Smoking and obesity increase susceptibility to severe COVID-19 and sepsis


An international collaboration of scientists from the UK, Norway and the U.S. have identified genetic evidence supporting a causal effect of smoking and obesity on increasing susceptibility to severe COVID-19 and sepsis.

Published online in Circulation today, the results show that both smoking and higher body mass index (BMI, a measure of obesity) increase risk of severe COVID-19.

The same was also true for the risk of developing sepsis, which is a dangerous inflammatory response to infection, experienced by many patients with severe COVID-19.

Confirming the causal connection also highlights that stopping smoking and losing weight can be effective interventions for reducing the risk of developing severe COVID-19 and sepsis.

Led by Dr. Dipender Gill, from St George’s, University of London and Imperial College London, the “Mendelian randomisation” study considered separate datasets of 3,199 patients with severe COVID-19 and 10,154 patients with sepsis.

Using genetic proxies for BMI and smoking, the researchers were able to assess whether the presence of these genetic signposts in patients were related to an increased likelihood of severe COVID-19 or sepsis.

A typical observational study would examine the association of a risk factor, such as smoking or obesity, on various outcomes, such as mortality or disease risk.

In contrast, this research looked at differences in DNA that are associated with smoking and obesity – known as genetic variants.

By analyzing the association of these genetic variants with severe COVID-19, other confounding factors that could also play a role in affecting disease risk, for example relating to lifestyle or environment, could be better ruled out.

With such interference reduced, the results of this study represent evidence for causal effects of smoking and obesity on susceptibility to severe COVID-19.

The study also describes that there are various mechanisms by which smoking and obesity may elevate the risk of suffering from severe COVID-19 and sepsis, including inflammation and immune dysregulation.

Dr. Dipender Gill, a clinician scientist and senior author on the paper from St George’s, University of London and Imperial College London, said:

“While it’s already known that smoking and obesity increase the risk of many serious health conditions, including heart disease, stroke and certain types of cancer, our findings highlight that the implications of smoking and obesity are exacerbated in the current COVID-19 pandemic.

Our work supports that something can be done to reduce risk of severe COVID-19, and in particular that losing excess weight and stopping smoking can make a difference.

Now, more than ever, it’s essential that campaigns highlighting the benefits of losing excess weight and stopping smoking remain central to public health strategies.”

Dr. Mark Ponsford, Welsh clinical academic trainee at Cardiff University, and first author, said:

“Observational studies can be vulnerable to bias—for instance because of how patients are recruited or data are collected. We used an approach known as ‘Mendelian Randomisation,’ a technique that uses genetics to reduce the risk of bias.

Studying large publicly-available genetic datasets from well-characterized UK and Norwegian populations, we calculated genetically-predicted exposure to modifiable cardiovascular risk factors.

We found that smoking and obesity increased the risk of developing sepsis.

Applying this approach to genetic association studies of severe COVID-19, we found the same outcome. This adds to the growing body of evidence that reducing smoking and obesity are important for public health.”

Dr. Stephen Burgess, author on the paper and group leader at the Medical Research Council Biostatistics Unit, University of Cambridge, said:

“Previous research has demonstrated that those who are overweight and smoke are at higher risk of severe COVID-19.

Our findings strengthen the evidence that obesity and smoking are causal risk factors, meaning that losing weight and stopping smoking will both reduce the risk of severe COVID-19.”

Dr. Tormod Rogne, author on the paper from the Norwegian University of Science and Technology, said:

“A potential issue when you evaluate whether measured BMI and self-reported smoking are associated with COVID-19 is that external factors not accounted for, such as chronic diseases, may confound the associations.

The genetic predisposition to BMI and smoking, on the other hand, is generally not affected by such external factors.

This fact allowed us to use the study participants’ genes to estimate the unconfounded association between BMI, smoking and risk of COVID-19.”

The adipose tissue as target of COVID-19

Body weight excess is a well-established respiratory disease risk factor, especially for sleep apnea [Gottlieb D.J., Punjabi N.M. Diagnosis and management of obstructive sleep apnea: a review. J. Am. Med. Assoc. 2020;323:1389–1400. ], and the reported correlation between obesity and severe cases of COVID-19 infection is therefore unsurprising.

The underlying pathophysiology is likely multi-stranded, ranging from complement system hyperactivation, increased interleukin-6 and interferon secretion, chronic inflammation, presence of comorbidities such as diabetes and hypertension, and a local mechanical deleterious effect of fat accumulation in the chest.

