key: cord-0785278-58li6dl1 authors: Michalakis, Konstantinos; Panagiotou, Grigorios; Ilias, Ioannis; Pazaitou‐Panayiotou, Kalliopi title: Obesity and COVID‐19: A jigsaw puzzle with still missing pieces date: 2020-10-18 journal: Clin Obes DOI: 10.1111/cob.12420 sha: 3d163bf2f36e3f698d92a98ac03e67b8f480feb0 doc_id: 785278 cord_uid: 58li6dl1 Apart from posing various mechanical and medical issues compromising general health, obesity is a major factor for respiratory tract infections, due to specific inflammation and immunological compromise. The burden of obesity on morbidity and mortality of SARS‐CoV‐2 infection/COVID‐19 is considerable. Herein, we aimed to search the literature and present to the readers pathophysiologic pathways that may associate obesity and COVID‐19. We present potential mechanisms, which might partly explain why patients with obesity are more prone to suffer from respiratory infections in the context of COVID‐19. Better understanding of these pathways could eventually guide management strategies and therapies for COVID‐19 in the future. The world is struggling to fight the novel COVID-19 pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), previously known as "2019 novel coronavirus". 1 Per the World Health Organization (WHO), data converge that the infection fatality rate of COVID-19 is 0.5-1.0% 2 ; seasonal influenza has a rate of 0.1. 2 In an attempt to identify the risk factors that might aggravate the prognosis of outpatients or hospitalized patients, obesity might be a potential suspect, since it seems to interfere with the presence or worsening of respiratory tract infections (RTIs), a major component of the mortality of COVID- 19. 1 Obesity is defined as having a body mass index equal to or higher than 30 kg/m 2 for all populations worldwide, with the exception of China, where according to the World Health Organization obesity is defined as having a BMI equal to or higher than 27.5 kg/m 2 . 3 Obesity rates have almost tripled during the last 40 years, establishing it as an epidemic. Statistics from WHO in 2016, showed that 13% of the world population suffer from obesity (over 650 million subjects in total) and that 39% (more than 1.9 billion subjects) are overweight. 4 In industrialized countries, roughly half of the population is overweight or obese. In USA, the National Health and Nutrition Examination Survey (NHANES) report reported that 34% of inhabitants have obesity. 5 In the past, from the "Spanish" influenza of 1918 onwards, in all influenza epidemics, including the 2009 Influenza A virus (IAV) H1N1 pandemic, malnutrition and obesity were associated with severe disease, complications, hospitalization, need for treatment in intensive care units (ICU) and mortality. 6 This pattern seems to be replicated with and the World Obesity Federation has stated that "obesity-related conditions seem to worsen the effect of COVID-19 1 ; indeed, the Center for Disease Control and Prevention (CDC) reported that subjects with heart disease and diabetes are at higher risk of COVID-19 complications and that severe obesity (body mass index [BMI] of 40 kg/m 2 or higher) poses a higher risk for severe illness 7 ". Many pathophysiological changes occurring with increased adiposity may contribute to poor prognosis of COVID-19 patients. 8, 9 In the present review, we aimed to search the scientific literature for pathophysiologic pathways that associate obesity and COVID-19. We discuss published data regarding the association of obesity with the incidence and severity of respiratory tract infections (RTIs), along with RTI caused by COVID-19, focusing on molecular or hormonal pathways that may be possibly involved and drawing parallels to previous similar outbreaks of RTIs in previous epidemics. The PubMed, Google Scholar, MedRxiv and BioRxiv databases were accessed by all the co-authors to identify relevant English-language articles published up to September 15, 2020. The search terms included "human, coronavirus, COVID-19, SARS-CoV-2, cytokine, adipokine, obesity, complications, human, humoral immunity, cellular immunity". Twenty-eight articles were initially selected and additional publications of relevance to the present article were identified by reviewing the references of the eligible articles. Due to the very recent and not yet well-studied outbreak of COVID-19, epidemiological data and risk factors in the normal-weight and/or populations with obesity are still lacking. While age and male sex are regarded as significant risk factors, accumulating evidence suggests a strong association with an impaired cardiometabolic profile. Initial reports from Wuhan, China, where the COVID-19 first occurred, indicated a higher prevalence of hypertension and diabetes among patients with severe compared to non-severe illness. 