key: cord-338317-ro041w5l
authors: Lockhart, Sam M.; O’Rahilly, Stephen
title: When two pandemics meet: Why is obesity associated with increased COVID-19 mortality?
date: 2020-06-29
journal: Med
DOI: 10.1016/j.medj.2020.06.005
sha: 
doc_id: 338317
cord_uid: ro041w5l

Abstract A growing body of evidence indicates that obesity is strongly and independently associated with adverse outcomes of COVID-19 including death. By combining emerging knowledge of the pathological processes involved in COVID-19 with insights into the mechanisms underlying the adverse health consequences of obesity, we present some hypotheses regarding the deleterious impact of obesity on the course of COVID-19. These hypotheses are testable and could guide therapeutic and preventive interventions. As obesity is now almost ubiquitous and no vaccine for COVID-19 is currently available, even a modest reduction in the impact of obesity on mortality and morbidity from this viral infection could have profound consequences for public health.

Emerging evidence suggests that people with obesity are at increased risk of mortality from 67

Coronavirus Disease 2019 (COVID-19) but the mechanisms underlying this are poorly understood. An 68 improved understanding of the pathophysiological intersection of COVID-19 and obesity should help 69 guide preventive and therapeutic strategies for this vulnerable group. Here we summarise existing 70 knowledge regarding the pathophysiology of COVID-19 and consider how its various components 71 might be exacerbated by the presence of obesity. We end by suggesting some experiments which 72 could inform public health interventions and/or approaches to therapy. 73

The strong association of obesity with adverse outcomes in COVID-19 is real and relatively specific 74 to a subset of viral pneumonias. 75

Soon after the emergence of COVID-19 there was a flurry of reports from hospitals around the world 76 drawing attention to an apparent excess of obese patients among those ventilated 5, 10, 12, 45, 62 . 77 More recently, preprints have appeared which report much larger and more rigorous 78 epidemiological investigations. OpenSAFELY examined 5683 COVID-19 deaths in the UK and related 79 these to pre-existing potential risk factors documented in over 17 million electronic health records 80 72 . As in all studies to date, age was the most important pre-existing risk factor, but the effect of 81 obesity was highly significant and graded according to the severity of the obesity. The hazard ratio 82

(adjusted for ethnicity) for death for those with Class III obesity (Body Mass Index (BMI) >40kg/m2) 83 was as high as 2.28 (1.96-2.65). The ISARIC study of 16,749 COVID-19 related admissions to 84

Intensive Care Units in the UK reported a lower hazard ratio of 1.37 (1.16-1.63) associated with 85 clinician-reported obesity 19 . It should be noted, however, that BMI was not reported in this study 86 and reliance on clinical diagnosis is known to seriously underdiagnose obesity 53 . 87

In an analysis of COVID-19 mortality in over 300,000 patients with diabetes, obesity was associated 88 with mortality in both type 1 (T1D) and type 2 diabetes (T2D) 36 . Taken together with myriad smaller 89 studies it seems increasingly clear that obesity does indeed increase the risk of mortality and of 90 requiring admission to Intensive Care in people infected with SARS-CoV-2. In contrast to worse 91 outcomes once an obese person is infected, there is currently no evidence that obesity has a 92 significant impact on the risk of becoming infected by the virus in the first place. 93

Is there something about infection with the SARS-CoV-2 virus that interacts so adversely with the 94 obese state, or does being obese have a similar impact on other forms of viral pneumonia? Although 95 obesity has been associated with an increased risk of hospitalisation in seasonal influenza, a study of 96 almost 10,000 cases of seasonal influenza in the USA did not find any evidence of obesity as a risk 97 factor for requiring mechanical ventilation or death 6 . In contrast, it seems clear that during the 2009 98 H1N1 influenza pandemic, which largely spared the partly immune elderly, obesity was a strong risk 99 factor for adverse outcomes 51 . The role of obesity in severity of SARS-CoV-1 and MERS-CoV, other 100 pandemic coronavirus infections with poor outcomes, has not been thoroughly examined. The Acute 101