However, understanding the link between obesity and SARS-CoV-2 likely extends beyond the lung, and could aid proper tailoring of immunomodulatory treatments, together with improving stratification among those possibly requiring critical care.

As a multifactorial pathology, obesity is grossly defined by adipose tissue excess. However, not only adipose tissue is overdeveloped in obesity, but it also becomes dysfunctional. Main traits of adipose tissue dysfunction include a state of low-grade chronic inflammation, which further expands systemically as fat tissue secretes inflammatory cytokines.

In this regard, adipose dysfunction in obesity is highly dependent on fat tissue distribution across the body as not all adipose tissues depots accumulating in different areas are equivalent: for instance, fat accumulating in the visceral region, close to intra-abdominal organs such as the liver (called omental fat), the kidney (perirenal fat), the intestine (mesenteric fat), or the heart (pericardial fat) are more susceptible to become inflammatory in obese patients than fat accumulating subcutaneously.

In addition, sex hormones highly contribute in body fat distribution, and visceral fat accumulation is a feature of so-called android obesity, whereas premenopausal women more likely develop subcutaneous fat in the limbs and hip region, referred to as gynoid obesity.

As men are clearly overrepresented in patients with severe COVID-19, it is probable that total fat ratio (on average higher in women) is not the sole criterion.

Rather, the gender difference might reflect android fat distribution, more likely detrimental in the context of viral infection, presumably through its higher inflammatory response, and its close vicinity to vital organs (for instance intestinal ACE2 and adipocyte ACE2 in the abdominal region).

From the limited data available, it seems that the male prevalence for severity is also true for patient with BMI bellow 25.

However, it is important to have in mind that BMI is not a good estimate of the excess abdominal fat mass more often found in male even if their BMI is considered normal. Hence the requirement for better stratification and documentation of COVID-19 patients is urgently needed.

Another main feature of dysfunctional obese adipose tissue is metabolic inflexibility.

This concept refers to the physiological alternation of anabolic and catabolic states controlling either energy storage (post-prandially) or lipid mobilization (during fasting) when energy source to other organs is needed.

Obese adipose tissue is no more able to physiologically respond to hormones that govern this cycle, as it is mostly insulin-resistant, and less able to contain lipid mobilization, leading to a steady state leak of fatty acids.

This in turns promotes ectopic lipotoxicity due to excessive fatty acid exposure of many organs, as a basis for development of obesity-associated comorbidities, especially type II diabetes, fatty liver and cardiovascular diseases.

Of note, lipid mobilization by adipose tissue also physiologically participates in global immune activation, as cytokines are potent lipolytic molecules, a process that is thought to provide the energy source to support immune system responses.

How can adipose tissue excess or dysfunction be linked to the severity of SARS-CoV-2 infection?
Indirect links through altered dynamics at the whole body level

Obese patients often have respiratory dysfunction characterized by alterations in respiratory mechanisms, increased airway resistance, impaired gas exchange and lower lung muscle strength and respiratory volume.

Increased BMI was shown to gradually predispose to hypoventilation-associated pneumonia, pulmonary hypertension and cardiac stress.

Causality between these parameters and COVID-19 severity will be difficult to achieve but correlation might be established in large longitudinal studies as the number of patient has become excessively large in Europe and the USA. This will, however, require some level of standardized information collection of the patient at the hospital level.

Therefore, even in the absence of comorbidities of obesity, excess of adipose tissue might predispose individuals to severe COVID-19 outcome. We list below some possible mechanism that might explain this situation (Fig. 1 ).

Fig. 1
Fig. 1
An adipocentric view of severe COVID-19 risk in obesity. Schematic representation of possible contributions of adipose tissue excess in disease severity.

Reservoir for viral production

The possibility that adipose tissue may serve as a reservoir for viral production is another factor that might contribute to the increased risk from COVID-19 for patients with obesity (Fig. 2 ).

The presence of human adenovirus Ad-36, influenza A virus, Human Immunodeficiency Virus, Cyto-MegaloVirus, Trypanosoma gondii, and Mycobacterium tuberculosis in the adipose tissue has been reported [31].

Although these observations are poorly documented so far, analogy can be made for COVID-19, but will need to be validated by postmortem analysis.

The infection of the adipose tissue by SARS-CoV-2 is supported by observations at the gene expression levels from public databases that adipocytes express ACE2 receptor for SARS-CoV-2 as well as TMPRSS2.

