A recent meta-analysis reported that individuals with obesity have a greater risk of hospitalization, intensive care unit admission, and death from COVID-19.1 Particularly, obesity is a strong risk factor for hospitalization and death among adults aged < 65 years.2 Obesity has also been identified as an independent risk factor for severe morbidity and mortality during the H1N1 influenza3 and Middle East respiratory syndrome epidemics.4 Several mechanisms, such as obesity-related comorbidities, metabolic dysfunction, immune impairments, and adipose tissue inflammation, have been proposed to explain the link of obesity with COVID-19 and other respiratory infectious diseases.1

In this article, environmental pollutants are proposed as another possible mechanism to explain the higher risk of severe COVID-19 in obese individuals. Although it is largely unknown to researchers and clinicians, human adipose tissue is extensively contaminated with various environmental pollutants.56 Typical examples of environmental pollutants stored in the adipose tissue are persistent organic pollutants (POPs).

POPs are a group of organic compounds with common features, such as strong lipophilicity, high persistence in the environment due to resistance to degradation, bioaccumulation in the adipose tissue of living organisms, and prolonged half-lives reaching several years to decades in humans.7 Specific compounds include organochlorine pesticides, polychlorinated biphenyls, dioxins, and polybrominated diphenyl ethers. Many other chemicals that are not traditionally classified as POPs are also commonly detected in human adipose tissue.89

The immune system is one of the targets of xenobiotic-induced toxicity.10 Early epidemiological and toxicological studies have shown that various environmental chemicals, including POPs, impair the immune system at high doses.1112 Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces several immunotoxic effects on both innate and adaptive immune responses through aryl hydrocarbon receptors.1314 In a previous study, TCDD administration to laboratory animals resulted in decreased resistance to numerous bacteria, viruses, and parasites.15 In addition to TCDD, other POPs, classified as organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers, have also demonstrated immunotoxicity in many in vitro and in vivo studies.161718

Early toxicological studies have focused on the immunotoxicity of high doses of individual chemicals; however, recent studies have highlighted the effect of chronic exposure to low-dose environmental pollutants on the immune system.1920 In contemporary society, humans are chronically exposed to a tremendous number of low-dose environmental pollutants. Although many POPs were banned several decades ago, humans are still exposed to them in the form of lipophilic chemical mixtures because they have widely contaminated the food chain on earth.21

Studies on marine mammals have suggested that immunotoxicity may occur due to chronic exposure to low-dose environmental pollutants, because a wide array of environmental pollutants modulate the immune system.22 In addition, a recent human study demonstrated that chronic exposure to low-dose POPs was linked to T cell immunosenescence, which is a hallmark of an aging immune system.23 An aging immune system is directly related to the risk of increased susceptibility to infectious diseases.24

Currently, the most important source of exposure to POPs is inside the body—human adipose tissue. Once POPs enter the body through external sources, they are primarily stored in adipose tissue and are very slowly released into the circulation through lipolysis.25 Therefore, serum concentrations of POPs in humans, which are commonly used to assess the POP exposure status in epidemiological studies, reflect the quantity of POPs released from the adipose tissue into the circulation and are not directly related to the level of exposure to external sources of POPs. The accumulation of POPs in adipose tissue occurs throughout the lifetime—from the fetal stage to death. Therefore, although external sources of exposure to POPs would have been eliminated, POPs in adipose tissue still play a role as an internal exposure source and affect human health.

Under normal physiological conditions, adipose tissue lipolysis is tightly regulated by hormonal signals, depending on the caloric needs.26 Unlike lean healthy persons, in obese individuals POPs are released into the circulation more easily through uncontrolled lipolysis, which is a feature of hypertrophic dysfunctional adipocytes.27 Uncontrolled lipolysis is further enhanced by insulin resistance.28 Therefore, it is highly plausible that obese individuals show higher serum concentrations of POPs with immunotoxicity. This may be a possible mechanism for the relationship between obesity and the increased risk of morbidity and mortality in COVID-19.

It is worth noting that low-dose POPs have recently emerged as a risk factor for many metabolic diseases, including type-2 diabetes,729 which is another risk factor for increased morbidity and mortality in COVID-19. Also, low-dose POPs can induce pro-inflammatory change in adipose tissue regardless of obesity.3031 Therefore, chronic exposure to low-dose POPs can be a more fundamental factor to explain the higher risk of severe morbidity and mortality in patients with COVID-19 (Fig. 1).

Weight management is crucial for individuals who are overweight or obese. However, inadequate consideration of the dynamics of POPs during weight loss may lead to unexpected consequences.25 Intentional weight loss improves short-term clinical profiles, but a long-term consequence is the increased amount of POPs released from the adipose tissue into the circulation due to the shrinkage of the storage sites.32

This mechanism may explain the unexpected finding from a large randomized controlled study on intensive weight loss among overweight or obese patients with type 2 diabetes. In this clinical trial, the intensive weight loss group failed to attain any benefit on the development of cardiovascular diseases compared to the control group, despite an improvement in many known risk factors for cardiovascular diseases.33 Therefore, the ideal strategy of weight management should consider both fat mass and the dynamics of POPs.

With regards to the amount of adipose tissue mass, obesity and weight loss are opposites; obesity is the status of having a significant fat mass, while weight loss is the process of losing fat mass. However, both increase the release of POPs from adipose tissue into the circulation. The difference is that in obese patients small amounts of POPs are continuously released into circulation for a long period of time, but weight loss releases relatively large amounts of POPs during the period of weight loss.

POPs in circulation would be more harmful than POPs in the adipose tissue because of their easy access to critical organs. Therefore, dealing with POPs in circulation in everyday life is very important for both obese persons and those who want to lose weight. In fact, a healthy lifestyle consisting of proper diet and exercise has been suggested as a practical method to increase the elimination of POPs from the circulation and mitigate their possible harmful effects at the cellular level.333435363738 In addition, slow and steady weight loss is better than rapid weight loss because the increase in POPs in circulation during weight loss is proportional to the magnitude of weight loss.32

The dynamics of POPs accumulated in adipose tissue can be a possible mechanism to explain the relationship between obesity and severe COVID-19. Low-dose lipophilic chemical mixtures, such as POPs, add another challenge to weight management and emphasize the importance of preventing obesity. In this context, it is unfortunate that the containment strategy to combat the COVID-19 pandemic has worsened the obesity epidemic because social distancing and stay-at-home policies have hindered weight management.39 The relationship between obesity and environmental pollutants warrants further investigation by researchers, clinicians, and public health officials.