Respiratory Distress Syndrome (ARDS) has some pathophysiological similarities to COVID-19 102 pneumonia. While obesity has been reported to increase the risk of developing ARDS of a variety of 103 aetiologies 32 , it has been reported to be associated with increased survival rates, something that has 104 come to be known as the ARDS obesity paradox 67 . Thus, the association of obesity with worse 105 outcomes in acute lung infection or widespread alveolar damage of other types, appears to be 106 strongest and most consistent with COVID-19 and pandemic H1N1 influenza. 107 108 What are obese patients with COVID-19 dying from? 109

The majority of COVID-19 patients die having required artificial ventilation for hypoxemic respiratory 110 failure due to COVID-19 pneumonia 59 . Emerging post-mortem histopathology of the COVID 19 lung 111 offers insights into the underlying pathophysiology. Briefly, there is evidence of diffuse alveolar 112 damage, as in other forms of viral pneumonia, but sometimes this is patchy 2, 48 . What is striking, and 113

shared to a degree with the pathology of pandemic H1N1 influenza 2 , is the extent of pulmonary 114 capillary microangiopathy which is considerable and near universal, at least in some series 9 . 115

Complement deposition has also been observed in the endothelium in association with the 116 formation of microthrombi 44 . This suggests that COVID-19 may lead to a state of alveolar 117 hypoperfusion due to a microthrombotic pulmonary angiopathy. The frequent finding of elevated 118 levels of fibrin D-dimers in a large proportion of hospitalised patients is consistent with a thrombotic 119 process, as is the frequent occurrence of venous thrombosis and pulmonary emboli during the 120 course of the illness 16, 35 . The clinical characteristics of COVID-19 pneumonia are still being defined 121 but in early reports from European centres a substantial proportion of ventilated patients were 122

reported to have preserved pulmonary compliance with well aerated lungs, suggesting that hypoxia 123 is being driven by microvascular dysfunction 29, 30 . Reports of CT based lung perfusion imaging 124 supports this 40 . However, a subsequent larger study from the USA described a cohort of patients 125

with respiratory mechanics more in keeping with classical ARDS [24] . Finally, patients who are 126 seriously ill with COVID-19 have evidence of high levels of inflammation with high CRP and 127

circulating pro-inflammatory cytokines 11 . Indeed, it has been suggested that a hyperinflammatory 128 response, occurring downstream of a vigorous activation of either adaptive or innate immunity, or 129 both, may drive the underlying pathophysiological process 47 and IL-6 antagonists are being trialled 130 in severely ill patients 65 . 131

Obesity is associated with a wide range of adverse health outcomes with diverse underlying 133 pathogenic processes. For some, e.g. sleep apnoea and reflux oesophagitis, the expanded mass of 134 adipose tissue itself is directly and mechanically contributing to the disease. T2D is one of the 135 commonest sequelae of obesity. An increase in circulating insulin levels in both fasting and post-136 prandial state is one of the earliest metabolic disturbances associated with obesity and it is due to 137 impaired insulin action, principally in liver and skeletal muscle 57 . This "insulin resistance" clearly 138 predisposes to developing T2D, which ensues when beta cell compensation fails. 139

The mechanism whereby chronic over-nutrition leads to insulin resistance appears to primarily 140

involve not the expanded adipose tissue itself, but the additional excess nutrient that is stored 141 ectopically in the major insulin responsive tissues, muscle and fat 41 . An alternative hypothesis 142

suggests that adipose tissue inflammation contributes directly to insulin resistance in obesity. 143

Inflammation undoubtedly occurs in obesity however it has less compelling underpinning support 144 from human genetics or human pharmacology 52 . 145 146 How might the metabolic state of obesity intersect with and exacerbate pathological mechanisms 147 in COVID-19? 148

Enhanced production of cytokines. A corollary of storing excess fat in non-adipose tissue is that the 149 adipose tissue has reached or is reaching the limits of its ability to store fat safely. Thus, in adipose 150 tissue biopsies from obese, insulin resistant people, one frequently sees an excess of dead and dying 151 adipocytes, often accompanied by an excess of infiltrating macrophages, usually arranged in crown-152 like structures 13 . These macrophages are activated and contribute to the production of a systemic 153 pro-inflammatory state, characterised by increases in circulating levels of cytokines such as TNFα, IL6  154 and IL1β 46, 66 . Lipotoxic damage to other cells such as hepatocytes can also contribute to the 155 enhanced inflammatory state. If increased inflammation contributes to alveolar damage, then this 156 provides an obvious potential route whereby the metabolic risk factors could drive increased 157 mortality. 158

