Abstract

An influenza-like virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19 disease and spread worldwide within a short time. COVID-19 has now become a significant concern for public health. Obesity is highly prevalent worldwide and is considered a risk factor for impairing the adaptive immune system. Although diabetes, hypertension, cardiovascular disease (CVD), and renal failure are considered the risk factors for COVID-19, obesity is not yet well-considered. The present study approaches establishing a systemic association between the prevalence of obesity and its impact on immunity concerning the severe outcomes of COVID-19 utilizing existing knowledge. Overall study outcomes documented the worldwide prevalence of obesity, its effects on immunity, and a possible underlying mechanism covering obesity-related risk pathways for the severe outcomes of COVID-19. Overall understanding from the present study is that being an immune system impairing factor, the role of obesity in the severe outcomes of COVID-19 is worthy.

Introduction

Pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), first identified in Wuhan, China, is responsible for COVID-19 [1,2]. Millions of individuals have been infected by this virus and has caused the deaths of more than 4.2 million people worldwide up to July 2021 [3]. The genomic characterization of SARS-CoV-2 was first done on 7 January 2020, and it has a specific difference in structure than previously identified pandemic virus SARS-CoV and Middle East respiratory syndrome-coronavirus (MERS-CoV), though they are closely related [4]. Initially, it was thought that COVID-19 is less complicated than SARS-CoV and MERS-CoV. However, in the recent case of illness, the rapid transmission level from human to human and the percentage of mortality worldwide implies that SARS-CoV-2 is more severe than previously identified SARS-CoV and MERS-CoV [4,5]. World Health Organization recommends dry cough, dyspnea, fever, sputum production, headache, bloody cough, diarrhea, lymphocytopenia, fatigue as symptoms of COVID-19 disease. Symptoms of viral pneumonia observed in severe cases may lead to acute respiratory distress syndrome (ARDS), acute cardiac injury, the incidence of grand-glass opacities, and finally, death [6,7]. Patients who are currently suffering from obesity (BMI ≥ 35) or overweight, hypertension, diabetes, and cardiovascular diseases (CVDs) are very susceptible to severe infection and have a higher risk of morbidity if infected by SARS-CoV-2 [1,4,8–10].

In the current world, obesity is increasing highly with a prevalence of one-third of the total population, and the rate is very high in U.S.A. (42.4%) and Europe (53.1%) [11–13]. In pulmonary infection, obesity is described as an independent risk factor [14]. Increased abdominal fat hinders the ventilation of the lung base, resulting in increased oxygen demand in the blood. [15]. The incidence of abdominal obesity is high in the Asian population. Abnormal secretion of cytokines like interferon, tumor necrosis factor-α (TNF-α) from abdominal adipose tissue is responsible for chronic low-grade inflammation. Such inflammation suppresses the immune system and impairs lung function [16]. Individuals who are obese face a very high risk of severe consequences in COVID-19, as obesity is a risk factor for several chronic disease conditions [17,18]. A French study indicates that 47.6% of patients with obesity (BMI > 30 kg/m2) and 28.2% of patients with severe obesity (BMI > 35 kg/m2) were admitted to the hospital to manage COVID-19 [19]. In addition, the percentage of the patients who require invasive mechanical ventilation is more for increasing body mass index category [19]. Furthermore, obesity is correlated with multiple disease conditions like hypertension, diabetes, and cardiovascular illness, responsible for morbidity worldwide [20,21]. In particular, hypertension, diabetes, and CVD are more significant risk factors for COVID-19 morbidity [22]. A very high mortality rate for patients with obesity in pandemic influenza 2009 showed the course of interaction between obesity and infection with the H1N1 influenza virus [16,23–29].

The pandemic COVID-19 has rapidly spread across international borders of 222 countries, and a very high spread is observed in Europe, North America, Australia, and Asia, where obesity is highly prevalent. Up to 28 July 2021, almost 35487490 cases and 628098 deaths were confirmed in the United States, and 33956561 COVID-19 positive patients and 742847 deaths were officially reported in the European Union and the United Kingdom [30,31]. India, an Asian country, is similarly plagued by a high prevalence of infection and death by COVID-19 [3].

Both obesity and COVID-19 disease have a very high global incidence, and clinical evidence indicates that obesity is associated with severe COVID-19 disease outcomes. However, the correlation between COVID-19 disease’s severe outcomes and obesity is not officially established. Therefore, it is critical to close this gap immediately, as the death rate has been steadily increasing since the outbreak began. The current study aims to determine the global prevalence of obesity and COVID-19 disease and develop a coherent association among obesity, immunity, and COVID-19.

Prevalence of obesity and COVID-19

One of the most public health problems on the planet is obesity. It is positively associated with other health conditions such as hypertension, CVD, diabetes, end-stage renal disease, and to some extent, cancer [32–38]. The prevalence of worldwide obesity is very high. Currently, one-third of the world’s total population is obese or overweight. The rate of obesity has doubled within 40 years [11]. The overall summary of the epidemiological distribution of obesity is represented in Table 1.

