Obesity and Viral Infections

Abstract

The 2019 novel coronavirus disease (COVID-19) triggered a rapidly expanding global pandemic. The presence of obesity in patients with COVID-19 has been established as a risk factor for disease severity, hospital admission, and mortality. Thus, it is imperative those living with obesity be vaccinated against COVID-19. Although there is a timeframe COVID-19 vaccines are efficacious in those living with obesity, more studies need to be conducted to ensure that those long-lasting protection is maintained, as obesity has implications on the immune system.

Key points

• •In the United States, there have been more than 95 million cases of COVID-19.
• •Obesity is a risk factor for severe clinical course in patients with COVID-19, possibly due to underlying immune and inflammatory changes, pulmonary system impairments and cooccurring obesity-related conditions that are also risk factors for COVID-19.
• •There is a need for intensive COVID-19 management as obesity severity increases and also promotion of COVID-19 prevention strategies in those living with obesity including continued vaccine prioritization, masking and timely booster dosages.

Background

COVID-19 is the name of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which recently triggered a rapidly emerging global pandemic.¹ The source of the pneumonia outbreak was in Wuhan, China in late 2019.² The virus was found to be a member of the beta coronavirus family, in the same species as SARS-CoV and SARS-related CoVs that have been seen in bats.^{3 , 4} According to the World Health Organization, as of September 2022, there have been more than 611 million cases, resulting in more than 6 million deaths worldwide. In the United States itself, there have been more than 95 million cases of COVID-19 that have resulted in 1,050,631 deaths.⁵

COVID-19 clinical spectrum

A virus surface spike protein mediates SARS-CoV-2 entry into cells. The SARS-CoV-2 spike protein binds to its receptor human ACE2 through its receptor-binding domain and is proteolytically activated by human proteases. Coronavirus entry into host cells is an important determinant of viral infectivity and pathogenesis.^{6 , 7}

Patients with COVID-19 can range from being asymptomatic to having critical illness. According to the NIH, patients with mild illness are individuals who have fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste, and smell but who do not have shortness of breath, dyspnea, or abnormal chest imaging. Those with moderate illness show evidence of lower respiratory disease during clinical assessment or imaging and an oxygen saturation (SpO₂) greater than or equal to 94% on room air. Individuals with an SpO₂ less than 94% on room air, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (Pao ₂/Fio ₂) less than 300 mm Hg, a respiratory rate greater than 30 breaths/min, or lung infiltrates greater than 50% are considered to have severe illness. Those who progress to respiratory failure, septic shock, and/or multiple organ dysfunction have critical illness.8, 9, 10, 11

Increased plasma concentrations of proinflammatory cytokines including interleukin-6 (IL-6), IL-10, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein (MCP) 1A, tumor necrosis factor alpha (TNFα), and others are present in more severe cases and are associated with a worse prognosis.^{12 , 13}

Elevated lactate dehydrogenase, ferritin, D-dimer, and creatine kinase elevation are also associated with severe disease. Elevated D-dimer and fibrinogen are consistent with thrombosis and pulmonary embolism in severe disease.¹⁴

How does COVID-19 affect patients with obesity

The large number of people infected with COVID-19 combined with the wide spectrum of disease severity led to investigation of whether various phenotypes and baseline biomarkers are associated with a higher risk of infection and critical illness. Initial data on COVID-19 implicated several factors associated with worse disease severity including older age and comorbidities such as diabetes and hypertension.^{2 , 3}

Because of the close relationship between these conditions and metabolic syndrome, it was hypothesized that obesity may also be a risk factor for worse clinical outcomes. There were then studies looking at presenting characteristics and outcomes of US patients requiring hospitalization for COVID-19. A study looking at 12 major New York City hospitals included 5700 patients (median age, 63 years [interquartile range, 52–75; range, 0–107 years]; 39.7% women). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%).¹⁵

Petrilli and colleagues noted any increase in body mass (body mass index [BMI]>40, odds ratio [OR] 1.8, confidence interval [CI] 1.8–3.4) to be one of the strongest risk factors for hospital admission in patients among age, heart failure, and chronic kidney disease. Although early descriptive COVID-19 studies did not report on the direct association of obesity with disease severity, BMI was found to be higher in those with development of critical illness in COVID-19.^{4 , 5} Petrilli and colleagues found the strongest risks for critical illness besides age were associated with heart failure (OR 1.9, CI 1.4–2.5), BMI greater than 40 (OR 1.5, CI 1.0–2.2), and male sex (OR 1.5, CI 1.3–1.8).¹⁶ It was also later reported that in adults with COVID-19 a nonlinear relationship was found between BMI and COVID-19 severity. The lowest risk was BMI near the threshold between healthy weight and overweight and then increasing risk with higher BMI.¹⁷