Altered adipose tissue hormones Adipose tissue expansion not only results in elaboration of 159 inflammatory cytokines, but also changes the profile of secreted hormones. A key signature of 160 insulin resistance is an increase in the ratio of circulating leptin and adiponectin 24 . Obesity is 161 associated with higher circulating leptin and lower circulating adiponectin. There is some literature 162 associating high leptin levels with pulmonary inflammation but this is not, as yet, compelling (24, 163 25). There is, however, a growing body of evidence more securely implicating adiponectin as an 164

anti-inflammatory agent 61 . Notably, adiponectin-deficient mice develop inflammation of the 165 pulmonary vasculature 63 and are predisposed to experimental acute lung injury 39 suggesting that 166 the hypoadiponectinemia frequently seen in obesity could facilitate an exaggerated inflammatory 167 response directed to pulmonary capillaries. In addition to being lower in obesity and most insulin 168 resistant states it is worth noting that adiponectin levels have been reported to be significantly 169 lower in many of the COVID-19 "at risk" groups e.g. Male < Females 20 and South Asians < White 170

Europeans 1, 20 . Perhaps most interesting is the finding that, at equivalent levels of body fat, black 171

people also tend to have lower levels of adiponectin than white people despite having no more 172

insulin resistance and a lower propensity to store fat ectopically 8 . However, it should be noted 173

adiponectin levels tend to rise after the age of 70 3, 14 , and old age is by far the biggest risk factor for 174 COVID-19 mortality. However, it is possible that different causal pathways may mediate the risk of 175 age vs obesity on COVID-19 severity. is secreted from adipose tissue, associated with insulin resistance and likely contributes to 197 thrombotic risk in obesity by impairing fibrinolysis 23 . In addition, obesity is associated with increased 198 thromboxane metabolites and mean platelet volume (both validated indices of platelet activation) 199 that normalise with weight loss 15, 18 . Notably, obesity is a robust risk factor for the development of 200 thrombocytopenic thrombogenic purpura 69 with one group suggesting increased circulating 201 antibodies to ADAMTS13 in the obese 42, 76 . 202 Vasculature The role of the vasculature, particularly the endothelium, in the pathogenesis of 19 has recently been highlighted 34, 64 . In a comprehensive analysis of ACE2 (the SARS-CoV-2 204 receptor) expression in the human vasculature the highest expression was found in the pericytes of 205 heart and brain (but not the lung) with little in endothelial cells 34 . It was proposed that 206 microvascular dysfunction associated with obesity or type 2 diabetes could permit viral passage 207 across the endothelium to infect pericytes, with their dysfunction promoting subsequent endothelial 208 activation and microthrombosis 34 . The effects of diabetes on endothelial barrier function is well 209 established 56 and there is evidence from studies of large animals that endothelial permeability is 210 increased in obesity 27 . 211

Dysfunction of the systemic microcirculation is well described in obesity and the metabolic 212 syndrome 68 . While the effects of obesity on the pulmonary circulation are less studied, there is 213 emerging evidence of a pulmonary vascular dysfunction associated with obesity. In a rodent model 214 of obesity pulmonary resistance vessels were resistant to agonist and hypoxia induced 215 vasoconstriction ex vivo compared to lean controls 50 . If the vasoconstrictive response to hypoxia is 216 impaired in the human pulmonary vasculature then this could potentially exacerbate shunting in 217 COVID19 pneumonia, thus contributing to hypoxia. 218

The key functional unit of the lung is the alveolar-capillary unit. Key cells include type 1 219 pneumocytes (AT1) separated from capillary endothelial cells by a fused basement membrane and 220 the less numerous type 2 pneumocytes (AT2) that produce surfactant and serve as alveolar 221

progenitors. ACE2 is the proposed receptor for SARS-CoV-2 and in the alveolus it is expressed 222 predominantly (if not solely) by AT2 34 . Critical to gas exchange and pulmonary function, the alveolar 223 capillary unit is the primary site of injury in COVID-19. Understanding how obesity interacts with pre-224 morbid alveolar function and injury may guide pre-emptive therapeutic intervention. 225