Table 1
Prevalence of worldwide obesity
Geographical regionPercentage of obese people Resources
North America U.S.A. Average obesity 42.4%
Severe obesity 9.2%
Non-Hispanic black 49.6% 
[39
 Canada 38% [40
South America Brazil General obesity 20.7%
Abdominal obesity 38% 
[41–43
 Native Americans 72% [44
Europe Overall 53.1% [13
 Switzerland 43.3%  
 Denmark 45.2%  
 Belgium 46.8%  
 Sweden 50.0%  
 Netherlands 50.1%  
 Austria 50.8%  
 Ireland 50.8%  
 Norway 51.5%  
 Poland 53.6%  
 Spain 53.8%  
 Germany 54.9%  
 United Kingdom 54.9%  
 Estonia 55.2%  
 Finland 55.5%  
 Portugal 57.1%  
 Slovenia 58.0%  
 Lithuania 59.6%  
 Czech Republic 60.1%  
 Hungary 61.6%  
Asia China General obesity 13.2%
Abdominal obesity 44% 
[45–47
 South Asia Varied range of abdominal obesity [48–51
 Iran 21.7% [52
 Saudi Arabia 27.6% [53,54
 Qatar 40.4% [55
 Kuwait 55.3% [55
Africa Native African 1.3–47.7% [56–58
 Immigrant Africans 3.6–49.4% [56–58
Oceania Australia Men: 27.5%
Women: 29.8% 
[59
 New Zealand Men: 28.1%
Women: 30% 
[60
Geographical regionPercentage of obese people Resources
North America U.S.A. Average obesity 42.4%
Severe obesity 9.2%
Non-Hispanic black 49.6% 
[39
 Canada 38% [40
South America Brazil General obesity 20.7%
Abdominal obesity 38% 
[41–43
 Native Americans 72% [44
Europe Overall 53.1% [13
 Switzerland 43.3%  
 Denmark 45.2%  
 Belgium 46.8%  
 Sweden 50.0%  
 Netherlands 50.1%  
 Austria 50.8%  
 Ireland 50.8%  
 Norway 51.5%  
 Poland 53.6%  
 Spain 53.8%  
 Germany 54.9%  
 United Kingdom 54.9%  
 Estonia 55.2%  
 Finland 55.5%  
 Portugal 57.1%  
 Slovenia 58.0%  
 Lithuania 59.6%  
 Czech Republic 60.1%  
 Hungary 61.6%  
Asia China General obesity 13.2%
Abdominal obesity 44% 
[45–47
 South Asia Varied range of abdominal obesity [48–51
 Iran 21.7% [52
 Saudi Arabia 27.6% [53,54
 Qatar 40.4% [55
 Kuwait 55.3% [55
Africa Native African 1.3–47.7% [56–58
 Immigrant Africans 3.6–49.4% [56–58
Oceania Australia Men: 27.5%
Women: 29.8% 
[59
 New Zealand Men: 28.1%
Women: 30% 
[60

Pandemic disease causd by SARS-CoV-2 or new coronavirus has spread rapidly across the world. After the first detection at the end of December 2019 in Wuhan, China, it spread to almost 222 countries up to July 2021 [1,2,61]. The virus spread epidemically in the United States, Europe, China, South Asia, Latin America, and Africa. The number of confirmed cases exceed 186 million, and the number of deaths worldwide due to COVID-19 disease is more than 4 million. Published research found that obese people are more likely to be infected with respiratory viruses and encounter a greater degree of illness and negative impacts, including higher infection rates, ICU, and death [62,63]. A higher incidence of obesity (41.7%) was observed in the case studies of 5700 patients hospitalized with COVID-19 disease in New York City, indicating obesity as an understated risk factor for severe outcomes of COVID-19 [64]. Intensive Care National Audit and Research Center (ICNARC) report stated that the patients admitted to the ICU for COVID-19 related complications in the United Kingdom are 38% obese [65]. Data from China also found that obesity raises the risk of extreme COVID-19 almost three-times as long as hospital stay raises [66]. The French retrospective analysis on ICU admitted COVID-19 patients found that 76% of patients were overweight [19]. So worldwide, very high prevalence of obesity makes the COVID-19 patient highly susceptible to higher disease complications.

Impact of obesity on immunity

Obesity is associated with a metabolic disturbance with a high risk for some other chronic disease [67,68]. Obesity-induced dysfunctions of the immune system are responsible for the progression of some chronic diseases and metabolic impairment. Obesity-related physiological dysfunction causes fat accumulation in the lymphoid tissue that ultimately breaks the tissue structure and integrity of lymphoid organs, disturbing the leukocyte population and lymphocyte function [69,70]. The bone marrow-derived pluripotent hematopoietic stem cell is responsible for producing lymphoid and myeloid type blood cells. NK cell, B and T lymphocytes are lymphoid types, macrophage, monocyte, granulocyte, erythrocyte, megakaryocyte, dendritic cell, and mast cells are myeloid type cells. In the further development of T lymphocyte, the thymus plays a significant role [71–75].

