In recent days, scientific information has been accumulating regarding the relationship between the SARS-CoV-2 pandemic and the "pandemic" of obesity. These are two diseases that are spreading across the world without borders and at varying speeds. Obesity has tripled since 1975, affecting citizens of all countries worldwide, and although it is not an infectious disease but a chronic one (and therefore its globalization cannot be called a pandemic), it tends to become established in humans without much successful treatment. In many countries, the situation is critical. In the United States in 2020, it is estimated that more than 40% of the adult population is obese , and that in the African American population these figures are close to 50%. The question that is now beginning to concern health professionals is whether obese people, with this high prevalence worldwide, are more susceptible to developing serious problems when infected with SARS-CoV-2, and what mechanisms may be involved in this increased susceptibility. The data available so far allow us to conclude that diabetes mellitus, hypertension , and obesity increase individual susceptibility to SARS-CoV-2 infection, as well as the risk of serious complications and death from COVID-19.
In the Portuguese case, knowledge of the relationships between these chronic diseases, which may include obesity, but also diabetes and hypertension, and Covid-19 is of utmost importance. This is because these diseases are very prevalent in Portugal, because many Portuguese citizens share more than one of these diseases, and because their expression in our society is greatly influenced by social gradients. For example, based on the results of the National Health Survey with Physical Examination (INSEF) regarding the health status of the national adult population in 2015, the prevalence of diabetes was approximately 10%, the prevalence of hypertension was 36%, and the prevalence of obesity was 29%. More serious than these alarming numbers in the millions is the fact that the prevalence of diabetes, hypertension, and obesity varies greatly depending on age, education level, and employment status, being systematically higher in the older population, with lower levels of education and without paid professional activity. In other words, the elderly, the poorest, and those with less education are the ones where these chronic diseases are much more frequent (sometimes more than double). At a time when the Covid-19 pandemic is already affecting more than ten thousand Portuguese people, we know that these are precisely the population groups that will suffer the most from this infectious disease and will be the first to suffer its consequences.
This relationship, in a way, forces us to rethink the determinants of infectious diseases that in the past primarily affected the malnourished, that is, those malnourished due to insufficiency, and today also affect those malnourished due to excess, namely the obese. Unlike the previous and well-known epidemic catastrophes of the Middle Ages, these epidemics are not accompanied by periods of famine, but they also affect the obese, who are, in a way, the malnourished of our times. The fact that the disease first appeared in China and some neighboring countries with younger populations and lower prevalences of obesity and chronic diseases initially led to obesity being overlooked. However, this relationship and our understanding of it have changed radically in recent weeks.
As the infection spread through Western countries, particularly Europe and then the United States, the need arose to rethink the risk and its relationship with chronic disease, especially obesity . Recognizing the importance of obesity in the course of COVID-19, ESPEN (European Society for Clinical Nutrition and Metabolism), in its position paper on nutritional intervention in patients with COVID-19, highlights two aspects of malnutrition as potential risk factors for future pandemics.
The relationship between obesity and COVID-19 has been revealed by studies such as those that analyzed the characteristics and clinical outcomes of 112 patients with cardiovascular disease infected with SARS-CoV-2, showing that a high BMI was frequently present in critically ill patients and those who did not survive the disease. Another study published with data from 383 COVID-19 patients in China suggests that obese patients, particularly males, have a higher risk of developing severe pneumonia.
Furthermore, an article published in JAMA suggests that the higher prevalence of obesity among elderly Italians, compared to China, may explain the differences found in mortality rates between the two countries.
This evidence led the CDC (Centers for Disease Control and Prevention) to include individuals with morbid obesity in the list of risk groups for developing severe COVID-19 disease.
Although the discussion about the relationship between obesity and COVID-19 is recent, since the 1918 "Spanish flu" pandemic it has been known that malnutrition (both excess and deficiency) is associated with a worse prognosis for this type of viral infection . In the outbreaks of "Asian flu" from 1957 to 1960 and the "Hong Kong flu" of 1968, it was possible to confirm that obesity and diabetes led to higher mortality and longer disease duration , even in patients without other comorbidities that increase the risk of complications associated with influenza virus infection. During the 2009 pandemic caused by the H1N1 influenza virus , obesity was associated with a higher risk of severe illness, hospitalization, and death.
Next, we refer to different mechanisms that may help explain the relationship between obesity and COVID-19.
A state of chronic low-grade inflammation present in obesity, diabetes, and metabolic syndrome
Several steps in the innate and adaptive immune response are altered due to the low-grade chronic inflammation present in obesity, diabetes, and metabolic syndrome. Obese individuals exhibit elevated levels of pro-inflammatory adipocytokines (e.g., leptin, resistin, and visfatin) and reduced levels of anti-inflammatory adipocytokines (e.g., adiponectin and IL-10). This altered hormonal environment leads to changes in the immune response , contributing to the pathogenesis of obesity-related complications. In a baseline state, obese patients present with elevated levels of several pro-inflammatory cytokines (TNF-α, MCP-1, and IL-6), mostly originating from visceral and subcutaneous adipose tissue, which compromise the innate immune response. In a context of chronic inflammation associated with obesity, antigen presentation leads to reduced macrophage activation and attenuated production of pro-inflammatory cytokines by these cells . This reduced activation of macrophages after antigen presentation seems to explain the lower success rate of influenza vaccination in obese individuals . In obesity and metabolic syndrome, the responses of B and T lymphocytes are also diminished. For this reason, there is greater susceptibility and an increase in the resolution time of viral infections. Leptin plays a regulatory role in the development, maturation, and function of B lymphocytes, so it is believed that leptin resistance, frequent in obesity, may have played a significant role in the 2009 H1N1 pandemic . Obesity decreases the response of cytotoxic T lymphocytes (CD8+ T) to influenza viruses , as well as antibody production after administration of the seasonal flu vaccine. This effect, in addition to the already described disruption in macrophage function, leads to a low response to influenza vaccination. An exacerbated pro-inflammatory response contributes to the severe lung lesions observed during influenza pandemics and in COVID-19.
