Thousands of academic articles have been published on Covid-19 over recent weeks, reflecting the amount of data being generated and the importance of finding ways to fight the SARS-CoV-2 virus. The more we learn about the disease, the more complex it appears to be, with as many questions as answers arising (1). However, one aspect of the disease is now quite well established – the major risk factors that make individuals more susceptible to severe Covid-19 illness. After advanced age and male sex, the major risk factors are obesity and other, related underlying health conditions such as hypertension, cardiovascular disease (CVD), type 2 diabetes (T2D) and respiratory diseases (2).
Obesity is a major risk factor for CVD, T2D, hypertension and many other serious conditions, including a number of cancers, and its role in the development of these diseases is the reason it is such a major public health concern. However, Covid-19 has cruelly exposed another health issue associated with obesity – increased susceptibility to infections, particularly respiratory infections. Individuals with obesity often have respiratory dysfunction due to the presence of large fat deposits around the chest and upper abdomen. This is characterised by altered respiratory mechanisms, increased airway resistance, impaired gas exchange and low lung volume and muscle strength (3). As a result, obesity increases the risk of contracting respiratory tract infections including influenza and pneumonia (4, 5).
In the 2009 Influenza A H1N1 pandemic, patients with obesity were disproportionately affected by the virus, with more than twice the mortality rate of people with normal weight (6). Although this was an influenza virus, not a coronavirus, this should nevertheless have been a warning sign that people with obesity are likely to be at greater risk during viral respiratory pandemics. This warning was enhanced by a later study which looked at the response to the H1N1 vaccine. People with obesity initially produced high levels of antibodies, but within 12 months their antibody titres had dropped significantly, and they had double the risk of contracting the virus (7). This suggests that obesity compromises the immune system and its ability to fight viral respiratory infections.
In the case of Covid-19, it is most likely that the impact of obesity on the severity of the disease is due primarily to immune system dysfunction. A range of functional abnormalities have been identified in obesity, but in viral infections the dysfunction of Natural Killer (NK) cells is particularly relevant as they are important in both the initial stage of infection and then clearing the virally infected cells (8). The low-grade, chronic inflammation caused by excess visceral adipose tissue surrounding vital organs in the abdominal cavity, which is implicated in cardiometabolic complications of obesity, has also been highlighted as a possible cause of the over-exaggerated immune response seen in many Covid-19 fatalities (9).
It has also been suggested that visceral adipose tissue may act as a ‘reservoir’ for Covid-19. Adipose tissue expresses the protein ACE2 which is the entry point for SARS-CoV-2 into cells, so it is feasible the virus could infect visceral adipose tissue which then becomes a reservoir for more extensive viral spread, increased viral shedding, immune activation, cytokine amplification and systemic tissue damage (10).
Research into this disease will be ongoing for many years, and it is important to elucidate the mechanisms by which obesity contributes to the severity of Covid-19 illness, in order to identify potential targets for treatment. Two relatively simple areas for investigation would be zinc deficiency and vitamin D deficiency. Both these nutrients are essential for effective regulation of the immune system, and obesity increases the risk of deficiency of both (11, 12). Testing patients for zinc and vitamin D status would therefore be warranted, so that deficiencies could be corrected. In addition to playing a vital role in immune function, zinc also acts intracellularly to inhibit the RNA polymerase enzyme which replicates viral RNA (13), so any deficiency in circulating zinc could hinder the body’s attempts to fight the virus.
While it is vital we understand as much as possible about this new virus and learn how we might be able to minimise the impact of similar future outbreaks, it is arguably even more important to renew and re-invigorate our efforts to tackle obesity. We need to reduce obesity rates, not just to help limit the impact of future pandemics, but also to reduce the devastating effects of CVD, T2D and other obesity-related illnesses on the health and well-being of the millions of people with obesity, and ease the burden these diseases place on our healthcare systems. Unfortunately, healthcare professionals are not generally well trained to manage patients with obesity. A 2015 analysis of the NHS workforce estimated that fewer than 0.1% had received any specialised obesity training (14), which may be due to the fact obesity is not considered a disease in the UK. In the US, where obesity is recognised a disease, obesity is higher on the agenda but a very recent study revealed that U.S. medical schools “are not adequately preparing their students to manage patients with obesity” (15). It is vital that the curricula of medical and nursing courses are reviewed in relation to obesity, and that specialised training is provided to existing health professionals, to ensure they have the knowledge and skills to support and treat patients with obesity.