Obesity causes the deposition of fatty content in the lymphoid tissue, changes tissue architecture, and increases the lymphoid tissue’s inflammatory gene expression [72,76]. These ultimately affect hematopoietic niches and suppress the erythropoiesis process [77,78]. In addition, obesity is strongly linked with the alteration of thymic tissue structure, which is correlated with increasing age [72,79]. The obesity-induced change in thymic architecture is responsible for the lower thymic output of naive T cells and ultimately reduced immune function [72,80]. T-cell infiltration in adipose tissue is observed high in individuals with obesity and, to some degree, the lymphocyte activation antigen produced from obese adipose tissue [81]. Again B-cell activity is also regulated in response to high-fat diet-induced obesity [82]. An overall summary of the effect of obesity on the immune system parameter is presented in Table 2.

Table 2
Impact of obesity on the immune system
Parameter of the immune systemModelLevel of change in the immune systemResources
Development of leukocyte HFD-fed mice ↑Myeloid progenitor cells
↓Lymphoid progenitors
↓Thymic output of naive T cells 
[72
 Obese and insulin-resistant patients ↓Thymic output of naive T cells [72
 Adipocyte-rich bone marrow in C57BL/6J mice ↓ Hematopoiesis [77
 Leptin receptor-deficient mice ↓ Hematopoiesis [83
Inflammation of leukocytes HFD-induced obese mice ↑ T-cell infiltration in adipose [84
  ↑M1 macrophages  
  ↓ M2 macrophages in adipose [85
  ↑ TH1
↓ Treg cells in adipose 
[81,86
 Obese human subjects ↑ CD4+ T cells
↓ CD8+ peripheral T cells 
[87
  ↑ NF-κβ activation in PBMCs [88
  ↑Migration inhibition factor (MIF), IL-6
↑ TNF-α
↑ MMP-9 mRNA expression in PBMCs 
[88
 Morbidly obese human subjects ↑ TH1 and ↑ Treg cells [89
  ↑ CD4+ and CD8+ T-cell proliferation [89
Lymph HFD-induced obese mice ↓ Inguinal lymph node size
↓ T-cell count 
[90
  Impaired lymphatic fluid transport, and dendritic cell migration [90
Bone marrow Obese male and female Adiposity in bone marrow [91
 HFD-fed Wistar rat ↑ Proinflammatory gene expression of mesenchymal stem cells [92
Spleen↑ HFD-fed mice Increased memory T cell
↓ T-cell receptor diversity 
[72
Thymus HFD-fed mice ↑ Thymic involution and adiposity [72
 Leptin deficient (ob/ob mice) ↓ Thymus size and cellularity
↑ Thymocyte apoptosis 
[93
Clinical leukocyte profiles Weight loss, overweight, and obese subjects ↓WBC count [94
Immunity parameters Diet-induced obese mice ↓ Dendritic cell antigen presentation
↓ Maintenance of influenza-specific CD8+
memory T cells 
[95
 Leptin-deficient (ob/ob) mice ↓ Cell-mediated immunity [96
 Diabetic and obese mice ↑ Lung cancer metastasis
↓ NK cell function
at early cancer stages 
[97
 Overweight children and child obesity ↑ Tetanus vaccine failure risk [98,99
 Obese adults ↑ Risk of influenza vaccine failure
↑ Allergic disease 
[100
 High obesity prevalent in community ↑ Influenza-related hospitalizations [101
Inflammatory cytokines and chemokines Diet-induced obese mice ↓ TGFβ concentration in the lung and
↑ TGFβ concentration in BALF 
[102,103
  ↑ TNFα concentration in plasma
↑ mRNA expression in lung
↑ BALF concentration 
[103,104
  ↑ G-CSF concentration in lung [105
  ↓ MIP1α concentration in BALF
↑ MIP1α concentration in lung 
[105
  ↓ IL-5 concentration in BALF at the time of infection [105
  ↑ Leptin concentration in serum
↑ mRNA for Leptin expression in lung 
[106,107
  ↓ IL-1β concentration in the lung and
↓ mRNA for IL-1β expression in the lung during influenza infection 
[104,105,107
  ↓ mRNA for IL-2 expression in lung [108
  ↑ IL-6 concentration in serum and lung during infection [105,108
  ↓ Adiponectin concentration in serum and lung BALF [103,107
  ↑ Plasma MIP2α concentration [109
  ↑ MCP-1 concentration in BALF during infection [110
  ↓ Lung mRNA expression for IFNα and IFNβ [108
Immune cell HFD-induced obese mice ↓ Macrophage migration to the lung
↑ M1 polarization 
[110
  ∼ NK cells count in lung [102,108,110
 Leptin-deficient OB model mice ↑ Number of alveolar macrophages in BALF [110,111
  ↑ NK cells count in lung [102,108,110
 HFD-induced obese mice ↓ Plasmacytoid dendritic cell count in the lung
↓ Antigen presentation during influenza infection
↓ T-cell proliferation
↓ Lung double negative dendritic cell
↓ pDCs count during infection 
[95
  ↑ Neutrophil polarization
↑ Neutrophil net production
↑ BALF infiltration during influenza infection 
 