The mechanism by which SARS-CoV-2 enters cells is not fully elucidated, but apart from direct fusion of the virus with the plasma membrane, it seems that all different types of endocytosis might be involved [32].

These membrane trafficking events include clathrin-mediated endocytosis, caveolin-mediated endocytosis, macropinocytosis and phagocytosis. Caveolin-mediated endocytosis is especially interesting to study as caveolae are particularly abundant in adipocytes [33], caveolins participate in adipocyte function [34] and because caveolin was shown to interact with various viral proteins [35].

Further, in obese patients the increased number of adipocytes would increase the pool of infection susceptible cells. Of note, adipose tissue, contains not only adipocytes, but cells of stroma vascular fraction among which adipocyte precursors and macrophages [36].

These latter cells also express ACE2 and represent a potential target of SARS-Cov-2 infection and thus may contribute to increased inflammatory situation.

All these aspects of SARS-CoV-2 endocytosis clearly need to be further investigated with modern cell biology approaches such as RNA interference and high-resolution imaging.

Further, a still unsolved question relates to how the virus would reach the adipose tissue and be spread from its entry sites, mainly the respiratory and intestinal tracts. In line with the view that adipose tissues located at close vicinity of virus entry sites organs might in turn be infected, a recent study has demonstrated a bacterial signature in mesenteric adipose tissues without apparent blood presence, likely the result of a leak from gut microbiota in diabetic patients [37].

Fig. 2
Fig. 2
Overview of possible adipocyte pathways to worsen COVID-19. The left side depicts four scenarios for the possible adipocyte contribution in COVID-19 severity. SARS-CoV-2 virus is shown in green and adipocyte unilocular lipid droplet (LD) in yellow. Pro-inflammatory cytokines released in the blood in response to viral infection are shown as coloured dots. The right side illustrates the importance of non-adipocyte dependent but obesity-related whole body systemic alterations in vascular, cardiac, and pulmonary functions.

Another possibility is that lipid droplets, which are instrumental in the adipose tissue could provide a platform for virus replication and assembly, as already documented for Hepatitis C Virus which hijacks liver fat for virus production [38].

With regard to the hypothesis that adipose tissue is an infection site for the SARS-CoV-2 virus, it remains to be established if viral loads are indeed proportional to adipose tissue mass in patients. Of interest, it cannot be excluded that during infection, the ACE2 activity decreases leading to increased levels of angiotensin II and thus increased inflammation and pulmonary damage.

However, it must be kept in mind that in most cases when the clinical situation rapidly deteriorates the viral load is very low or even undetectable, suggesting that a massive exit from a potential reservoir may not be directly involved.

It is also noteworthy that lipids play a vital role in viral infection and viral life cycle. Indeed, lipids directly contribute to the fusion of the viral membrane to the host cell, to viral replication, and to viral endocytosis and exocytosis [39].

For instance, lipids are key to the formation and function of the viral replication complex, and provide some of the energy required for viral replication. Moreover, specific lipids are required for the formation of double-membrane vesicles needed for viral genome amplification and for the production of viral particles.

Viral internalization occurs through endocytosis and viral release from cells occurs through exocytosis both process being tightly regulated by lipids [40].

Of note among these lipids, cholesterol seems to play a particularly important role for numerous viruses. It is therefore possible that lipid availability and lipid metabolism modifications occurring in obese patient also contribute to improve several steps of the virus life cycle and thus to the severity of the disease.

Chronic inflammatory status generates inappropriate immune response

It is now recognized that obesity and other related metabolic diseases develop in the long term with a state of low-grade chronic inflammation, first limited to the adipose tissue but further extending to many other metabolic organs.

A common suggestion to explain overrepresentation of obese patients experiencing a virus induced cytokine storm is that they start with an already challenged immune system, which could explain exaggerated responses (Fig. 2). Immune-related changes in obese adipose tissue have been extensively explored in the last years, because they are thought to be a major origin of insulin resistance in obesity.

First recognized was adipose tissue production of pro-inflammatory cytokines [41], followed by studies that discovered more extensive immune changes related to adaptive immunity [42].

In line, the activation of the NLRP3 inflammasome downstream of Toll-like receptors signalling and changes in the proportions and function of lymphocyte subpopulations were reported in many studies [43].

It has been proposed that high fat diet triggers innate immune activation at the expense of adaptive immune response, causing host defence vulnerability towards viral pathogens and chronic excessive cytokine release [44].