Emerging data also showed that obesity is an independent predictor of intensive care unit (ICU) admission, mechanical ventilation, and death.17, 18, 19, 20 Risk for invasive mechanical ventilation increased over the full range of BMIs possibly because of impaired lung function associated with higher BMI.²¹ Although only some studies found an increased risk of ICU admission in obese patients younger than 60 years, Hajifathalian and colleagues found this association to hold true across all age groups including adults older than 60 years specifically.^{1 , 22}

Multiple studies went on to confirm that obesity is a major risk factor for COVID-19 disease severity and significantly affects disease presentation, development of critical illness, need for hospitalization, critical care requirements, and mortality.²³ The Centers for Disease Control and Prevention (CDC) assessed 148,494 adults with a COVID-19 diagnosis during an emergency department or inpatient visit at 238 US hospitals during March to December 2020; 28.3% were found to be overweight and 50.8% were found to have obesity. Overweight and obesity were risk factors for invasive mechanical ventilation, and obesity was a risk factor for hospitalization and death, particularly among adults younger than 65 years. The CDC recognized obesity as a risk factor for severe COVID-19. The Advisory Committee on Immunization Practices considers obesity to be a high-risk medical condition for COVID-19 vaccine prioritization.^{17 , 24}

Early global studies looking at risk factors for clinical course of illness and mortality also noted similar trends. A retrospective study assessing the clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China²⁵ showed that among the 191 patients included in this study, 137 were discharged and 54 died in the hospital. Of the patients with comorbidities (48%), hypertension was the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (OR 1·10, 95% CI 1·03–1·17, per year increase; P = 0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; P < 0·0001), and D-dimer greater than 1 μg/mL (18·42, 2·64–128·55; P = 0·0033) on admission. The potential risk factors of older age, high SOFA score, and D-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. There were also temporal changes in laboratory markers from illness onset in patients hospitalized with COVID-19. Markers such as D-dimer, IL-6, lactate dehydrogenase, and troponin among others were more elevated in nonsurvivors than survivors.

Pathogenesis related to obesity

COVID-19 leads to fast activation of innate immune cells, especially in patients developing severe disease.²⁶ Circulating neutrophil numbers are consistently higher in survivors of COVID-19 than in nonsurvivors, whereas the infection also induces lymphocytopenia that affects mostly the CD4⁺ T cells.²⁷ Levels of many proinflammatory effector cytokines, such as TNFα, IL-1β, IL-6, IL-8, G-CSF and granulocyte-macrophage colony-stimulating factor, and chemokines, such as MCP1, inducible protein-10, and macrophage inflammatory protein 1α, reflect innate immunity and are elevated in patients with COVID-19.¹² The SARS-CoV-2 infection can drive an uncontrolled inflammatory response, leading to a cytokine response in the host.²⁸ Levels of such markers are higher in those who are critically ill and also associated with increased mortality.^{12 ,} 29, 30, 31 The most important mediators of cytokine storm in COVID-19 disease are IL-6, IL-10, and TNFα.³ On the contrary, it was noted that in COVID-19 cases that were postulated to be milder such as those with anosmia tended to have lower IL-6 levels and lower cytokine storm.³² The inflammatory response in COVID-19 can lead to more clinical complications such as development of acute respiratory distress syndrome, cardiac injury, thromboembolic disease, and disseminated intravascular coagulation rather than the direct viral cytopathic injury alone.^{1 , 33 , 34}

Likewise, obesity, a common metabolic disease affecting 41.8% of the United States from 2017 to March 2020 (NHANES, 2021) and a risk factor for other chronic diseases such as type 2 diabetes, heart disease, and some cancer,³⁵ can lead to a state of chronic inflammation termed “metaflammation.”36, 37, 38, 39 This state is characterized by a sustained proinflammatory response from the immune system and adipose tissue secreting proinflammatory markers such as TNFα, IL-1, and IL-6, leading to oxidative stress.^{40 , 41} This metaflammation also contributes to the pathogenesis of several obesity-related conditions, such as type 2 diabetes mellitus, cardiovascular disease, and nonalcoholic fatty liver disease.^{23 , 31 , 42}