  ↓ Mature bone marrow B cells and cross-reactive H1N1 and PR8 antibodies during influenza infection [112
  ↓ T-cell count
↑ OCR: ECAR ratios 
[112,113
Parameter of the immune systemModelLevel of change in the immune systemResources
Development of leukocyte HFD-fed mice ↑Myeloid progenitor cells
↓Lymphoid progenitors
↓Thymic output of naive T cells 
[72
 Obese and insulin-resistant patients ↓Thymic output of naive T cells [72
 Adipocyte-rich bone marrow in C57BL/6J mice ↓ Hematopoiesis [77
 Leptin receptor-deficient mice ↓ Hematopoiesis [83
Inflammation of leukocytes HFD-induced obese mice ↑ T-cell infiltration in adipose [84
  ↑M1 macrophages  
  ↓ M2 macrophages in adipose [85
  ↑ TH1
↓ Treg cells in adipose 
[81,86
 Obese human subjects ↑ CD4+ T cells
↓ CD8+ peripheral T cells 
[87
  ↑ NF-κβ activation in PBMCs [88
  ↑Migration inhibition factor (MIF), IL-6
↑ TNF-α
↑ MMP-9 mRNA expression in PBMCs 
[88
 Morbidly obese human subjects ↑ TH1 and ↑ Treg cells [89
  ↑ CD4+ and CD8+ T-cell proliferation [89
Lymph HFD-induced obese mice ↓ Inguinal lymph node size
↓ T-cell count 
[90
  Impaired lymphatic fluid transport, and dendritic cell migration [90
Bone marrow Obese male and female Adiposity in bone marrow [91
 HFD-fed Wistar rat ↑ Proinflammatory gene expression of mesenchymal stem cells [92
Spleen↑ HFD-fed mice Increased memory T cell
↓ T-cell receptor diversity 
[72
Thymus HFD-fed mice ↑ Thymic involution and adiposity [72
 Leptin deficient (ob/ob mice) ↓ Thymus size and cellularity
↑ Thymocyte apoptosis 
[93
Clinical leukocyte profiles Weight loss, overweight, and obese subjects ↓WBC count [94
Immunity parameters Diet-induced obese mice ↓ Dendritic cell antigen presentation
↓ Maintenance of influenza-specific CD8+
memory T cells 
[95
 Leptin-deficient (ob/ob) mice ↓ Cell-mediated immunity [96
 Diabetic and obese mice ↑ Lung cancer metastasis
↓ NK cell function
at early cancer stages 
[97
 Overweight children and child obesity ↑ Tetanus vaccine failure risk [98,99
 Obese adults ↑ Risk of influenza vaccine failure
↑ Allergic disease 
[100
 High obesity prevalent in community ↑ Influenza-related hospitalizations [101
Inflammatory cytokines and chemokines Diet-induced obese mice ↓ TGFβ concentration in the lung and
↑ TGFβ concentration in BALF 
[102,103
  ↑ TNFα concentration in plasma
↑ mRNA expression in lung
↑ BALF concentration 
[103,104
  ↑ G-CSF concentration in lung [105
  ↓ MIP1α concentration in BALF
↑ MIP1α concentration in lung 
[105
  ↓ IL-5 concentration in BALF at the time of infection [105
  ↑ Leptin concentration in serum
↑ mRNA for Leptin expression in lung 
[106,107
  ↓ IL-1β concentration in the lung and
↓ mRNA for IL-1β expression in the lung during influenza infection 
[104,105,107
  ↓ mRNA for IL-2 expression in lung [108
  ↑ IL-6 concentration in serum and lung during infection [105,108
  ↓ Adiponectin concentration in serum and lung BALF [103,107
  ↑ Plasma MIP2α concentration [109
  ↑ MCP-1 concentration in BALF during infection [110
  ↓ Lung mRNA expression for IFNα and IFNβ [108
Immune cell HFD-induced obese mice ↓ Macrophage migration to the lung
↑ M1 polarization 
[110
  ∼ NK cells count in lung [102,108,110
 Leptin-deficient OB model mice ↑ Number of alveolar macrophages in BALF [110,111
  ↑ NK cells count in lung [102,108,110
 HFD-induced obese mice ↓ Plasmacytoid dendritic cell count in the lung
↓ Antigen presentation during influenza infection
↓ T-cell proliferation
↓ Lung double negative dendritic cell
↓ pDCs count during infection 
[95
  ↑ Neutrophil polarization
↑ Neutrophil net production
↑ BALF infiltration during influenza infection 
 
  ↓ Mature bone marrow B cells and cross-reactive H1N1 and PR8 antibodies during influenza infection [112
  ↓ T-cell count
↑ OCR: ECAR ratios 
[112,113

Here, ↑, increased; ↓, decreased; ∼, unchanged. Abbreviations: BALF, bronchoalveolar lavage fluid; G-CSF, granulocyte-colony stimulating factor; HFD, high-fat diet; IL-2, interleukin-2; IL-5, interleukin-5; IL-6, interleukin-6; MIP1α, macrophage inflammatory protein 1α; MIP2α, macrophage inflammatory protein 2α; MMP-9, matrix metalloproteinase-9; NF-κβ, nuclear factor κ B; NK, natural killer; PBMC, peripheral blood mononuclear cell; pDC, plasmacytoid dendritic cell; PR8, Puerto Rico 8; TGFβ, transforming growth factor-β; TH1, T-helper cell-1; Treg, regulatory T cell; WBC, white blood cell.