Although it is tempting to link the initial state of chronic low-grade inflammation to the severity of COVID-19 in obese patients, some questions remain.

Particularly, why other related viruses like SARS-CoV and MERS-CoV, that apparently target very similar cells would not induce aggravation effects in obese patients. Indeed, although low-grade inflammation is a common trait of obesity, to our knowledge, the association between disease severity and obesity is specific to SARS-CoV-2.

The occurrence of a cytokine storm is not restricted to viral infection and can also occur during cancer treatment. In favour of the state of low-grade inflammation in obesity as a factor aggravating cytokine storm outcomes, a study in obese rodent models (ob/ob or diet induced obesity) reported that adiposity could promote lethal cytokine storm after administration of stimulatory immunotherapy regimens in aged mice [45].

Exaggerated-adipose tissue lipolysis in response to proinflammatory cytokines

Besides the above-mentioned hypothesis that adipose tissue excess could participate in the cytokine storm, the possibility also exists that it could be a site of an inadequate response in face of cytokine afflux (Fig. 2).

Indeed, adipocytes respond to cytokines by promoting lipid mobilization, and release large amounts of free fatty acids through activated lipolysis [46]. Although more common lipolytic stimuli are fast or cold stress triggering adrenergic receptors activation, cytokines can also potently stimulate fatty acid release from fat cells [46].

The mechanism of cytokine-mediated lipolysis is likely to involve changes in gene expression, particularly inhibition of the expression of perilipin 1, which is an adipocyte specific lipid droplet coating protein to preserve from lipid degradation by cytoplasmic lipases [47].

Thus, massive cytokine-mediated lipolysis could induce a burst of unbuffered circulating free fatty acids in the blood, with detergent-like properties further aggravating virus-mediated cytolysis. In support of a profound alteration of lipid metabolism in COVID-19 patient a small cohort longitudinal study found that a decrease in low-density lipoprotein (LDL) was positively correlated with the severity of the disease [48].

In agreement with this observation, LDL-cholesterol and total cholesterol levels decreased in a large cohort of patients with COVID-19 denoting a parallel development of hypolipidemic profile and the severity of COVID-19 [49].

This might reflect metabolic deficiency in liver, the most active lipoprotein producer. Thus more detailed knowledge of blood lipid changes in the course of severe COVID-19 is urgently needed.

Potential role of adipose-derived products in aggravating COVID-19 infection

The cytokine storm is described as the massive and unrestrained secretion of various cytokines and chemokines by different immune cells such as lymphocytes, monocytes, and macrophages.

These cytokines include interferons, IL, growth factors, TNFα and allow cellular communication to boost immune response to fight inflammation.

However, the considerable and uncontrolled cytokine secretion may trigger an excessive inflammation leading to extensive damage to vital organs including lung, liver, and kidney.

The fact the balance between the different cytokines that are over-secreted varies between patients could explain the heterogeneity of the symptoms seen in severe COVID-19 cases (Fig. 2).

In addition to cytokines, lipokines including the eicosanoid family of inflammatory mediators are also recognized as major player in inflammation and are potentially massively produced by the adipose tissue.

Eicosanoids include prostaglandins, thromboxanes, leukotrienes, and hydroxyeicosatetraenoic acids. They are generated from 20-carbon polyunsaturated fatty acids (PUFAs) mostly released from cell-membrane phospholipids by the action of phospholipases, especially phospholipase A2 [50].

The membrane phospholipids of inflammatory cells and adipose tissue taken from humans consuming Western-type diets typically contain approximately 20% of fatty acids as the omega-6 PUFA arachidonic acid thereby favouring inflammation [44].

On the contrary increased intake of omega-3 fatty acids appears to be anti-inflammatory [51]. The adipose tissue uses lipokines to communicate with distant organs that might play an anti-inflammatory action such as the recently identified 12(13)-diHOME, 12-HEPE and fatty acid–hydroxy–fatty acids (FAHFA) species [[52], [53], [54]]. How these lipids change in severe COVID-19 is presently unknown.

The adipose tissue is largely composed of adipocytes, but is also irrigated and as such it is relatively abundant in blood cells including immune cells that altogether may contribute to an excess of cytokine and lipokine secretion.

One possible link between the severity of SARS-CoV-2 infection and the amount of adipose tissue comes from the recent identification that interferon increase ACE2 expression, suggesting the possibility of a positive feedback loop leading to further increased viral production within the adipose tissue [55]. This possibility remains however to be tested.