Circulating Surfactant proteins A and D have been shown to be increased in patients with obesity 226

and Type 2 Diabetes 21, 43 , assuming these proteins are expressed only in the lung and secreted to 227 the apical membrane, and this suggests that obesity may affect the integrity of the alveolus. The 228 science of ectopic fat has largely focused on the liver, muscle and heart, where a large body of 229 evidence clearly describes the adverse consequences to these tissues of a chronic excess of 230 intracellular lipid. More recently, however, work is emerging suggesting that, in states of over-231 nutrition, ectopic lipid can appear in cells of the pulmonary alveolus resulting in ultrastructural 232 abnormalities and altered surfactant production 25 . Genetic enhancement of endogenous lipid 233 synthesis specifically in mouse AT2 cells results in alveolar inflammation 54 . Remarkably, AT2 cells of 234 aged mice were noted to demonstrate similar gene expression changes to these mice and also 235 exhibited increased lipid content 4 suggesting that "fatty lung" could potentially be a common causal 236 pathway whereby both obesity and age worsen COVID-19 pathology. Similarly, genetic deletion of 237 the lipid sensor Liver X Receptor (LXR) resulted in accumulation of lipid in type 2 pneumocytes and, 238

subsequently, pulmonary inflammation and foam cell accumulation 17 . 239

Insulin Resistance, not fat mass, is key to the link between Obesity and poor COVID Outcomes 241 If true, this is important, as even short-term low calorie diets can improve insulin sensitivity within 242 days 38 . Human genetics should ultimately come to our aid here as meta-analysis of Genome Wide 243 SNP data from COVID victims throughout the world can be undertaken to examine whether the 244 genetic risk scores for insulin resistance are better predictors of outcome than those for obesity per 245

se. In the meantime, animal models of SARS infection might be able to provide some early 246 information through the examination of effects of insulin-lowering and insulin-sensitising 247 medications. Some commentators have argued that as it is difficult for obese patients to attain 248 normal weight then there is not much that can be done given the rapid spread of the COVID-19  249 pandemic. However, if improving insulin sensitivity reduces risk then even a modest amount of 250 caloric restriction, combined with physical activity and perhaps an insulin sensitising/lowering drug 251 such as metformin, may provide a way of reducing risk of death for the large number of at risk obese 252 people 253 

SARS-CoV-2 causes pneumonia by first entering the AT2 through ACE2 which is abundantly 263 expressed on their surface. These cells are lipid rich, storing polar lipids in lamellar bodies, and their 264 structure, and possibly function, are influenced by diet and obesity, at least in animal models 25, 55, 75 . 265 Experiments should be undertaken to examine the effects of lipid content of cells on ACE2 266 expression, viral uptake, replication and release. Some viruses e.g. Hepatitis C seems entirely reliant 267 on intracellular fat droplets to facilitate its movement around a cell 49 . Viral infections of cells 268 frequently lead to a rapid switch from oxidative phosphorylation to aerobic glycolysis, the so called 269

Warburg effect 60 . Ectopic lipid in cells elsewhere is known to be associated with metabolic 270 inflexibility 26 , the inability to shift rapidly between fat and carbohydrate metabolism. Might AT2 271 cells that have excess lipid be less able to switch to aerobic glycolysis and thus be more prone to cell 272 death during viral infection? Indeed, in mice, diet-induced obesity is associated with downregulation 273 of fatty acid synthase (Fasn) in lung and genetic deletion of Fasn in AT2 cells impairs induction of 274 glycolysis in response to hyperoxic stress in vitro and predisposes to acute lung injury in mice 55 . 275

Though unproven, it is likely that ectopic lipid in lung will start to reduce quickly after people go into 276 negative energy balance, so that modest changes in diet and exercise may be have benefit. 277

In summary, we have applied insights into the pathophysiology of the adverse consequences of 279 obesity and emerging evidence regarding the pathological mechanisms in COVID-19 to suggest 280 possible routes whereby obesity can exacerbate the tissue damage associated with infection by the 281 SARS-CoV-2 virus. These hypotheses suggest several tractable experiments in cells, animals and 282 humans, some of which we are undertaking and which we encourage others to pursue. Obesity is a 283 notoriously difficult condition to "cure" and this may explain why widespread public health 284 messaging about weight loss in the obese as a preventive measure to reduce COVID-19 mortality has 285 not been vigorously pursued. If obesity is exerting its effects on COVID-19 outcome through its 286 metabolic sequelae, such as insulin resistance, then those abnormalities start to improve very 287 rapidly when energy intake drops below energy expenditure. In addition to its effects on energy 288 expenditure, regular physical activity, even of moderate intensity and duration can also improve 289 insulin sensitivity and lower circulating insulin levels 37 . The potential implications for unintended 290 adverse consequences of intense COVID-19 "lockdown" strategies that limit opportunities for 291 exercise are obvious. 292