Chronic inflammation is a typical characteristic of obesity primarily due to weight gain and adipose tissue dysfunction caused by metabolic tissue stress. Hypertrophic adipocytes are more likely to trigger endoplasmic reticulum and mitochondrial stress, supporting chronic, proinflammatory activation in adipose tissue. These ultimately lead to inflammatory leukocyte infiltration and enhanced cytokine secretion [114,115]. Adipose tissue also secretes into circulation several proinflammatory cytokines, chemokines, and adipokines, contributing to low-grade chronic inflammation. Besides, viruses may also demonstrate tropism for various tissues and cell types like adipose tissues and adipocytes [116]. SARS-CoV-2 may also have adipose tissue tropism, leading to intrapulmonary and systemic inflammation [117]. Chronic inflammation associated with obesity can inhibit macrophage activation and relocation, disrupt the formation of neutralizing antibody and memory T cells, and decrease activation of the immune system’s effector cells, suppress immune functions and host defenses [118,119]. Thus, we conclude that chronic inflammation of obesity, both systemic and local, leads to immune dysfunction, which increases the risk associated with severe outcomes of COVID-19 disease.

Impact of obesity on influenza

A very highly contagious disease, influenza, that affects the respiratory system is caused by the influenza virus. It is highly contagious and responsible for affecting 3–5 million individuals and kills 290000–650000 people globally each year [120]. Only in the United States, ∼12000–56000 people die every year from the influenza virus [121]. Influenza virus is an RNA virus, and a lipid layer encapsulates the nucleic acid segment with two surface proteins, hemagglutinin, and neuraminidase. Four strains (Influenza Virus - A, B, C, and D) have been identified [122–124].

The Spanish flu pandemic in 1918 was the most devastating influenza virus attack in the last century. This virus attacked almost one-third of the world’s population, and ∼50 million people died worldwide [125–127]. No other influenza pandemic after the Spanish flu pandemic is so severe as the 1918 pandemic. Another serious influenza pandemic is H1N1 influenza, also called swine flu, spread in 2009 [128,129]. The virus spread rapidly in ∼168 countries, and approximately more than 123000 people died worldwide in 2009 [130]. Obesity was identified as an independent risk factor for higher morbidity resulting from H1N1 infection [131]. The previous record suggested that 61% of adult obese people died due to the influenza attack in 2009 [131]. Generally, obese people with BMI in the range of 30–35 kg/m2 have 1.45-times, and BMI greater than 35 kg/m2 have a 2.12-times higher risk of hospitalization in seasonal influenza [132]. The current pandemic COVID-19 is also an influenza-like disease and represented similar complications in the case of the overweight and obese patient.

Impact of obesity on cardiovascular function

Obesity is a proven contributing factor for other lifestyle disorders like CVD, hypertension, coronary artery disease, diabetes mellitus (DM), insulin resistance (IR), renal dysfunction. Obesity mediated most significant change in morphology of cardiac system, that is hypertrophy of left ventricle (LV), whereby high blood pressure and IR are essential factors for LV mass [133]. Obesity is also involved with heart failure and diastolic dysfunction of LV [134]. Obesity amplifies the effects of multiple cardiovascular risk factors, accelerates the development of CVD, and has a detrimental impact on cardiorenal function. As part of this, an adverse effect on the myocardium occurred due to obesity-mediated activation of the renin–angiotensin–aldosterone system (RAAS), resulting in overexpression of angiotensin II [135]. In addition, obesity is also associated with an increased risk of thrombosis. This is due to chronic inflammation caused by obesity, which results in the down-regulation of anticoagulant regulatory proteins (antithrombin, protein-C, and TFPI), the overexpression of coagulant factor (tissue factor), and adhesion molecule (P-selectin), all of which increase thrombin synthesis, platelet activation, and ultimately thrombosis [136]. Again an individual with obesity has some metabolic considerations like reduction in β-cell function and development of IR. As a result, it is difficult for an obese individual to cope up metabolically and immunologically with a severe infection like COVID-19. Altogether, the integrated metabolic control needed for complicated cell interactions and efficient host protection is disrupted, causing a functional immunological deficiency.

In the destruction of pancreatic β-cells, SARS-CoV-2 plays a role through interactions with angiotensin-converting enzyme-2 (ACE-2). Again, in patients with COVID-19, acute cardiac injury is particularly prominent and is correlated with severe clinical outcomes [4]. However, all the heart failure cases (23%) noticed in hospitalized COVID-19 patients were not pre-existing cardiomyopathy [137]. In a study of 150 COVID-19 patients, the definitive cause of death in 7% of patients was acute myocarditis [138]. However, histology of the postmortem myocardium demonstrated rapidly progressive myocarditis with inflammatory mononuclear infiltrates in the myocardial tissue [139]. These findings suggest a correlation between obesity and COVID-19-mediated acute cardiac injury and related severe outcomes.