Apart from the production of proinflammatory molecules, which largely originate from macrophages, and not adipocytes, a diversity of other molecules is derived from fat cells, and the adipose tissue is now recognized an endocrine organ [56].

Among adipose tissue hormones, the potential role of obesity-associated high leptinemia and that of low adiponectinemia in the immune response to SARS-CoV-2 infection is unknown.

As abundant producers of Plasminogen Activator Inhibitor-1 (PAI-1) a serine protease inhibitor inactivating urokinase and plasminogen activators, obese adipocytes are also potential players in thrombosis and dysregulated blood coagulation. Interestingly, PAI-1 adipocyte production is higher in visceral adipose depots [57].

Fine-tuning of immune responses is achieved through cohabitation of the host with a community of commensal microbes that participate in the shaping of self-defense to invaders. It is now well established that obesity is associated with gut microbiota dysbiosis, featured by a loss of diversity in bacterial genes, which can be reversed by nutritional intervention [58]. As gut microbes are also active producers of host metabolites, a working hypothesis could be that some of them participate in inappropriate viral responses to SARS-Cov-2 in obesity.

Adipose tissue contribution through the renin angiotensin system (RAS)

In addition to ACE2, the SARS-Cov-2 virus receptor, several other proteins of the classic RAS are also produced in adipose tissue.

These include renin, angiotensinogen (AGT), angiotensin I, angiotensin II, angiotensin receptors type I (AT1) and type 2 (AT2), and angiotensin-converting enzyme 1 [59].

Expression of AGT, ACE, and AT1 receptors is higher in visceral compared with subcutaneous adipose tissue [55]. Thus, the adipose tissue RAS is a potential link between obesity and hypertension (Fig. 2).

Whether or not SARS-CoV-2 binding to its ACE2 receptor also modulates angiotensin pathway is presently unclear. Since Angiotensin II can regulate adipose tissue metabolism, particularly by inhibiting lipolysis, a possibility exists that exacerbated response of obese patients might involve local interaction with the adipose tissue RAS system.

Furthermore, the adipose tissue RAS regulates the expression of adipose tissue-derived endocrine factors including prostacyclin, nitric oxide, PAI-1, and leptin [60].

More recently, it has been observed in critical care units in charge of patients with COVID-19 that the proportion of smokers were lower that usually observed in the global French population, which led to the hypothesis that nicotine, could decrease susceptibility to viral infection.

As a mechanistic basis for this hypothesis, nicotine is known to modulate the RAS system, especially to reduce ACE2 expression through binding to nicotinic acetylcholine receptors or nAChRs [61]. These clinical observations provide further evidence for the importance of the RAS balance, and have raised interest for the prevention of infection by limiting the presence of the cellular receptor for virus entry.

It is also well known that the adipose organ is a reservoir of environmental pollutants known as endocrine disruptors such as persistent organic pollutants, heavy metals, “nonpersistent” phenolic compounds among others. The pollutants exert several dysregulations such as modification of lipid metabolism and increased inflammation.

The amount of these pollutants is exacerbated in patients with obesity. Thus one can hypothesize that pollutants might favour virus entry through modifications of membrane fluidity.

Lastly the adipose organ is the largest endocrine organ and links metabolism and immunity [62] and is composed with white and brown adipose tissues that have different functions. White adipose tissue (WAT) is specialized in the storage and release of fatty acids.

By contrast, brown adipose tissue (BAT) as well as the beige adipocytes dissipates energy in the form of heat by uncoupling mitochondrial respiratory chain from ATP synthesis. The presence of brown/beige adipose tissue is associated with metabolic health and the amount of brown/beige adipocytes is reduced in obesity and with aging [63,64].

The expression of inflammatory markers is lower in brown than in white adipose tissues, providing further support that brown adipose tissue is generally more resistant to inflammation. It is worth to postulate that overweight and obese patients might be more prone to SARS-CoV-2 infection as they develop low grade infection with adipose tissue macrophages polarized to pro-inflammatory (M1) instead of M2 macrophages (anti-inflammatory) brought by brown and beige adipose tissues.


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More information: Mark J. Ponsford et al. Cardiometabolic Traits, Sepsis and Severe COVID-19: A Mendelian Randomization Investigation, Circulation (2020). DOI: 10.1161/CIRCULATIONAHA.120.050753


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