. * However, the effect sizes in the studies with smaller sample sizes were not statistically significant. 48,72,73 In the studies that found that being an individual with obesity did not significantly increase the odds of being admitted to the ICU, individuals with morbid obesity (defined as BMI ≥ 35) did significantly increase the odds of ICU admittance. Our pooled data (from 22 studies) showed that individuals with obesity increased the odds of being admitted to the ICU by 74% (OR = 1.68; 95% CI, 1.46-2.08; p < 0.0001) ( Figure 5 and Table S5).
Reports that had smaller sample sizes from the United Kingdom and some other countries showed that patients with obesity had higher but insignificant odds of invasive mechanical ventilation (IMV) than patients without obesity. 48,72,86 Reports from Mexico and some U.S. cities showed significantly higher odds of IMV in patients with obesity than in patients without obesity. † The pooled data (from 14 studies) showed a 66% increase in IMV in patients with obesity (OR = 1.66; 95% CI, 1.38-1.99; p < 0.0001) ( Figure 6 and Table S6).

| Being an individual with obesity and COVID-19 prognosis
The association between obesity and COVID-19 prognosis is complex, because patients discharged from ICUs may be still hospitalized or deceased later. For example, 4.5% died after they were discharged from ICU; 11.5% remained in the hospital after leaving the ICU in one study. 31 A few studies showed that individuals with F I G U R E 4 Meta-analysis of the association between individuals with obesity and the risk of hospitalization with COVID-19  Figure 7 and Table S7). ‡ We excluded two studies that had very large OR and very wide 95% CI, one study in China (OR = 32.08; 95% CI, 6.73-153) 65

| WHY ARE INDIVIDUALS WITH OBESITY AT SERIOUS RISK FOR COVID-19?
Being an individual with obesity is associated with numerous underlying risk factors for COVID-19, including hypertension, dyslipidaemia, type 2 diabetes (T2D) and chronic kidney or liver disease. Coronaviruses are typically not associated with severe disease and were mostly thought to cause only mild respiratory infections until the emergence of the 2002 severe acute respiratory syndrome coronavirus (SARS-CoV) in Guangdong, China. The SARS-CoV outbreak was ultimately contained thanks to its low viral load within the beginning stages of symptom onset, allowing time for identification and isolation of infected individuals. 107 The 2009 influenza pandemic, caused by an outbreak of the upper respiratory influenza A H1N1 virus, identified individuals with obesity as an independent risk factor for severe influenza morbidity and mortality. 10 Subsequently, emergence of the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 exhibited high prevalence among individuals with obesity. 108 The growing evidence detailed above demonstrates that obesity increases the risks of hospitalization, severity and in some cases death with viral respiratory infections, increasing the likelihood that obesity may also independently increase the risk for COVID-19, another respiratory viral disease. Several reports summarize the current understanding of the pathogenicity and immune response to SARS-CoV-2 based on available data from animal and human studies. 109

| Individuals with obesity's metabolic and physiological impairments linked to COVID-19
Being an individual with obesity is a major risk factor for severe cases of certain infectious diseases, like influenza, hepatitis and nosocomial infections. 111,112 However, other infections, like tuberculosis, community-acquired pneumonia and sepsis, have more favourable clinical outcomes in adults with obesity compared with lean adults. 113 This supports the 'obesity paradox' hypothesis, where underlying characteristics of individuals with obesity influence the physiological response to infection. As with influenza infections, being an individual T A B L E 1 Body mass index (BMI) (kg m −2 ) distributions among COVID-19 patients (mean with 95% CI or median with interquartile range) Hyperglycaemia, a key hallmark of T2D, is highly associated with individuals with obesity. Importantly, uncontrolled serum glucose has been shown to significantly increase COVID-19 mortality. 116  liver, heart and kidneys. 109,142 This mechanism is thought to drive increased incidence of ischemic and coagulopathy conditions in COVID-19 patients.

| Inflammatory considerations of COVID-19 in individuals with obesity
ARDS and acute lung injury (ALI) are two of the primary causes of morbidity and mortality among adults infected with SARS-CoV-2. 143 Presentation of ARDS and ALI is characterized by respiratory failure due to excessive pro-inflammatory cytokine production. This inflammatory state leads to extensive lung damage, hypoxemic respiratory failure regardless of oxygen administration and pulmonary oedema not caused by congestive heart failure. 144  Men also experience a higher burden of COVID-19 than women. 59 Being a man with obesity increases aromatase activity, which can convert testosterone to estradiol. 152 Oestrogen receptor signalling can subsequently down-regulate IL-6 expression through inhibition of NF-κB, 153 which has been shown to confer protective effects against influenza A virus in women through stimulation of neutrophil and virus-specific CD8 T cell responses. 154 Interestingly, however, men with obesity have impaired oestrogen receptor signalling, which leads to increased androgenic hormones and elevated oestrogen production from adipose tissue. 155 Recently, androgen depletion therapy has been shown to protect against COVID-19 in male prostate cancer patients. 156 However, more information is needed to understand the mechanism of action of androgens and androgen depletion therapy. Nonetheless, adequate control of proand anti-inflammatory responses during SARS-CoV-2 infections is critical to limit nonspecific tissue damage and subsequent development of ARDS, which has a higher burden among COVID-19 cases with obesity.

