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Obesity and COVID-19: A Virchow's Triad for the 21st CenturyFunding This study was funded by Science Foundation, Ireland (12/RC/2273_P2).
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-strand β-RNA virus which causes coronavirus disease-2019 (COVID-19). The majority of infected subjects remain asymptomatic or experience mild disease but many require hospitalization including intensive care admission and have substantial morbidity and mortality.
Early COVID-19 characterization identified significant numbers of (often younger) patients without significant pre-existing medical disorders that developed a severe clinical phenotype characterized by rapid cardiorespiratory deterioration that was attributed to a “cytokine storm.” This hyperinflammatory syndrome with high mortality and apparent stochastic nature has been particularly alarming to clinicians and remains incompletely understood.
Recent reports have also highlighted that many younger subjects hospitalized with COVID-19 are overweight. In a large series of 5,700 patients hospitalized in New York, the rate of mechanical ventilation was 12.2% and the death rate of those ventilated was 88%. The overall rate of obesity in this series was 41%. Obesity is associated with well-recognized deleterious effects on pulmonary mechanics and ventilation including lower lung volumes, lower respiratory muscle strength, and impaired gas exchange. Strategies that have been adopted to overcome these anomalies and improve oxygenation include prone ventilation. In other types of pneumonia, including acute respiratory distress syndrome (ARDS), an “obesity paradox” has been previously observed where the risk of death is decreased in those with higher body mass index. The mechanisms responsible for this paradox are speculative but its existence contrasts with the severity of COVID-19 respiratory failure where precipitous decline in clinical course of a subset of critically ill patients with COVID-19 cannot be explained by deterioration in pulmonary parameters alone.
A minority of COVID-19 patients evolve a rapid inflammatory syndrome with an ARDS-like clinical phenotype (∼30%) and multiorgan failure approximately 8 to 9 days after symptom onset. In a second shunt phenotype (>60%) patients show well-preserved lung mechanics but severe hypoxia, high respiratory compliance, and high shunt fraction. While direct lung injury due to SARS-CoV-2 infection plays a central role in the pathophysiology of all COVID-19 patients, it does not explain the differential severity of the disease between lean and overweight subjects, nor the profound mismatch between hypoxia and ventilatory compromise in some patients. Disease severity is significantly mediated by multifaceted host responses and obesity may be one “hidden driver” of the heterogeneous host response and hyperinflammatory COVID-19. We posit that adipose tissue acts as a powerful inflammatory reservoir for SARS-CoV-2 viral replication in overweight subjects with more adipose tissue generating a larger inflammatory response than in lean subjects. This inflammatory disorder in subjects with obesity may drive heterogeneity in vascular injury, in situ thrombosis events, and thromboembolic complications in the systemic and pulmonary vascular system ([Fig. 1]).
SARS-CoV-2 enters human cells by binding to the angiotensin-converting enzyme 2 (ACE2) on the plasma membrane, which is widely expressed in lung alveolar cells, cardiomyocytes, and vascular endothelium. ACE2 is also expressed in adipocytes, smooth muscle cells, and myofibroblasts, and its expression has been found to be significantly upregulated in obesity. Enhanced ACE2-mediated viral access and replication in local organ adipose tissue very likely leads to significant paracrine/endocrine elaboration of proinflammatory cytokines and adipokines that mediate inflammation in COVID-19. This activation may include inter alia elements of the complement system  and an unbalanced renin–angiotensin system (RAS), whereby RAS is activated and the counterregulatory ACE2/MAS receptor system is downregulated. Patients with severe COVID-19 show higher plasma levels of interleukin (IL)-2, IL-6, and IL-7, with IL-6 being an independent predictor of mortality.  Inflammatory cytokines released from visceral and perivascular adipose tissue include IL-6, IL-2, granulocyte colony-stimulating factor, interferon-γ, monocyte chemotactic protein-1, and tumor necrosis factor-α, and these same cytokines are primarily responsible for recruitment of monocytes and T-lymphocytes to infected and inflamed organs. Magro et al recently reported COVID-19 pneumonitis without classic ARDS features including complement activation, septal capillary injury, and mural and luminal fibrin deposition, in addition to neutrophil infiltration. Moreover numerous emerging studies indicate COVID-19 association with elements of disseminated intravascular coagulation and regional pulmonary intravascular coagulopathy. Activation of the immune, complement, and coagulation systems already exists in obesity and may contribute to augmented tissue injury seen in organs directly impacted by SARS-CoV-2 tissue damage, such as the lungs ([Fig. 1]).
Furthermore, SARS-CoV-2-mediated inflammation via these pathways may occur in other “pockets” of adipose tissue in the heart, kidney, liver, and vasculature, explaining some of the more unexpected clinical phenomena seen in younger subjects with COVID-19, such as stroke, acute kidney injury, and apparent myocardial infarction. Cases of ST-elevation myocardial infarction (STEMI) without demonstrable coronary occlusion have been widely reported and remain unexplained. These “STEMIs” have been speculated to represent SARS-CoV-2 myocarditis or acute coronary syndrome secondary to sepsis or hypoxia. It is also conceivable that lung-associated SARS-CoV-2-mediated inflammation of epicardial white adipose tissue may masquerade as a STEMI with the epicardium and adjacent adipose tissue known to share a common microcirculation.
Beyond local effects, systemic release of inflammatory cytokines/adipokines from adipose tissue may promote a Virchow's triad of events including vascular thrombosis, endothelial dysfunction, and blood flow stasis through reactive oxygen species and vasoconstriction ([Fig. 2]). Such an inflammatory thrombogenic vasculopathy may in part explain the precipitous multiorgan failure and also the variability of clinical course and treatment response in some patients.
The role of obesity and the potentially deleterious impact of adipose tissue in COVID-19 warrant significant worldwide attention. Recognition of enhanced risk in overweight subjects should be at the forefront of clinical decision-making in COVID-19. Stratification based on traditional risk scores (APACHE, SAPS, SOFA, and MPM), lung injury phenotype, and circulating inflammatory markers, such as soluble urokinase plasminogen activator receptor (suPAR), known to be elevated in obesity at baseline and to predict poorer clinical course in COVID-19, may guide earlier intervention in these groups. In parallel we need to gain a deeper understanding of the biology of inflammation and thrombotic vasculopathy in these patients, in particular how adipose tissue plays a role in this aspect of disease amplification. While awaiting successful vaccines, preemptive strategies to lessen the severity of the inflammatory, thrombogenic, and vasculopathic phenotypes in COVID-19 will prove important. These may involve monoclonal antibodies against pivotal cytokines in the inflammatory cascade. In addition, prospective targeting of downstream elements of complement activation (monoclonal antibodies) and thrombophilia (thrombin inhibitors) in obese subjects from a preventive and therapeutic aspect may be useful with clinical trial results of such approaches eagerly awaited.
Received: 18 May 2020
Accepted: 18 June 2020
17 July 2020 (online)
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Stuttgart · New York
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