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Tackling obesity during the COVID‐19 pandemic

Institute of Endocrinology, Beilinson Hospital, Petach Tikva, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Diabetes Unit, Department of Endocrinology and Metabolism, Faculty of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel Department of Clinical & Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Pisa, Italy Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK Department of Endocrinology & Metabolism, Antwerp University Hospital, Edegem‐Antwerp, Belgium Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China Li Ka Shing Institute of Health Science, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China Key Laboratory for Endocrine andMetabolic Diseases of Ministry of Health, Department of Endocrine andMetabolic Diseases, Rui‐Jin Hospital, Shanghai Jiao‐Tong University School of Medicine, Shanghai, China


| INTRODUCTION
Most people contracting coronavirus disease 2019 (COVID- 19) develop a non-serious disease with some remaining entirely asymptomatic. However, the disease may manifest severely and lead to mortality secondary to the development of respiratory failure and disseminated organ failure. 1 Potential risk factors for severe illness include advanced age and underlying medical conditions, such as diabetes mellitus and cardiovascular disease. 1,2 Furthermore, studies have consistently shown that obesity is an important risk factor for severe COVID-19 (Table 1). [3][4][5][6][7][8][9][10] The prevalence of obesity has been rising steadily, globally, with a recent report in the United States revealing that 42% of adults are obese, while 9% fulfil the criteria for severe obesity. 11 The current COVID-19 pandemic mandated lockdown in many countries with closure of schools and non-essential businesses. While clearly effective in curbing the epidemic spread, a further increase in the prevalence of obesity is a predictable untoward outcome, 12 as people eat more and exercise less. 13 A study to assess the effects of lockdown during COVID-19 epidemic on lifestyle in patients with type 2 diabetes in North India reported carbohydrate consumption and frequency of snacking increased in 21% and 23% of study participants, respectively, while exercise duration decreased in 42% and weight gain was documented in 23% of patients. 14 A survey in China showed that during semi-lockdown, normal-weight individuals had less awareness of weight gain, the average steps per day and the average moderate or vigorous-intensity exercise declined significantly for both genders. 15 Increased caloric consumption during the lockdown, as well as poor food choices, increased intake of fast-foods and pre-ordered meals which are frequently high in salt, saturated fat and sugar are possible contributors to weight gain. Moreover, the reduced availability of indoor gyms or outdoor physical activities markedly reduced the opportunity for regular exercise. These restrictions, combined with the sedentary lifestyle imposed by the lockdown, will inevitably lead to further weight gain.
Amit Akirov and Avivit Cahn contributed equally to this paper.

| OBESITY AND COVID-19
An early report based on UK Biobank data suggested a doseresponse association between body mass index (BMI), waist circumference and positive testing for COVID-19. 16 Obesity was associated with an approximately threefold increased risk for severe COVID-19 (33.3% vs. 14.7%, respectively), and longer hospital stay (median 23 vs. 18 days, respectively) was noted in obese versus non-obese patients. 4 Obesity has also been associated with a significantly higher rate of Intensive Care Unit (ICU) admission or death. 8 Furthermore, obesity class I (BMI > 30 kg/m 2 ) and obesity class II (BMI > 35 kg/m 2 ) have been associated with an increased risk for need of invasive mechanical ventilation in patients hospitalized for COVID-19, independent of age, sex, diabetes mellitus and hypertension. 9,13 Lighter et al. reported that among those under 60 years of age, obesity (BMI > 30 kg/m 2 ) was twice as likely to result in hospitalization for COVID-19 and in the need for critical care. 17 A study from France also supported the association between obesity and severe COVID-19, including increased risk for ICU admission in obese individuals. 5 Kass and colleagues investigated the association of BMI and age in patients admitted to ICUs in the United States due to COVID-19.
Their study demonstrated a shift in the age threshold of developing severe COVID-19 disease in obese patients, such that severe obesity places young patients in their 30s at a similar risk category as elderly normal-weight patients. 18 Similarly, Busetto et al. from Italy reported that overweight or obese patients hospitalized due to COVID-19 were more than 10 years younger compared to those with normal weight, yet despite their younger age, these patients required invasive mechanical ventilation and ICU admission more frequently. 6 A study from China reported similar findings, noting the association of obesity with high mortality risk in young patients with COVID-19. 3 The French Coronavirus SARS-CoV-2 and Diabetes Outcomes study included 1317 patients with diabetes and confirmed COVID-19, and revealed a significant and positive association between BMI and death or mechanical ventilation within a week of admission. 19 Data from England reported that patients with type 1 or type 2 diabetes were at increased risk for COVID-19 associated mortality, and there was a U-shaped relationship with BMI. In patients with type 1 diabetes and BMI ≥40 kg/m 2 mortality was more than double that of those with BMI 25-29.9 kg/m 2 , and in those with type 2 T A B L E 1 Risks associated with obesity and recommendations during COVID-19 pandemic