Patients with obesity also often have respiratory dysfunction due to alterations in respiratory mechanisms, increased airway resistance, impaired gas exchange, and low lung volume and muscle strength. Thus, they are also predisposed to hypoventilation-associated pneumonia, pulmonary hypertension, and cardiac stress. Many of the obesity-related conditions such as diabetes mellitus and cardiovascular disease are considered to result in increased vulnerability to pneumonia-associated organ failures.²³

For these underlying reasons, obesity is a recognized risk factor for severe COVID-19 possibly related to chronic inflammation, impaired lung function, and cooccurring obesity-related conditions, which are also risk factors for COVID-19.^{21 , 43} Early in the pandemic, a study by Stefan and colleagues noted that 85% of the patients with obesity required mechanical ventilation and 62% of the patients with obesity died versus patients without obesity of whom 64% required mechanical ventilation and 36% died.²³

More than 900,000 adult COVID-19 hospitalizations occurred in the United States between the beginning of the pandemic and November 18, 2020. Models estimate that 271,800 (30.2%) of these hospitalizations were attributed to obesity.⁴⁴ Although children diagnosed with COVID-19 are less likely to develop severe illness compared with adults, children diagnosed with obesity may suffer worse outcomes from COVID-19. A study found that in patients with obesity younger than 18 years, having obesity was associated with a 3.07 times higher risk of hospitalization and a 1.42 times higher risk of severe illness (ICU admission, invasive mechanical ventilation, or death) when hospitalized.⁴⁵

There are also changes in the innate immune response to COVID-19 in individuals with obesity. In mice with obesity, it has been shown that there is increased expression of ACE2, the receptor facilitating COVID-19 infection. Alveolar macrophage metabolism is altered in the lung environment of those with obesity, with baseline chronic inflammation affecting early microbial containment. Circulating bone marrow–derived monocytes can be affected by obesity-related metabolic stressors such as poor blood glucose control and hyperlipidemia.^{22 , 31 ,} 46, 47, 48, 49

Thus, the immune dysregulation and systemic inflammation seen in those living with obesity, combined with impairments in the cardiovascular, respiratory, metabolic, and thrombotic pathways that characterize COVID-19, may potentiate critical illness.^{50 , 51} Similarly, worst outcomes in those with obesity were also observed with the H1N1 influenza virus where weight was found to affect risk for hospitalization, mechanical ventilation, and death, independent of other comorbidities.⁵²

COVID-19: obesity and disparities

Evidence emerged from studies throughout the pandemic that some racial and ethnic minorities as well as socioeconomically disadvantaged groups are bearing a disproportionate burden of illness and death due to disparities in testing, treatment, and overall access to care. According to the CDC, data from 2018 to 2020 showed that non-Hispanic Black adults had the highest prevalence of self-reported obesity (40.7%), followed by Hispanic adults (35.2%), and non-Hispanic White adults (30.3%). Hispanic and non-Hispanic Black adults have a higher prevalence of obesity and are more likely to suffer worse outcomes from COVID-19.⁵³

Azar and colleagues conducted a study in a large California health care system in which African American had 2.7 times the odds of hospitalization after adjusting for age, sex, comorbidities, and income compared with non-Hispanic White patients.54, 55, 56, 57, 58

Many of the disparities have also contributed to risk factors such as obesity and type 2 diabetes in racial and monitory groups. Disparities include access to care, biases on the part of the patients and providers due to prior negative experiences, distrust of the medical community, neighborhood design, access to healthy, affordable foods and beverages, access to safe and convenient places for physical activity, and so forth; this further highlights the need to address social determinants of health particularly in populations disproportionately affected by obesity and more likely to have worse outcomes from COVID-19.¹⁷

These findings should not be used to further stigmatize a patient population that already suffers from biases but rather understand this important link and continue to treat patients with obesity thoroughly.