Effects of obesity on lung function
Infection with the H1N1 influenza virus and now with SARS-CoV-2 has a disproportionate impact on obese patients. This is not surprising considering the effects of obesity on lung function and the release of pro-inflammatory cytokines. Obese patients have a smaller expiratory reserve volume, lower functional capacity, and reduced respiratory system compliance. Additionally, in patients with abdominal obesity, when supine, there is restricted diaphragmatic movement, hindering normal ventilation . The most severe cases of COVID-19 develop cytokine release syndrome, also known as a "cytokine storm," triggering a state of hyperinflammation. In COVID-19 patients, dyspnea on hospital admission , as well as increased levels of cytokines (IL-6, IL-10, and TNFα), lymphopenia (of CD4+ and CD8+ T cells), and lower expression of IFNγ in CD4+ T cells are associated with a worse prognosis. Due to the role of these pro-inflammatory factors, there is increased vascular permeability, fluid and cells in the pulmonary alveoli, resulting in dyspnea and even respiratory failure. The IL-6 pathway appears to be particularly important in cytokine release syndrome in COVID-19 patients, and blocking the IL-6 receptor is being studied as part of the therapeutic intervention for severe COVID-19.
Obesity and attenuated immune response via interferon deficiency
Studies in animal models of obesity infected with influenza virus show greater disease severity, a higher number of secondary bacterial infections, and reduced vaccine efficacy. In these animal models of obesity, an attenuated immune response occurs, possibly resulting from reduced levels of interferon, adaptive cellular response, and antibody-mediated response. Exposure to the H1N1 virus in animal models of obesity (induced by diet or genetics) results in greater virulence and morbidity. Interferon deficiency appears to favor the emergence of mutations that enhance the virulence of the influenza virus. These results are not limited to animal models. In epithelial cells obtained from the bronchi of obese patients, a decrease in the interferon-mediated response has been observed, as well as greater replication of the influenza virus .
Obesity and low levels of physical activity
Reduced physical activity is another relevant issue associated with obesity. Low physical activity, alone or in combination with insulin resistance, limits the immune response against infectious agents , particularly in macrophage activation and inhibition of pro-inflammatory cytokines. Physical activity and exercise offer benefits in metabolic pathology (obesity, diabetes, metabolic syndrome) and immune health (immune activation, vaccine efficacy, and immunosenescence). Intervention studies with physical activity in elderly women have demonstrated potential risk reduction for complications through a modulating effect on inflammation, improved immune response, and vaccine response.
Several mechanisms could explain the greater severity of COVID-19 in obese patients. But do obese individuals also have a higher risk of contracting the disease?
The SARS-CoV-2 virus appears to use angiotensin-converting enzyme 2 (ACE2) as its "entry point into cells." Obese patients frequently present with comorbidities that require drug therapy that modifies ACE2 expression. Thus, one point still to be clarified is the impact on the risk of contracting COVID-19 and its progression when using drugs that increase ACE2 expression. We know that ACE2 expression is increased in diabetes, but it is also increased by drugs used in its treatment such as GLP-1 agonists (liraglutide) and thiazolidinediones (pioglitazone). ACE inhibitor antihypertensives and cholesterol-lowering drugs such as statins also increase ACE2 expression .
Finally, some recent studies suggest that obesity may increase the contagiousness of viral respiratory infections. Several factors support this idea of increased contagiousness: obese individuals with influenza transmit the virus for up to 104% longer than individuals of normal weight ; as described above, the delayed and smaller-scale production of interferon favors the emergence of more virulent viral strains ; the delay in interferon production, in contrast to the rapid replication of viral RNA, increases the likelihood of the emergence of new strains with greater virulence ; additionally, there is a positive correlation between body mass index and exhaled viral load . All these factors may suggest that the quarantine applied in the context of COVID-19 may need to be longer for obese individuals, with all the risks that this "additional stigmatization" would entail.
Being obese increases the risk of infection and its complications at an individual level. However, the data presented above, although much of it based on other viral respiratory infections, suggests that in a population with a high prevalence of obesity, there is a greater likelihood of the emergence of more virulent viral strains, an extended transmission period to the entire population, and potentially higher mortality in the context of a pandemic. In addition to all the measures proposed for mitigating COVID-19, adopting a healthy lifestyle with a balanced diet and physical activity, promoting weight loss when necessary, can be the difference between experiencing a manageable or fatal case of COVID-19.
There is still much to learn about this new relationship between obesity and COVID-19, but one thing is certain: the way we will view obesity in the future, now that new and successive waves of infection are expected, whether from SARS-CoV-2 or another variant, will transform the work of healthcare professionals, and nutritionists in particular.
Written by
Pedro Graça, Director of the Faculty of Nutrition and Food Sciences at the University of Porto