Risk associated with Obesity Recommendation
Obesity shifts the prevalence of severe COVID-19 disease to a younger age 18 Encourage obese individuals, at any age, to pay special care to social distancing recommendations Increase awareness of health care teams to the risks associated with obesity In infected young obese patients provide care and monitoring similar to that provided to elderly patients 18 Obesity is associated with increased risk of venous thromboembolism in patients with COVID-19 22,23 Have a low threshold of initiating anti-coagulants in obese patients with COVID-19, as a correlation between heparin use and lower mortality rates has been observed 32 Initiate statins in obese patients with dyslipidaemia poorly controlled by diet alone, as this has been noted to be associated with lower risk for pulmonary embolism 23 Vitamin D deficiency, more prevalent in the obese, may increase the risk for complications of COVID-19 30 Vitamin D supplementation may protect against acute respiratory infections, 33 however, this is still under discussion Concomitant hypertension and hyperglycaemia increase the risk for severe COVID-19 disease [34][35][36] Strive for better control of blood pressure 36 and glucose during the pandemic 34,35 Maintain telehealth contact with primary care to ensure continuous supply of medications and access to medical advice where needed Periods of quarantine and lockdown lead to further exacerbation of the obesity pandemic 12 Telehealth services may prevent marked weight gain during lockdown periods 37 Utilize the media to deliver health-promoting messages encouraging physical activity and balanced diet diabetes and BMI of ≥40 kg/m 2 mortality risk was almost 1.5-fold higher. 20 The OpenSAFELY collaborative reviewed electronic medical records from over 17 million UK adults, aiming to identify risk factors for mortality from COVID-19. The study noted that both diabetes and obesity were associated with increased risk for death from COVID-19. The fully adjusted model showed a dose-response association between BMI and mortality, with an increase of 27%, 56%, and 127% in mortality risk for those with BMI 30-34.9, 35-39.9, and ≥40 kg/m 2 , respectively. 21

| PATHOPHYSIOLOGICAL MECHANISMS
Obesity has been observed to be associated with severe COVID-19 disease, independent of diabetes, hypertension and cardiovascular disease-concomitant disorders also known to contribute to severe disease. 18 Several potential underlying mechanisms have been proposed. Disruption of lung function in patients with obesity secondary to excess pressure on the diaphragm while lying supine was suggested to limit ventilation and reduce mucous and probably viral clearance. 18 Obesity is associated with an increase in pro-inflammatory cytokines, and it has been proposed that the pro-inflammatory state, hypoxia, immobilization and diffuse intravascular coagulation triggered by SARS-CoV-2 infection increase the risk for thromboembolism in these more susceptible individuals. 22 Poyiadji et al. reported that in patients with COVID-19 BMI >30 kg/m 2 was associated with a 2.7-fold increased risk for pulmonary embolism.
Interestingly, the researchers also reported that statin therapy prior to admission may reduce the risk for thromboembolism in both obese and non-obese patients. 23 Endothelial dysfunction which is a known characteristic of obesity, hypertension and diabetes mellitus may also contribute to the excess morbidity. The acute endothelial damage induced by SARS-CoV-2 may promote lung microvascular dysfunction, vascular leakage, alveolar oedema and hypoxia with those having pre-existing alterations at greater risk. 24  Visceral adipose tissue may play an important role in the predisposition to worse COVID-19 outcomes. Interleukin-6, which can be secreted from visceral adipose tissue, was found to be increased in patients who died of COVID-19. Furthermore, ectopic visceral fat is also important, as studies have shown that patients with obesity present accumulation of adipose tissue within the lung parenchyma, which correlated with inflammatory infiltrate and pulmonary injury. 27 Visceral deposition of fat within the abdomen was also reported to be independently associated with worse clinical outcomes in patients with

| CONCLUSION
While the present data support the increased tendency of obese people to develop severe COVID-19 disease once contracted, an increased risk of infection with increasing BMI has not been clearly demonstrated. There is need for additional studies to explore the benefits of various interventions in reducing the morbidity and mortality of obese patients, and a holistic approach addressing the infected individuals as well as the overall obese population must be adopted.