Obesity and its impact on lung function

The very high prevalence of obesity increased the risk of morbidity and clinical feature of many respiratory diseases, as it causes a significant change in lung and chest wall function. These functional and mechanical changes in the lung and airway wall cause asthma, dyspnea, obstructive sleep apnea, obesity hypoventilation syndrome, airway hyperresponsiveness, wheeze, ARDS, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension [15,140,141]. In obese subjects, the deposition of fat in the mediastinum and abdominal cavities alters the lung and chest wall’s mechanical properties, thus changes the lung’s structure, physiology, and function [15,142,143]. This changed structure also limits the breathing pattern. Generally, air flows into the lung due to the negative pressure gradient within the pleural space. As fat deposits in the thoracic and abdominal area, pleural pressure and intra-abdominal pressure increased in obese subjects, ultimately restricting the diaphragm’s downward movement and outward movement of the chest wall [144,145]. These results reduce functional residual capacity (FRC), proportional to obesity from overweight to severe obesity [146]. Tidal volume is also slightly reduced, and a shallow breathing pattern is noticed, increasing overall minute ventilation [147,148]. Moreover, the mechanical effect of obesity causes narrowing of the airway, which leads to gas tapping, respiratory inhomogeneity, and resistance [149].

Excessive adipose tissue elevation is associated with increased inflammatory cytokines and the immune cell, causing lung function disturbance [15]. In obese individuals, the expression of proinflammatory adipokine leptin increases that plays a role in the ventilator drive and worsens the asthmatic conditions [150,151]. Other inflammatory chemokines like TNF-α, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, and high sensitivity C-reactive proteins (hs-CRPs) increased in obesity [152,153]. The development of obesity also increases macrophage infiltration and mast cell propagation [151,154]. Mast cells are critical mediators for an allergic reaction, and obesity-induced mast cell proliferation is a potential mechanism of airway dysfunction. Increased levels of circulating leukocytes have been documented in obesity [155]. There is strong evidence that airway disease and lung dysfunction are associated with chronic inflammation during adipogenesis [154–156].

Pathway of COVID-19 infection

SARS-CoV-2 is transmitted by zoonotic transmission from animal to human and spread rapidly among humans via respiratory droplets and fecal–oral transmission. The symptoms developed within 11.5 days on average, and symptoms are dry cough, fever, muscle pain, joint pain, difficult breathing, diarrhea, dizziness, headache, nausea, and blood coughing [4,157,158]. Previous studies on SARS-CoV suggested that this virus principally targets the airway epithelial cell layer, vascular endothelial cell, alveolar epithelial cell, and macrophages in the lung, expressing a protein called ACE-2 [159,160]. ACE-2 is the target receptor for SARS-CoV-2 [161]. In obese individuals, more significant adipose tissue proliferation contains adipocytes that have higher expression of ACE-2 receptors. The ACE-2 receptor count of the fatty tissue in obese individuals is much higher than lung, which makes fat a potential reservoir for SARS-CoV-2 as it is the entry site of the virus [162].

The coronavirus has a large homogeneous protein called Spike protein or S protein, which gives the viral characteristic crown-like appearance. S proteins have two subunits: the S1 and the S2. The receptor-binding domain in the S1 subunit binds with ACE-2 of the host epithelial cell, triggering a sequence of events that enter the SARS-Cov-2 virion into the host cell [163,164]. The S2 subunit consists of two heptad repeat regions (HR-1 and HR-2) and a fusion peptide region (FP). The transmembrane protease serine-2 (TMPRSS-2) plays a role in triggering the cleavage of S protein of SARS-CoV-2 and releasing viral genetic material into the host cell. The overall mechanism of viral transmission and replication in the host cell is represented in Figure 1.

Typical mechanism of SARS-CoV-2 viral transmission and replication in the airway epithelium cell

Figure 1
Typical mechanism of SARS-CoV-2 viral transmission and replication in the airway epithelium cell
Figure 1
Typical mechanism of SARS-CoV-2 viral transmission and replication in the airway epithelium cell

