key: cord-0993859-lxnuayz5 authors: Lui, Briana; Samuels, Jon D.; White, Robert S. title: Potential Pathophysiology of COVID-19 in Patients with Obesity date: 2020-06-07 journal: Br J Anaesth DOI: 10.1016/j.bja.2020.05.055 sha: 0014140920bfe62e1753149fb9c2b1fa0110d955 doc_id: 993859 cord_uid: lxnuayz5 nan To the Editor: We read with great interest Memtsoudis and colleagues' correspondence, "Obesity as a risk factor for poor outcome in COVID-19 induced lung injury: the potential role of undiagnosed obstructive sleep apnea," which reported an over-prevalence of obesity among both critically ill COVID-19 patients with respiratory failure admitted to the Intensive Care Unit (ICU) and severely ill patients not admitted to the ICU. 1 The authors suggested that obstructive sleep apnea associated baseline inflammation and generation of intrathoracic shear forces may potentially explain the co-occurrence of obesity and severe to critical COVID-19 disease. We commend the authors for their novel contribution to the evolving literature on COVID-19 and its potential risk factors and pathophysiology. We wish to further propose several pathophysiological pathways that may explain the disproportionate incidence of adverse outcomes among obese COVID-19 patients. Preliminary studies suggest a strong association between obesity and COVID-19 mortality and morbidity. An unpublished observational cohort study of 16,749 COVID-19 patients in the United Kingdom found that obese patients were 37% more likely to die in-hospital than nonobese patients after adjusting for comorbidities and demographic characteristics (preprint data available at: https://www.medrxiv.org/content/10.1101/2020.04.23.20076042v1). Among a cohort of 383 COVID-19 patients in Shenzen, China, patients identified as obese had a 142% higher risk of developing severe pneumonia compared to non-obese patients. 2 The Intensive Care National Audit & Research Centre (ICNARC) report on COVID-19 in critical care showed that the distribution of body mass index (BMI) of COVID-19 patients matched that of the general population, suggesting that obesity is likely not linked to severe COVID-19 infection requiring an ICU admission. 3 However, the report does support evidence of an increased risk of death among obese patients admitted to the ICU. Obesity should at the least be viewed as a potential risk factor for severe COVID-19 manifestations or worse outcomes, and clinicians and scientists should gain a better understanding of the possible mechanistic role obesity plays in the pathogenesis of COVID-19. 4, 5 COVID-19 enters human cells via binding of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) to the human angiotensin-converting enzyme 2 (ACE-2) receptor. 6 This receptor is expressed in the heart, lungs, kidneys, and intestines, thereby providing a multimodal entry point for the virus to infiltrate the body. Preliminary unpublished data indicate that ACE-2 receptor levels are higher in adipose tissue in comparison to lung tissue, suggesting that adipose tissue might be vulnerable to SARS-CoV-2 infection (preprint data available at: https://www.preprints.org/manuscript/202002.0315/v1). This presents a risk for adverse outcomes for obese patients with more adipose tissue and a greater number of ACE-2 receptors in comparison to their non-obese counterparts. Alterations of adipose tissue distribution and function linked to obesity have been shown to promote production of pro-inflammatory cytokines and induce chronic systemic inflammation. 7 Increased production and release of cytokines further exacerbates activation of kinase receptors, triggering a positive feedback loop of inflammation and metabolic dysfunction. Among obese patients with COVID-19, this heightened inflammatory response may put them at greater risk for a cytokine storm, an overresponse of the immune system characterized by uncontrolled release and attack of cytokines on the body's own tissues and organs. Although obesity-specific clinical data are lacking, general findings provide evidence supporting the cytokine storm concept with COVID-19 non-survivors having significantly higher levels of interleukin-6 (IL-6), a cytokine that regulates homeostasis and inflammation, compared to survivors. 8 Research will need to explore these mechanisms in the context of the obesity paradox, the epidemiologically-observed inverse relationship between obesity and mortality amongst select medical and surgical populations (interestingly, with surgery being a proinflammatory inducing event). 9 Furthermore, it is well-documented that elevated levels of inflammatory biomarkers among obese patients are linked to increased risk of comorbidities, including cardiovascular disease, diabetes mellitus, metabolic syndrome, and liver disease. 7 The presence of these comorbidities in COVID-19 patients has been shown to be associated with greater vulnerability to multi-organ injuries. 10 Ultimately, many patients die from complications that stem from these underlying illnesses, providing yet another reason for clinicians to be extra vigilant when treating and monitoring obese patients with COVID-19. Obesity as a risk factor for poor outcome in COVID-19 induced lung injury: the potential role of undiagnosed obstructive sleep apnoea Obesity and COVID-19 severity in a designated hospital in Shenzhen Intensive Care National Audit and Research Centre. ICNARC report on COVID-19 in critical care Obesity and impaired metabolic health in patients with COVID-19 Risk of COVID-19 for patients with obesity The Renin-Angiotensin-Aldosterone System in Coronavirus Infection -current considerations during the pandemic Obesity and Inflammation: Epidemiology, Risk Factors, and Markers of Inflammation Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study The obesity paradox: perception vs knowledge As research surrounding COVID-19 continues to evolve, it is crucial to consider obesity as a potential risk factor for adverse outcomes. A better understanding of the pathophysiological contributors linking obesity with severe to critical COVID-19 disease will not only help inform medical management of obese patients, but also aid in the development of successful therapeutics to prevent and treat COVID-19.