Researchers in a pivotal study recently featured in Nature Communications have uncovered vital insights into why individuals with obesity are at an elevated risk for severe influenza. This comprehensive investigation combines both human clinical data and animal model analysis to unravel the complexities of immune response in obesity that heighten the vulnerability to influenza.
The global health landscape is facing a critical challenge with the rising prevalence of obesity, affecting over 13% of adults worldwide. The risks associated with obesity have been underscored during viral pandemics, such as the H1N1 outbreak and the recent COVID-19 pandemic, where obesity has been consistently linked with worse outcomes and heightened severity of respiratory infections.
This latest study seeks to bridge the knowledge gap in understanding how obesity mechanistically contributes to increased susceptibility to viral infections, beyond the recognised impacts of altered lung function, cardiovascular issues, and metabolic disturbances.
Researchers embarked on a meticulous study design, sampling blood and airway cells from individuals with obesity —those with a BMI over 35 kg/m^2—undergoing bariatric surgery. The study meticulously matched these participants with control subjects of normal weight, ensuring parity in age, gender, and ethnicity.
The investigative team conducted thorough clinical sampling using state-of-the-art techniques, including blood analysis, nasal synthetic absorptive matrix (SAM) sampling, and bronchoscopy.
A suite of laboratory experiments followed. These involved exposing various cell types, including bronchoalveolar lavage (BAL) cells and bronchial epithelial cells (BECs), to different strains of influenza viruses. The response of these cells was measured through advanced techniques like RNA extraction, protein quantification, and a range of assays including flow cytometry and metabolomics.
In vivo studies also played a role, with mice models used to examine the effects of administering recombinant mouse leptin followed by influenza virus infection. This holistic approach aimed to dissect the immune response in both the peripheral and airway-specific compartments.
The study’s findings are eye-opening. Contrary to initial assumptions, the researchers found no significant difference in the response of bronchial epithelial cells between individuals with obesity and individuals of a normal-weight, suggesting that epithelial inflammation is not inherently altered in those with obesity during influenza infection.
However, the study did identify a significant compromise in the antiviral responses of BAL macrophages from patients with obesity. These cells displayed a reduced induction of critical interferons, such as IFN-α, IFN-β, and IFN-λ, which are vital components of the body’s antiviral defence system. Moreover, the production of key pro-inflammatory cytokines like IL-6, IL-8, and TNF was found to be less effective in individuals with obesity.
Metabolomic analysis of the BAL fluid identified significant changes in metabolite levels in patients with obesity, providing a clue to altered biochemical pathways in the lungs due to obesity.
The data from the MOSAIC cohort added a further layer of understanding, highlighting that immune dysregulation in patients with obesity was confined to the airway mucosa, with no significant systemic immune disturbances.
The study’s revelations pave the way for potential therapeutic strategies, including the manipulation of leptin pathways, which may be pivotal in mitigating the risk of severe influenza infections in populations with obesity.
By casting light on the molecular and immunological shifts that occur in the context of obesity, this research could form the foundation for developing tailored interventions that bolster the immune response in this high-risk group, enhancing their resilience to influenza and other viral respiratory infections.Read More
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.
1. Bernstein L and Cha AE (2020) Doctors keep discovering new ways the coronavirus attacks the body. Washington Post. Published 10 May 2020. https://www.washingtonpost.com/health/2020/05/10/coronavirus-attacks-body-symptoms/?arc404=true
2. Centres for Disease Control and Prevention (2020) Coronavirus Disease 2019 (COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html
3. Murugan, A. T. & Sharma, G (2008) Obesity and respiratory diseases. Chron. Respir. Dis. 5: 233–242
4. Phung DT, Wang Z, Rutherford S, Huang C, Chu C (2013) Body mass index and risk of pneumonia: a systematic review and meta-analysis. Obes Rev. 14: 839e57.
5. Gounder AP, Boon ACM (2019) Influenza Pathogenesis: The Effect of Host Factors on Severity of Disease. J Immunol. 202: 341‐350.
6. Louie JK, Acosta M, Winter K, et al. (2009) Factors Associated With Death or Hospitalization Due to Pandemic 2009 Influenza A(H1N1) Infection in California. JAMA. 302: 1896–1902.
