From the onset of the COVID-19 pandemic, it has become clear that obesity is linked to an increased risk for complications. Among 438 adults hospitalized with COVID-19 from March 1 to May 31, 2020, nearly 90% had at least 1 underlying condition, and obesity was most commonly reported (73%; Table 1).1 Other underlying conditions, including hypertension, diabetes mellitus, and chronic lung disease, were considerably less prevalent.1

In March 2021, the World Obesity Federation reported that COVID-19 mortality rates were 10 times higher in countries where more than 50% of the population is overweight.2 Given that the current prevalence of obesity in the US is 42%, many patients whom nurse practitioners (NPs) and physician assistants (PAs) are managing are obese.3 This article will review the pathophysiology of obesity and COVID-19 and provide essential information for NPs and PAs supporting patients in the treatment and prevention of COVID-19.

Table 1. Underlying Conditions in Patients (N=438) With COVID-19 in US Hospitals1

Underlying ConditionPercentage of Hospital Admissions
for COVID-19, %
Chronic metabolic disease36.7
Diabetes mellitus30.9
Chronic lung disease26.7

Epidemiologic Review of Patients With COVID-19 and Obesity

The increased risk for severe outcomes of COVID-19 for patients with obesity is evident in the literature.4,5 A hospital in Wuhan reported that nonsurvivors of COVID-19 were more likely to have a BMI greater than 25 kg/m2 compared with survivors (88.2% vs 18.9%; P<0.001).6

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In a study from the United Kingdom, 72% of patients admitted to the critical care unit for COVID-19 were overweight or obese, and mortality was 60.9% among patients with a BMI >30.7,8 Data from the United States show that obesity is linked to an increased risk of SARS-CoV2 infection and increased severity of COVID-19, including significantly higher rates of hospitalization, severe cases, intensive care unit admission, invasive mechanical ventilation, and mortality.9,10

Additionally, patients with obesity are more likely to have diabetes and hypertension, both of which are recognized as major risk factors for COVID-19 complications.11

Obesity appears to overcome protective factors associated with younger age with regard to COVID-19 severity (Table 2).12

Table 2. Risk for Admission to Acute or Critical Care for COVID-19 in Patients With Obesity Younger Than Age 60 Years12

BMIAdmission to Acute CareICU Admission
30 to 342× more likely1.8× more likely
≥352.2× more likely3.6× more likely
BMI, body mass index; ICU, intensive care unit

Pathophysiology of Severe COVID-19

It is pivotal for NPs and PAs managing patients with COVID-19 to understand the pathophysiology of the infection. Two theories have been proposed as the foundational mechanism behind the link between severe COVID-19 presentation and obesity: the cytokine storm and the bradykinin storm.

Cytokine Storm

The cytokine storm was the first theory proposed. Research shows that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors, which are prevalent in the lung, heart, ileum, kidney, and bladder.13 In the lung, these receptors are mostly located on epithelial cells of the alveolar space. The virus often destroys these cells, causing distal lung damage in the early phases of infection.13 Thus, pneumonia is a feature of nearly all serious COVID-19 cases.14

Cytokine storm leading to acute respiratory distress syndrome (ARDS) is another common manifestation of severe infection. High levels of cytokines attract neutrophils and cytotoxic T cells, possibly causing lung damage.13 There is a positive correlation between interleukin 6 (IL-6) levels and severe disease in SARS-CoV-2 infections. Certain rare subsets of inflammatory monocytes further elevate IL-6 levels and accelerate inflammatory response in severe infection.13 In addition, central ACE2 receptors in the midbrain may be affected, resulting in sympathetic activation and vasoconstriction. This in turn leads to capillary leaking in the lungs, increasing the risk for ARDS.15 This level of endothelium involvement can cause hypercoagulability, leading to pulmonary and peripheral venous thromboembolic disease in multiple organs and possibly life-threatening respiratory failure.16

Obesity is associated with higher inflammatory cytokine levels, leading to a more severe disease course. Higher levels of the proinflammatory adipokine leptin and lower levels of anti-inflammatory adiponectin trigger subcutaneous adipose tissue to produce increased levels of inflammatory cytokines, which affect innate immunity.17,18

Interleukin-6, a proinflammatory cytokine shown to activate the inflammatory cytokine cascade for many days, is a possible cause of cytokine storm and a strong predictor of mortality.18,19 Thus, it is possible that adipose tissue acts as a significant source of IL-6 and potentially causes a cytokine storm in patients with obesity.18,19

Bradykinin Storm

More recently, researchers have theorized that SARS-CoV-2 induces a renin-angiotensin system (RAS)-mediated bradykinin storm that causes fluid from blood vessels to leak into tissues and organs, which underlies severe COVID-19 symptoms.20-22 Garvin et al used a computer model of previously collected gene expression data from the lung fluid of patients with COVID-19 and found that SARS-CoV-2 decreased ACE levels in lung cells and increased ACE levels.20 The researchers suggested that this imbalance increases the level of bradykinin, which is a potent part of the vasopressor system, induces hypotension and vasodilation, and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2 (Figure).

“The virus therefore acts pharmacologically as an ACE inhibitor by reducing its RNA expression more than 10-fold, which is supported by our BAL RNA-seq analysis,” Garvin and colleagues wrote.20

At the same time, levels of hyaluronic acid (which can trap up to 1000 times its weight in water) increased and levels of enzymes that degrade hyaluronic acid decreased in patients with COVID-19 infection. The combination of vascular permeability from increased bradykinin production and hyaluronic buildup in the lungs “could produce a hydrogel that significantly inhibits gas exchange in bronchoalveolar spaces,” according to Garvin and colleagues.20

Figure. Critically disrupted RAS and Bradykinin pathways in COVID-19 BAL samples.
(A) Significantly differentially expressed genes: red ovals indicate genes upregulated in COVID-19, blue are downregulated, colors are scaled to the log2-fold-change values for COVID-19. The overall effect is to shift the system to production of Ang1-9 and AGTR2-driven sensitization of BK receptors involved in pain (BDKRB1) and NO-dependent vasodilation (BDKRB2). Several points of inhibition maintain this imbalance. The suppression of NFkappaB by the virus decreases its binding to the ACE promoter and subsequent transcription (lower left). Decrease in the activation of Vitamin D and its receptor (VDR), which normally inhibits REN production, in combination with the upregulation of ACE2, increases flux of angiotensin to Ang1-9 (top left). Decrease in the expression of the SERPING1 gene, lifts suppression of FXII of the intrinsic coagulation cascade, resulting in further production of BK from kallikrein and KNG (both upregulated) (top right). BK levels are further increased because ACE, which normally degrades it, is decreased. A surge in Ang1-9 further sensitizes the effects of bradykinin at BDKRB2. Other enzymes that degrade BK are also downregulated such as MME, which is meant to degrade Ang1-9 , BK, and another important peptide Apelin (APLN). (B) The result of a hyperactive bradykinin system is vasodilation to the point of vascular leakage and infiltration of inflammatory cells. Reprinted from Garvin et al.20

Similarly, van de Veerdonk et al hypothesized that SARS-CoV-2 infection causes a dysregulated bradykinin system resulting in leaky blood vessels in the lungs and possibly excess fluid buildup.21

Clinical trials of 2 currently available agents that target the kinin system ­— icatibant and lanadelumab ­— are ongoing. A small exploratory study by van de Veerdonk found that icatibant decreased the need for supplemental oxygen in patients taking the agent compared with those in a control group.22