Given how rapidly large trials of a wide variety of pharmacological agents in COVID-19 are currently 293 being undertaken (some with a rather tenuous rationale 22 ) it should be possible to consider 294 undertaking trials of simple interventions in people with obesity either before or immediately after 295 the onset of COVID-19 symptoms. These could involve diet and exercise intentions that do not aim 296

for unrealistic amounts of weight loss but would be designed to ameliorate insulin resistance. These 297 interventions could be supplemented by drugs that assist in modest weight loss and lower 298

circulating insulin, such as metformin or SGLT2 inhibitors, or agents that improve insulin sensitivity, 299 reduce ectopic lipid and increase circulating adiponectin, such as pioglitazone. Such approaches 300

would also be applicable to T2D, another condition which predisposes to increased mortality from 301 36, 72 . In the majority of T2D cases, obesity precedes and contributes to the 302 development of diabetes through inducing compensatory hyperinsulinemia, necessitated by insulin 303 resistance, which eventually exhausts the ability of genetically vulnerable pancreatic beta cells to 304 maintain insulin production. There is evidence that, in both T1D and T2D, the level of glycaemia is 305 related to COVID-19 outcomes 36, 77 . We urgently need to know if the intensification of glycaemic 306 control using an approach which sensitises patients to insulin would provide benefits to the COVID-307

19 infected T2D patient that are greater than those achieve by approaches that increase levels of 308 circulating insulin, either through exogenous injection or the stimulation of endogenous secretion. 309

Obesity affects a very large proportion of the population of most developed and developing 310 countries. Understanding the nature of the link between chronic positive caloric imbalance and 311 COVID-19 pathology could provide novel avenues to reduce the death toll produced by this 312

dangerous new viral infection. Funding agencies will need to foster the interdisciplinary approaches 313 that will be required to respond to this new biomedical challenge which lies at the intersection 314 between traditional disciplines. 315 Obesity is a disorder of energy balance that ensues when energy intake exceeds expenditure. 552

Adipose tissue expansion occurs to safely store excess energy safely in triglyceride rich lipid droplets. 553

This process is associated with adipose tissue inflammation and elaboration of pro-inflammatory 554 cytokines, increased components of the complement system and altered adipose tissue hormones. 555 1) Increased inflammatory cytokines are secreted into the systemic circulation and can act on the 556 alveolar capillary unit to potentiate the inflammatory response to SARS-CoV-2 infection. 2) Adipose 557 tissue expansion is associated with a reduction in Adiponectin secretion from the adipose tissue that 558 is that at least partly driven by systemic insulin resistance. Mouse studies suggest adiponectin is 559 abundant in the pulmonary endothelium in the healthy lung and adiponectin deficiency results in 560 pulmonary vascular inflammation and pre-disposes to experimental lung injury. 3) Increases in 561 circulating complement components elaborated from adipose tissue occur in expanded adipose and 562

in association with insulin resistance and could pre-dispose to complement activation and 563 subsequent thrombotic microangiopathy. When the capacity for adipose tissue to expand is 564 exceeded lipid is deposited in other organs. Lipid deposition in skeletal muscle and liver likely plays a 565 causal role in the development of insulin resistance and hyperinsulinemia. 4) Systemic insulin 566 resistance is associated with endothelial dysfunction that may pre-dispose to thrombosis and 567 contribute to lung injury via vascular inflammation and enhanced endothelial permeability. 5) Insulin 568 resistance is robustly associated with increased plasminogen activator inhibitor-1 (PAI-1) which 569 impairs fibrinolysis and may contribute to risk of thrombosis in COVID-19. 6). Finally, ectopic lipid 570 may actually be directly deposited in type 2 pneumocytes pre-disposing to lung injury in SARS-CoV-2 571 infection. 572

Obesity is associated with increased COVID-19 related mortality. Lockhart and O'Rahilly review the pathophysiological mechanisms that may underlie this link and converge on a set of testable hypotheses to guide investigation of the effects of obesity on COVID-19.

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