Within the endosome, the S1 subunit cleaved away. The S2 subunit folds by itself, thus bringing the HR-1 and HR-2 regions together that helps in membrane fusion and release the viral package into the host cell cytoplasm [165–167]. Coronavirus genetic material is a single-stranded RNA that can replicate by using replicating material from the host cell. The virus uses the host cell ribosome to replicate polyprotein [168]. Like the main coronavirus proteinase (3CLpro) and the papain-like protease (PLpro), the two enzymes are involved in expressed polyprotein cleavage, and the cleaved product is used for replicating a new virus. An RNA-dependent RNA polymerase is expressed by coronavirus to synthesize the daughter RNA genome, synthesizing the complementary RNA strand using virus RNA as a template [169]. Thus the virus produces millions of copies in the host body. The SARS-CoV-2 virus is cytopathic responsible for injury or death of virus-infected cells and tissue-associated vascular leakage as part of the virus multiplication cycle [170–172]. The cytopathic virus is responsible for programmed cell death by pyroptosis and subsequent inflammatory response [173,174]. The clinical study suggested that COVID-19 patients admitted in the hospital and required intensive care have elevated plasma levels of TNF-α, IL-2, IL-6, IL- 10, G-CSF, IP-10, MCP-1, and MIP-1α [4]. Under COVID-19 disease condition, this elevated plasma level of different inflammatory mediators accelerates the chronic inflammatory condition due to obesity. Thus, the virus SARS-CoV-2 activates macrophages, monocytes, and B cells in the local immune response and kills the lung cells. A dysfunctional immune response is also noticed in some cases, which causes severe lung and systemic pathology.

Obesity and COVID -19 pandemic

The pandemic COVID-19 has already shown its gruesomeness worldwide, causing a vast number of human deaths. The infection of COVID-19 becomes complicated with pre-existing comorbidity like diabetes, CVD, renal failure, and others. Recently, WHO declared obesity as an independent risk factor for case severity in COVID-19 disease [15]. Italian National Institute of Health launched a study on COVID-19 throughout the country and reported that pre-existing non-communicable diseases like obesity, diabetics, hypertension CVD, and renal failure are responsible for 99% of COVID-19-related deaths [175]. A study in New York suggested that younger patients (age < 50) with a BMI above 40 kg/m2 is a risk factor for COVID-19 mortality [176]. U.K. Intensive Care National Audit and Research Centre reported that two-third of the total people with serious COVID-19 complications were overweight or obese according to the WHO obesity scale [177]. Another study in the United States shares their experience that people having obesity aged less than 60 years is a newly identified epidemiologic risk factor for COVID-19 morbidity [178].

Several molecular events can explain the correlations between obesity and severe outcomes of COVID- 19, as displayed in Figure 2. How ACE-2 plays a role in the endocytosis of SARS-CoV-2 is clearly described in the Pathway of COVID-19 infection section. Generally, ACE-2 is overexpressed in adipocytes; thus, the elevated level of ACE-2 in obesity might play a role in cross-talking between obesity and COVID-19 case severity [162,179–181]. We presumed that obesity-induced ACE-2 overexpression, as a functional receptor for SARS-CoV-2 invasion, may play a role in acute respiratory failure progression can be a factor in increasing COVID-19 vulnerability. In another way, obesity alters the immune function causing an imbalanced release of inflammatory cytokines that weaken the host defense against influenza type virus [182–184]. Chronic inflammatory state due to obesity is the responsible factor for the imbalanced release of proinflammatory cytokines, inhibition of macrophage migration and activation, impair the formation of neutralizing antibody and memory T cells that suppress the immune system activation, and host defense against SARS-CoV-2 [126–128].

Possible biomolecular pathways through which obesity promotes the severe outcomes and mortality of COVID-19 disease condition

Figure 2
Possible biomolecular pathways through which obesity promotes the severe outcomes and mortality of COVID-19 disease condition
Figure 2
Possible biomolecular pathways through which obesity promotes the severe outcomes and mortality of COVID-19 disease condition

It is interesting to note that excess fat is associated with the complementary system’s hyperactivation, theoretically capable of inducing inflammatory sequelae, eventually developing a condition described as ‘cytokine storm’ [185]. These may help disrupt lung function during SARS-CoV-2 infection. The previous study suggested that obese individuals also have a risk of vaccination failure [109]. Again, seriously infected patients with COVID-19 and obesity under intensive ventilation due to reduced oxygen saturation levels are difficult to regain normal oxygen saturation due to obesity-induced mechanical dysfunction of the lung [182]. General obesity and abdominal obesity are responsible for increasing airway resistance, reduced FRC, respiratory homogeneity, respiratory muscle insufficiency, increased pulmonary embolism, and gas tapping. These ultimately cause the reduction in overall lung function or lung injury. This type of lung functioning hindrance causes case severity and increased morbidity in individuals with obesity. Obesity-induced physiological dysfunction of the immune system cell also promotes the overall suppression of immunity for defense against SARS-CoV-2. A recent study on 247 COVID-19 patients demonstrated that the rate of hospitalization reduced with higher cardiorespiratory fitness found low in obese individuals [186,187]. In another way, obesity enhances thrombosis and venous thromboembolism that open the pathway of cardiovascular disturbance related to COVID-19 risk factors.