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11. Vimaleswaran KS, Berry DJ, Lu C, et al. (2013) Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 10: e1001383. doi:10.1371/journal.pmed.1001383
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14. Candesic (2015) College of Contemporary Health: Training Market for Obesity.
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From the early days of the coronavirus epidemic in China, we have been aware that older adults and people with underlying health conditions, such as diabetes and cardiovascular disease, are at greatest risk of severe illness and mortality caused by the virus, SARS-COV-2.
But when the epidemic spread to Europe, it quickly became apparent that overweight and obesity are also major risk factors for becoming critically ill with Covid-19. This was first noted in Italy (1), then in the UK, where 73% of the first 5,500 critically ill patients had overweight or obesity (2), and then the US. A recent publication in the Journal of the American Medical Association showed that, of 5,700 patients hospitalised with Covid-19 in the New York City area, 42% had obesity (3). Another study showed that, once hospitalised, patients aged below 60 with BMI > 30 are twice as likely to need critical care compared with patients with a BMI < 30 (4).
Given that hypertension and type 2 diabetes are two of the common comorbidities of obesity, this revelation was not surprising, but it also raised the question of whether obesity is an independent risk factor for critical illness or death from Covid-19, or if it is due just to the comorbidities. Data from Arthur Simonnet and colleagues in France showed that, of the Covid-19 patients in ICU, the need for ventilation rose with BMI, and this was independent of age, diabetes and hypertension – indicating that excess body fat itself increases an individual’s vulnerability to Covid-19 (5). Simonnet’s findings are supported by reports from the US that significant numbers of younger people with obesity, but otherwise healthy, are being hospitalised (6).
So how can obesity result in a worsening of symptoms and greater risk of death from Covid-19? One way is simply the physical presence of fat stores in the upper abdomen, which causes compression of the diaphragm and lungs, compromising respiratory function. However, probably the key factor is the effect that obesity has on the immune system.
In individuals with obesity, visceral adipose tissue in the abdominal cavity produces inflammatory cytokines that cause a chronic low-grade inflammatory state throughout the body. It is unclear how this affects the response to the viral infection in the lungs, but one theory is that inflammation caused by obesity occupies the immune system’s resources, reducing its ability to mount an effective response against the virus.
On the other hand, it has also been proposed that this constant activation of the immune system means that it over-reacts to the virus, causing excess inflammation and damage in the lungs (7).
There is also evidence that leptin may play an important role. Leptin is a hormone produced by adipose tissue, which is best known for its effects on reducing appetite by binding to receptors in the brain. In people with obesity, the CNS becomes resistant to leptin, so blood levels of leptin are high but it is ineffective at reducing appetite. However, T-lymphocytes, which are involved in the cell-mediated response to viral infections, also have leptin receptors and leptin deficiency or resistance can lead to dysregulation of cytokine production and increased susceptibility toward infectious diseases and inflammatory responses (8).
Research into the relationship between obesity and influenza viruses has been ongoing since the H1N1 ‘swine ‘flu’ influenza pandemic in 2009, and has shown that not only are individuals with obesity at increased risk of severe illness from the influenza virus, but they also respond less well to vaccines (9), and they are potentially more infectious because they shed virus for longer when infected (10).
When we add all this evidence up, it is clear that people with obesity are very vulnerable, not only to the current coronavirus, but also to influenza viruses and future viral pandemics.
Rising global obesity rates could be contributing to the spread of infection and are certainly putting added strain on already-stretched health services, highlighting the urgent need to tackle obesity and reverse this trend – something which governments and health systems around the world have so far failed to do.
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- Intensive Care National Audit Research Centre (2020) ICNARC report on COVID-19 in critical care. Published 17 April 2020. https://www.icnarc.org/Our-Audit/Audits/Cmp/Reports
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- Sattar N, McInnes IB, McMurray JJV (2020) Obesity a Risk Factor for Severe COVID-19 Infection: Multiple Potential
Mechanisms. Circulation. Published 22 Apr 2020. https://doi.org/10.1161/CIRCULATIONAHA.120.047659
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