When Obesity-Driven Meta-Inflammation Meets SARS-CoV-2

As the country has rounded the half-year mark in dealing with widespread COVID-19 infection, the initial puzzlement over why certain patients experience and even succumb to the worst ravages of the disease and others have a milder course has given way to increased understanding of some of the risk factors. A new study reveals that obesity, and the state of metabolic inflammation that often underlies it, may portend a more severe course of COVID-19.

Author Kanakadurga Singer, MD, MA, associate professor in the Department of Pediatrics, Division of Pediatric Endocrinology, at the University of Michigan Medical School’s Graduate Program in Immunology, and her colleagues undertook the study, published in Endocrinology, in order to delve into the metabolic processes driving inflammation and how these processes affect patient outcomes in the COVID-19 era.

The study found that being obese, having diabetes, and being male were particularly correlated with morbidity and mortality as a result of infection. Specifically, the dysregulation of the immune system that occurs with excess weight appears to play a significant role in the inflammatory state that leads to severe disease and even death in COVID-19 patients. When a person is obese, macrophages--or immune white blood cells--can create increased levels of cytokines and chemokines that perpetuate the inflammatory state.

In patients with diabetes that’s poorly controlled, excess glucose in the blood can cause higher levels of certain cytokines and C-reactive protein, a measure of systemic inflammation. According to the authors, data on COVID-19 patients whose diabetes was well controlled shows a 1.1% mortality rate, while data on those whose glucose levels were poorly controlled reveals a mortality rate of 11%. Hyperglycemia also can raise levels of glucose in the lungs, which may allow bacteria to flourish.

Being male is a risk factor for severe disease and death in COVID-19, possibly due to differences in levels of myeloid inflammation. It’s also possible that higher levels of androgens ramp up production of the cytokine IL-10, which may tamp down the body’s natural inflammatory response to the pathogen. These immune and endocrine differences give females, particularly premenopausal ones, an edge in surviving COVID-19.

Whether male or female, it’s clear that excess body mass is linked to worse outcomes from COVID-19 and other viruses. Obese people have higher circulating levels of chemokines such as CCL14 and MCP-1, and cytokines including IL-6, IL-8, IL-1_B, and TNF-a. These secreted proteins can cause a cytokine storm, in which the immune system is overwhelmed and goes into overdrive, with potentially fatal results.

A patient in the midst of a cytokine storm may progress to hypoxic respiratory failure. “[T]he association of obesity with physiologically defined hypoxic respiratory failure suggests a biologic interaction of obesity with SARS-CoV-2 infection,” the authors wrote in their study. “Obesity as a risk factor for severe infectious disease is not a new concept and is not limited to coronavirus infections. During the 2009 influenza A/H1N1 pandemic, it was noted that obese patients were more likely to experience more severe disease requiring hospitalization than normal weight patients.” The authors also mentioned that even when vaccinated, obese patients were more likely to be infected with influenza than those of normal weight, probably due to impaired T-cell function.

While young and middle-aged COVID-19 patients admitted to the hospital are more likely to end up in the ICU if they have a high BMI, it’s not yet clear if the higher risk of COVID-19 severity seen in the elderly is affected by weight. It’s possible that the natural age-related deficits occurring in the immune system, not excess weight, are the cause of high rates of illness and death from SARS-Co-V-2 in older people.

Because obesity has such a detrimental effect on COVID-19 patients, the authors put forth a compelling case for the deliberate inclusion of this population in vaccine and treatment research efforts. “The possibility of different vaccine or treatment efficacy in obese patients underscores the importance of adequate representation of obese individuals in clinical trials and a focus on patient-centered, rather than serologic, outcomes in evaluating efficacy,” they wrote.