7. Green WD, Beck MA (2017) Obesity Impairs the Adaptive Immune Response to Influenza Virus. Ann Am Thorac Soc. 14: S406-S409
8. O’Shea D, Hogan AE (2019) Dysregulation of Natural Killer Cells in Obesity. Cancers (Basel). 11: 573. doi:10.3390/cancers11040573
9. Sattar N, McInnes IB, McMurray JJV (2020) Obesity a Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.120.047659
10. Ryan PD and Caplice NM (2020) Is Adipose Tissue a Reservoir for Viral Spread, Immune Activation and Cytokine Amplification in COVID‐19. Obesity. doi:10.1002/oby.22843
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
12. Gu K, Xiang W, Zhang Y, Sun K, Jiang X (2019) The association between serum zinc level and overweight/obesity: a meta-analysis. Eur J Nutr. 58: 2971-2982
13. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ(2010) Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity invitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 6: e1001176. doi:10.1371/journal.ppat.1001176
14. Candesic (2015) College of Contemporary Health: Training Market for Obesity.
15. Butsch WS, Kushner RF, Alford S et al. (2020) Low priority of obesity education leads to lack of medical students’ preparedness to effectively treat patients with obesity: results from the U.S. medical school obesity education curriculum benchmark study. BMC Med Educ 20: 23. https://doi.org/10.1186/s12909-020-1925-z
Covid-19 and ethnicity
Over recent weeks, as the coronavirus pandemic has progressed, we have been inundated with data and statistics about the impact of the virus in a range of different countries, communities and demographic groups, but perhaps the most shocking are the numbers of people from black, Asian and minority ethnic (BAME) backgrounds who have died from Covid-19.
In the UK, concern was first aired when it was reported that the first ten doctors to die from the virus were all from BAME groups (1), and that more than 60% of all healthcare workers to die from the coronavirus were BAME individuals (2). Early data on the ethnic breakdown of Covid-19 patients entering hospital revealed that 34% were of BAME heritage, compared to 14% of the population as a whole (3). A recent report from the Institute of Fiscal Studies (IFS) revealed that people of British Black African heritage are 3.5 times more likely to die from Covid-19 compared with the white population; people of Black Caribbean heritage 1.7 times more likely and British Pakistanis 2.7 times more likely (2).
On the other side of the Atlantic, a similar picture has emerged with regard to African-Americans, who have accounted for 27% of Covid-19 deaths (a mortality rate 2.6 times that of white Americans) according to a recent report (4). These disparities in death rates between ethnic groups are likely to be due to a complex interplay of a multitude of factors which influence health behaviours, immune profiles, infection risk and health outcomes (5).
Social, economic and health issues
In the US, attention has focused on the fact that African Americans are often socioeconomically disadvantaged, live in more densely populated areas and more crowded conditions. This potentially increases transmission of the virus. They are also more likely to be employed in key worker roles, and less likely to be able to work from home, so have greater risk of infection (6). In addition, African-Americans have higher incidence of obesity, type 2 diabetes mellitus (T2DM) and hypertension than their white counterparts (7, 8) – these have been identified as the three biggest risk factors for severe Covid-19 illness after age (9).
These socioeconomic and health issues are similar for BAME communities in the UK. They often live in densely populated areas and sometimes live in extended, multi-generational cohabiting families, which could increase infection of vulnerable members of the community. People from BAME backgrounds also represent a disproportionate number of medical and support staff in the NHS, so may be more exposed to the SARS-CoV-2 virus (2). The Black African / Caribbean population has the highest rate of obesity of all ethnic groups in the UK (10), but the most significant health issue affecting BAME groups is T2DM, which is of course a significant risk factor for Covid-19 morbidity and mortality. Black and South Asian populations in the UK have 3-5 times the prevalence of T2DM compared to the white population, and are diagnosed on average 10-12 years younger (11). Clearly there are a number of social, economic and health factors which may be contributing to increased risk of infection and increased severity of Covid-19 in BAME populations, but there is one
further factor that should be considered – the possible role of vitamin D deficiency in vulnerability to Covid-19.
Vitamin D is essential for regulation of immune function, and has been shown to reduce the production of pro-inflammatory cytokines that are associated with lung damage caused by acute viral respiratory infections such as influenza and Covid-19 (12). In fact, supplementation with vitamin D reduces the risk of respiratory infection, particularly in people with low vitamin D status (13). Vitamin D is synthesised under the skin following exposure to UVB radiation from sunlight, so individuals who get insufficient sunlight are at risk of vitamin D deficiency. This is a particular issue during winter in countries further from the equator, when sunlight has insufficient UVB for vitamin D synthesis. People with darker skin colour who live in these countries, which includes many BAME communities, are at even greater risk, as are those who rarely go outside or expose very little skin to the sun (14).
It is therefore very interesting to note that the current coronavirus pandemic took hold at the end of winter in the northern hemisphere (the time of year when vitamin D status is at its lowest) and the countries most affected by the virus are in the northern hemisphere, above 35 degrees latitude (15). At the same time, countries at the end of summer in the southern hemisphere, such as Australia and New Zealand, have fared very well. Furthermore, a cross-sectional analysis of countries in Europe has shown a statistically significant correlation between population vitamin D levels and Covid-19 cases and deaths (16).