| Implications for treatment and vaccination strategies for being an individual with obesity
Obesity may also impair therapeutic treatments during COVID-19 infections. ACE inhibitors, which are commonly used to treat hypertension, may increase COVID-19 severity in T2D patients, especially those with poorly controlled blood glucose. 157 While discontinuing use of ACE inhibitors is not advisable at this time due to offsetting cardiovascular benefits, 158  binding. How these treatments in patients with obesity contribute to COVID-19 severity, however, will be a key question in their overall effectiveness. The IL-6 receptor (IL-6R) antagonist tocilizumab may reduce IL-6 signalling in severe COVID-19 cases where cytokine release syndrome is a major factor of mortality. 159 As noted above, chronic inflammation is a hallmark of individuals with obesity, which includes elevated levels of IL-6. Preliminary data suggest tocilizumab treatment can reduce fever and oxygen requirement. 160  middle-income countries. 174 The impact on not only malnutrition but increased food insecurity for the large proportion of lower income families is expected to be significant. 174 One might suspect we would see a decline in obesity if the food insecurity impacts the individuals with overweight and obesity in many low-and middle-income countries. This truly depends on how serious is the food insecurity and loss of income and how are diets shifted, if at all. We will see diet shifts in not only how we eat and drink but also how we move if inactivity grows greatly. If the diets shifts to increased consumption of refined carbohydrates, fried food and other unhealthy aspects of the traditional diet or to increased highly or ultraprocessed food we may experience increases in the prevalence of individuals with obesity. One can speculate but we truly do not know. Surveys on this topic are not published to date. Similarly studies in higher income countries suggest weight gains or no shift in weight. 175 At the same time, some studies from higher income countries suggest potential increases in obesity. 175,176 While we do not have data on sales of ultraprocessed foods and beverages, many reports both from organizations monitoring food purchases and global company reports suggest that in higher and middle-income countries access to fresh foods, especially fruits and vegetables is impacted due to breakdowns in local supply chains, and the demand for packaged processed food has increased, especially in the ready-to-eat and -drink categories. 8,177 These foods tend to be ultraprocessed and high in energy density, saturated fat, sodium and sugar. The attraction is partially that these foods require less storage and are highly palatable. In addition, they are relatively inexpensive due to the large economies of scale in their production. Particularly where costs loom greatly in food-purchasing decisions, as among the lower income segments of the population, these cheaper products may be consumed in much greater quantities. However, ultraprocessed foods are a major contributor to obesity and other non-communicable diseases (NCDs). The literature linking ultraprocessed foods with adverse health outcomes is large and consistent. [178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195] Additionally

| Policy implications
Vaccination remains the best protection against infectious diseases like COVID-19. Therapeutics targeted at limiting viral replication or remediating complications of infection may help limit severe cases and moderately reduce mortality. Public health experts agree that viral spread will continue to cause tremendous health and economic problems until we reach vaccination and/or community-acquired herd immunity. Current models project that intermittent times of social distancing and lockdown measures will be required until a viable vaccine can be widely produced, 197 and these measures are likely to extend into the foreseeable future. This paper highlights another concernthat is, vaccines may not be as effective in individuals with overweight/obesity. Given the large prevalence of the world population that is composed of individuals with overweight/obesity, it is imperative that governments ensure that testing and research focus not only on the general efficacy of vaccines and therapeutics but also on how they will impact individuals with obesity.
Furthermore, we must carefully monitor and regulate the consumption of ultraprocessed foods and beverages through fiscal policies such as taxation and regulating marketing and promotion of such foods. If as expected this behaviour is increasing, it will exacerbate other health concerns, including risks of increased adiposity and major NCDs. When compounded with reduced physical activity and increased sedentary behaviour, the risk of increased adiposity is clearly an important concern. Finally, the poor around much of the globe also face increased hunger and with it the potential for elevated stunting and its consequences, including the long-term risks of central visceral adiposity and many NCDs. Increasing hunger and stunting can have long-term adverse impacts on health and well-being in multiple ways, and major policies to mitigate this effect are critical when resources are available.
In addition to COVID-19's critical economic constraints, its impacts on diets may pose lifelong risks to populations around the globe. Food habits developed during this period, particularly the intake of ultraprocessed foods, represent a major health risk. Exact policy prescriptions will be country specific, and clearly, the concerns for higher and middle-income countries will differ from those of lowincome countries. NCD and individuals with obesity risks are far more predominant in the former, whereas the latter face high levels of the double burden of malnutrition, in which slow declines in stunting are likely to shift to increased stunting and wasting accompanied by rapid increases in individuals with obesity.
Creative policies to reduce consumption of ultraprocessed foods and increase consumption of healthier foods, such as legumes, selected whole grains, vegetables and fresh fruits, are important for all countries. A recent World Bank report suggests that the multipurpose Chilean model effectively administers multiple regulations and laws that reinforce each other and are impactful. 12,198,199 It is quite that likely Chile's policies could significantly reduce the current growth in consumption of ultraprocessed foods. Moreover, a tax accompanying purchases of those foods would potentially increase fiscal space in countries suffering from the economic impacts of COVID-19, albeit few countries have successfully allocated these resources for health or nutrition programmes. Some countries are finding ways to provide boxes of fresh vegetables and fruits to the elderly such as one programme in several Chilean cities 200 ; however, most low-and middleincome countries do not have the resources for such efforts though combined with taxation and marketing controls, such efforts would be more feasible. All countries need to consider how to enhance consumers' selections of healthy food options while reducing incentives to purchase ultraprocessed foods and beverages. To date, no country has combined these fiscal and regulatory policies. However, Israel's Chilean-style warning labels and promotion of healthy eating comes closest. 201 The COVID-19 pandemic challenges all countries enormously.
Our systems, institutions, health and welfare will feel the impacts for many years. The high prevalence of individuals with obesity exacerbates the threat to everyone's health, and the economic, social distancing and stay-at-home components compound the impacts. We will need creative solutions quickly to prevent undesirable dietary patterns and promote healthy eating, which is so critical to our future health and for building resilience against future threats.