COVID-19 vaccines and obesity

To combat the immense toll on global public health, vaccines against COVID-19 were developed. According to the vaccine safety and efficacy information for the Pfizer, Moderna, and Johnson & Johnson formulations, these vaccines showed a similar efficacy in both individuals with and without obesity. However, there have been conflicting studies. Clinical trials that assessed BMI and central obesity showed that induced antibody titers are lower in individuals with obesity when compared with healthy weight individuals; this highlights a potential early waning of vaccine-induced antibodies linked to obesity.^{59 , 60} Further studies investigating the clinical implications of the association between obesity and lower antibody titers will need to be conducted to understand the effectiveness and durability of these vaccines in individuals with obesity; this will become especially important, as boosters are being administered with the purpose of ensuring and sustaining long, lasting protection against COVID-19.

Multiple studies have shown that a booster or third dose of an SARS-CoV-2 vaccine helps provide protection, as immunity against this virus wanes.61, 62, 63 One study measured antibody levels to COVID-19 following the Pfizer BNT162b2 mRNA vaccination at baseline, 21 days after first dose, 30 to 40 days after second dose, and 90 to 100 days after second dose and compared between subjects with obesity versus those without. Early antibody titers were essentially equivalent between individuals with obesity versus those without. One and three months after second dose, antibody titers reported for subjects with obesity were significantly lower than those for subjects of healthy weight.⁵⁹ These findings were consistent with studies conducted following seasonal influenza virus vaccination.^{63 , 64}

Obesity hinders immune responses to vaccines and infections. These studies, however, only reported a waning of the antibody response and did not address the implications of decreased antibody titers in individuals with obesity clinically. Some studies conducted after COVID-19 vaccinations became widely available suggest that breakthrough infections were linked to obesity.⁶⁵

In addition, study methods differed across studies including measuring antibody titers at varying time points, using different antibody-measuring kits and different measures of obesity. The sample sizes in the clinical trials mentioned were also smaller compared with the vaccine trials and may not have been entirely representative of the general population of individuals with obesity.

Although the duration of the effectiveness may be shortened postvaccination in those with obesity, it must be highlighted that there is a window of time where protection is observed. More follow-up studies need to be done to assess how different patterns of fat distribution could be affecting immune responses to vaccination, long-term efficacy of the available COVID-19 vaccines, and optimal scheduling for boosters. Studies should also be expanded to include subjects of varying ages including in children with obesity.

At this time the Obesity Society critically evaluated data from published peer-reviewed literature and briefing documents from Emergency Use Authorization applications submitted by Pfizer-BioNTech, Moderna, and Johnson & Johnson and concluded that all 3 vaccines are highly efficacious and that their efficacy is not significantly different in people with and without obesity.⁶³

With increasing obesity rates, higher risk of severe viral infection and death by COVID-19, and potentially impaired vaccine-conferred protection and breakthrough infections in those with obesity, it is important to conduct further studies to provide medical treatment plans and vaccine schedules that will induce long-lasting, protective immune responses in patients with obesity.65, 66, 67, 68, 69, 70, 71, 72

Summary

Obesity is a risk factor for severe clinical course in patients with COVID-19, possibly due to underlying immune and inflammatory changes along with pulmonary system impairments and cooccurring obesity-related conditions that are also risk factors for COVID-19. These findings highlight the need for intensive COVID-19 management as obesity severity increases but also promotion of COVID-19 prevention strategies in those living with obesity including continued vaccine prioritization and masking and timely booster dosages. Providers should continue to advocate for individuals facing racial and socioeconomic health disparities and stigma to seek medical attention policies to treatment and/or prevention of COVID-19 while also encouraging and supporting a healthy BMI.¹⁷

Clinics care points

• •Obesity hinders immune responses to vaccines and infections. Studies, however, have only reported a waning of the antibody response and did not address the implications of decreased antibody titers in individuals with obesity clinically.
• •More follow-up studies need to be done to assess how different patterns of fat distribution could be affecting immune responses to vaccination, long-term efficacy of the available COVID-19 vaccines, and optimal scheduling for boosters. Studies should also be expanded to include subjects of varying ages including in children with obesity.
• •With increasing obesity rates, higher risk of severe viral infection and death by COVID-19, and potentially impaired vaccine-conferred protection and breakthrough infections in those with obesity, it is important to conduct further studies to provide medical treatment plans and vaccine schedules that will induce long-lasting, protective immune responses in patients with obesity.
• •Providers should continue to advocate for individuals facing racial and socioeconomic health disparities and stigma to seek medical attention policies to treatment and/or prevention of COVID-19 while also encouraging and supporting a healthy BMI.

Disclosure

The authors have no disclosures of commercial or financial conflicts of interest for any funding sources.