10 Both entities are associated with obesity, forming part of the criteria of the cluster of the metabolic syndrome. Furthermore, hypertension and diabetes, as well as cardiovascular disease were identified as risk factors associated with fatal outcomes. 11 However, most patients recruited in Chinese studies had normal BMI or a BMI compatible with overweight classification, but not obesity (please see above; in China obesity is defined by the World health Organization as having a BMI over 27.5 kg/m 2 3 ). Thus, increased BMI was not listed among the risk factors for COVID-19; however, this may reflect lower prevalence of obesity in the region due to a differential body fat distribution in individuals of Asian origin. 12 Nevertheless, it was reported that the percentage of patients with overweight BMI is markedly higher in non-survivors compared to survivors from COVID-19, 13 while most recent data have shown that in patients presenting with metabolic fatty liver disease, the presence of obesity correlated with a 6-fold increased risk for severe illness from COVID-19. 14 Results from a population-based surveillance program across 14 states representing approximately 10% of US population, have shown that among 1482 hospitalized patients in March 2020 for confirmed COVID-19, obesity was the second most common underlying condition in the general population, closely following hypertension, and first among younger individuals aged 18-49. 15 In this age group, 59% of COVID-19 patients that required hospitalization suffered from obesity and this proportion was substantially higher than any other underlying condition, suggesting that obesity might be one of the main risk factors for severe COVID-19 in young or middle-aged adults. 15 The same finding has been reported from Spain, 16 although regional data have not been officially published yet. Selected data on obesity and outcome are shown in Table 1 . [17] [18] [19] [20] [21] [22] [23] In western countries, although data from Italy have confirmed earlier Chinese reports, 24 a French study showed that patients with BMI > 35 kg/m 2 were at significantly higher risk for the requirement of intensive mechanical ventilation compared to normal-weight individuals (with BMI lower than 25 kg/m 2 ), even after adjusting for age, diabetes and hypertension. 25 These results were later replicated in a different hospital in France 26 and have generated more interest in the association between adipose tissue excess and disease pathophysiology. In a meta-analysis, patients with obesity and COVID-19 had a significantly elevated Odds Ratio of 1.20-7.36 to be critically ill and to be mechanically ventilated vs subjects with normal BMI. Being overweight (BMI > 25 kg/m 2 ) or having obesity with COVID-19 entailed an Odds Ratio of 1.22-3.68 for death compared with normal weight subjects. 27, 28 Emerging data from the UK National Intensive Care National Audit and Research Centre indicated that 7 out of 10 patients admitted to ICU were overweight or had obesity and increased body fat accumulation correlated with serious or fatal complications, 29 while in New York hospitals, patients that required mechanical ventilation were again predominantly males with obesity. 30 It has been established that obesity may impair outcomes in patients hospitalized for respiratory infections. In a study of 1455 individuals with obesity, the latter was correlated significantly with lower RTIs (adjusted OR = 2.02, 95%CI = 1.36-3.00) and upper RTIs (adjusted OR = 1.55, 95%CI = 1.22-1.96), with a stronger association for women. 31 Influenza-like illness, bronchitis and pneumonia, pharyngitis, laryngitis but also rhinitis and sinusitis proved to occur more T A B L E 1 Selected reports on the outcome of subjects with obesity and COVID-19 vs subjects without obesity 46 Regarding pure respiratory characteristics of these patients, the lungs of patients with obesity exert altered mechanics, leading to compromised lung ventilation and gas perfusion, thereby lowering oxygen supply due to trunk pressure on the lung parenchyma. 47 Central adiposity limits thoracic expansion and as a result, the pulmonary parenchyma at the lung bases is suppressed, along with a potential weakness of the thoracic muscles. 