Vitamin D deficiency could therefore be contributing to the disproportionate number of BAME individuals who are succumbing to Covid-19. It is also interesting to note that vitamin D status tends to fall with age, particularly for older people in care homes, and with rising BMI (17). Obesity is strongly associated with vitamin D deficiency, although why this is the case is not clear. The leading theory is that dysfunctional adipose tissue in obesity sequesters vitamin D and impairs its release so it is no longer bio-available (18). Vitamin D plays an essential role in glucose homeostasis, insulin sensitivity and regulation of adipokines such as leptin, as well as inflammatory cytokines (19). Vitamin D insufficiency may therefore be involved in mediating insulin resistance and inflammation associated with obesity.
Vitamin D deficiency could therefore be a part of the Covid-19 pandemic jigsaw, contributing to the vulnerability of people with obesity as well as those of BAME heritage. Routine vitamin D screening could be introduced for hospitalised Covid-19 patients, and BAME health and social care workers, especially those with excess weight, to establish whether there is a link and to provide the opportunity to correct any deficiencies as part of treatment and prevention measures.
Vitamin D is just one of many factors, as discussed here, which might contribute to the vulnerability of BAME individuals to Covid-19, but it could be contributing to a toxic combination of factors, including obesity and other comorbidities, that is putting our BAME communities, particularly those individuals working on the frontline of health and social care, at very high risk of severe Covid-19 illness. Unfortunately, the risk to BAME health workers could have been predicted, and measures to protect them put in place, as the mortality rate for the BAME population for the 2009 influenza A (H1N1) epidemic in England was nearly twice that of the white population (20). It is vital that research is undertaken to determine the underlying causes of the unacceptably high price BAME communities are paying in the current pandemic. In the meantime, health and social care workers of BAME heritage, especially those with excess weight, should be afforded the protection they merit as key workers at higher risk from Covid-19, including ensuring healthy vitamin D status.
- Siddique H (2020) UK government urged to investigate coronavirus deaths of BAME doctors. The Guardian. Published 10 April 2020. https://www.theguardian.com/society/2020/apr/10/uk-coronavirus-deaths-bame-doctors-bma
- Boyd C (2020) Death rate among black and Asian Brits is more than 2.5 TIMES higher than that of the white population, reveals stark analysis by Institute of Fiscal Studies. Mail Online. Published 1 May 2020. https://www.dailymail.co.uk/news/article-8276097/Clear-disparity-ethnic-groups-Covid-19-deaths-IFS-study.html
- 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
- APM Research Lab (2020) The colour of coronavirus: Covid-19 deaths by race and ethnicity in the US. Published 1 May 2020. https://www.apmresearchlab.org/covid/deaths-by-race
- Pareek M, Bangash MN, Pareek N, Pan D, Sze S, Minhas JS, Hanif W, Khunti K (2020) Ethnicity and Covid-19: an urgent public health research priority. The Lancet. 395(10234): 1421-1422.
- Gupta S (2020) Why African-Americans may be especially vulnerable to COVID-19. Science News. Published 10 April 2020 https://www.sciencenews.org/article/coronavirus-why-african-americans-vulnerable-covid-19-health-race
- Centers for Disease Control and Prevention (2020) National diabetes statistics report 2020. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf
- American Heart Association (2016) High blood pressure and African Americans. https://www.heart.org/en/health-topics/high-blood-pressure/why-high-blood-pressure-is-a-silent-killer/high-blood-pressure-and-african-americans
- Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, and the Northwell COVID-19 Research Consortium (2020) Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. Published online 22 April 2020. doi:10.1001/jama.2020.6775
- UK Government (2019) Ethnicity facts and figures. https://www.ethnicity-facts-figures.service.gov.uk/health/diet-and-exercise/overweight-adults/latest
- Goff LM (2019) Ethnicity and Type 2 diabetes in the UK. Diabetic Medicine. 36: 927-938 12
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- National Institute of Health and Care Excellence (2018) Vitamin D deficiency in adults – treatment and prevention. https://cks.nice.org.uk/vitamin-d-deficiency-in-adults-treatment-and-prevention#!backgroundSub:2
- Rhodes JM, Subramanian S, Laird E, Kenny RA (2020) Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity. Aliment Pharmacol Ther. 00: 1–4. DOI: 10.1111/apt.15777
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- 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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- Zakharova I, Klimov L, Kuryaninova V, Nikitina I, Malyavskaya S, Dolbnya S, Kasyanova A, Atanesyan R, Stoyan M, Todieva A, Kostrova G and Lebedev A (2019) Vitamin D Insufficiency in Overweight and Obese Children and Adolescents. Front. Endocrinol. 10: 103. doi: 10.3389/fendo.2019.00103
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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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