47 Obesity is often complicated by type 2 diabetes, which seems to be a risk factor for infections per se due to poor skin healing and higher vulnerability to infection. 48, 49 Fat deposition in the liver may often lead to liver steatosis and possible functional impairment, thus affecting the pharmacokinetics of medications, too, while co-existence of chronic renal insufficiency, a common comorbidity in obesity, may complicate the excretion of metabolites or toxic byproducts. 50 Interferons (IFNs) are released in response to viral infections. Smith et al showed that diet-induced obese mice had worse clinical presentation following influenza infection, with increased mortality (42% vs 5% in lean mice). 60 In the same report, reduced lung type I IFNα/β mRNA expression, reduced natural killer cell potential and diminished lung pro-inflammatory cytokine (IL-6, TNF-α and IL-1β) and chemokine mRNA expression 60 were noted. In COVID-19 patients, expression of IFNγ was lower in patients with moderate compared to mild disease. 61 Macrophage activation vs an antigen, along with B-and T-cell responses, are reduced in obesity. In studies of obese mice, respiratory infection disease showed increased severity and increased secondary bacterial infections, along with a delayed and barely blunted immune response and increased morbidity. 62 Obesity minimizes the response of CD8 + T cells to viruses. 6 Post-vaccination for influenza, subjects with obesity show lower antibodies' levels compared to lean subjects, and a weaker influenza-specific CD8 + T cell function; these subjects with obesity show a two-to 3fold higher incidence of influenza despite being vaccinated. 63 The cytokine leptin is released from excess adipose tissue, signalling to the brain the amount of this tissue, albeit with no tangible effect on adiposity per se. 51 Increased leptin (caused by leptin resistance) is often seen in obesity -similarly to insulin resistance -and may predispose to a proinflammatory status. Leptin resistance compromises defence to infection and increases susceptibility to respiratory infections. 64 however, in the absence of clinical evidence of any adverse effects of these agents, continuation of treatment has been advised. 76 Regarding DPP4, this receptor was shown to be a functional MERS-CoV target. 77 suggesting an involvement in immune response. 95 Low vitamin D levels are associated with presence of several chronic diseases and impaired immunity, thereby leading to higher risk for recurrent respiratory infections. 96 A comprehensive meta-analysis has shown that vitamin D replacement can reduce the risk for acute RTIs and its protective effects were even more evident in vitamin D deficient individuals. 97, 98 It is well established that individuals with obesity are more often vitamin D deficient 89 due to the soluble nature of vitamin D in fat, and therefore vitamin D supplementation, as an adjunct therapeutic approach aiming to prevent cytokine storm, 98 may be of importance in the population who suffer from obesity. This is why, at least 10 trials examining the association between vitamin D supplementation and COVID-19 outcomes are now registered with the ClinicalTrials.gov website. 99 Data collected during the early phase of the pandemic showed that lower serum 25-hydroxyvitamin D levels were associated with a higher risk for admission to ICUs due to COVID-19-related illness. 100 A thorough analysis of the UK Biobank data, using historic vitamin D levels that were collected many years before the COVID-19 outbreak, has also shown an association between vitamin D levels and COVID-19 infection. 101, 102 These findings were corroborated by a recent large study from Israel, though it is still unclear whether vitamin D replacement reduces the risk of severe illness from COVID-19. 103 Thus, more studies evaluating vitamin D levels in COVID-19 are needed to examine any associations more in depth. It seems that patients with high BMI -apart from being in danger to show a worse RTI clinical prognosis -are in fact more contagious in terms of spreading a virus or an infection, in general. As mentioned before, the immune response of an individual with obesity is compromised, partly because of reduced or delayed interferon production. This delay allows the virus to produce new potentially mutant strains, via RNA replication, thus making it more difficult for mounting a potent immune response. 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