Conclusion

COVID-19, a kind of influenza virus, is highly contagious, spread worldwide quickly, and declared a pandemic by the WHO. At the same time, obesity is highly prevalent worldwide and has been documented for impairing the adaptive immune system and responsible for mechanical dysfunction of the lung. Thus, including the previously established risk factors like diabetes, hypertension, CVD, renal disorder, obesity must be enlisted as individual risk factors for severe COVID-19 and mortality outcomes. Understanding the underlying mechanism of obesity-mediated severe outcomes of COVID-19, a diet enriched with the immune system booster and regular physical exercise can be a preventive measure for obese individuals to reduce the risk of the severe outcomes of COVID-19. Traditional health campaigns conveying the information of obesity-mediated case complications of COVID-19 may raise awareness among the general population. Further study with clinical research using the underlying mechanism may promote newer treatment options for obese COVID-19 patients.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • ACE-2

    Angiotensin-converting enzyme-2

  •  
  • ARDS

    Acute respiratory distress syndrome

  •  
  • BMI

    Body mass index

  •  
  • COPD

    Chronic obstructive pulmonary disease

  •  
  • CVD

    Cardiovascular disease

  •  
  • FRC

    Functional residual capacity

  •  
  • IR

    Insulin resistance

  •  
  • LV

    Left ventricle

  •  
  • MERS-CoV

    Middle East respiratory syndrome-coronavirus

  •  
  • SARS-CoV-2

    Severe acute respiratory syndrome coronavirus-2

  •  
  • TNF-α

    Tumor necrosis factor-α

  •  
  • TMPRSS-2

    Transmembrane protease serine-2

References

1.
Li
Q.
,
Guan
X.
,
Wu
P.
,
Wang
X.
,
Zhou
L.
,
Tong
Y.
et al.
(
2020
)
Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia
.
N. Engl. J. Med.
382
,
1199
1207
[PubMed]
2.
Zhu
N.
,
Zhang
D.
,
Wang
W.
,
Li
X.
,
Yang
B.
,
Song
J.
et al.
(
2020
)
A novel coronavirus from patients with pneumonia in China, 2019
.
N. Engl. J. Med.
382
,
727
733
[PubMed]
4.
Huang
C.
,
Wang
Y.
,
Li
X.
,
Ren
L.
,
Zhao
J.
,
Hu
Y.
et al.
(
2020
)
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
.
Lancet
395
,
497
506
[PubMed]
5.
Fuk-Woo Chan
J.
,
Yuan
S.
,
Kok
K.-H.
,
Kai-Wang To
K.
,
Chu
H.
,
Yang
J.
et al.
(
2020
)
Articles A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster
.
Lancet
395
,
514
523
[PubMed]
6.
Gao
Q.
,
Hu
Y.
,
Dai
Z.
,
Xiao
F.
,
Wang
J.
and
Wu
J.
(
2020
)
The epidemiological characteristics of 2019 novel coronavirus diseases (COVID-19) in Jingmen, China
.
SSRN Electron. J.
2
,
113
122
7.
Bai
Y.
,
Yao
L.
,
Wei
T.
,
Tian
F.
,
Jin
D.Y.
,
Chen
L.
et al.
(
2020
)
Presumed asymptomatic carrier transmission of COVID-19
.
JAMA
23
,
1406
1407
8.
Onder
G.
,
Rezza
G.
and
Brusaferro
S.
(
2020
)
Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy
.
JAMA
2019
,
2019
2020
9.
Yang
J.
,
Zheng
Y.
,
Gou
X.
,
Pu
K.
,
Chen
Z.
,
Guo
Q.
et al.
(
2020
)
Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: a systematic review and meta-analysis
.
Int. J. Infect. Dis.
94
,
91
95
[PubMed]
10.
Wang
D.
,
Hu
B.
,
Hu
C.
,
Zhu
F.
,
Liu
X.
,
Zhang
J.
et al.
(
2020
)
Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China
.
JAMA
323
,
1061
1069
11.
Chooi
Y.C.
,
Ding
C.
and
Magkos
F.
(
2019
)
The epidemiology of obesity
.
Metab. Clin. Exp.
92
,
6
10
12.
Adult obesity facts | Overweight & obesity | CDC
.
13.
Marques
A.
,
Peralta
M.
,
Naia
A.
,
Loureiro
N.
and
De Matos
M.G.
(
2018
)
Prevalence of adult overweight and obesity in 20 European countries, 2014
.
Eur. J. Public Health
28
,
295
300
[PubMed]
14.
van Kerkhove
M.D.
,
Vandemaele
K.A.H.
,
Shinde
V.
,
Jaramillo-Gutierrez
G.
,
Koukounari
A.
,
Donnelly
C.A.
et al.
(
2011
)
Risk factors for severe outcomes following 2009 influenza a (H1N1) infection: a global pooled analysis
.
PLoS Med.
8
,
e1001053
[PubMed]
15.
Peters
U.
and
Dixon
A.E.
(
2018
)
The effect of obesity on lung function
.
HHS Public Access
12
,
755
767
16.
Huttunen
R.
and
Syrjänen
J.
(
2013
)
Obesity and the risk and outcome of infection
.
Int. J. Obes.
37
,
333
340
17.
Ryan
D.H.
,
Ravussin
E.
and
Heymsfield
S.
(
2020
)
COVID 19 and the patient with obesity - the editors speak out
.
Obesity (Silver Spring)
28
,
847
10.1002/oby.22808
18.
Sharma
A.
,
Garg
A.
,
Rout
A.
and
Lavie
C.J.
(
2020
)
Association of obesity with more critical illness in COVID-19
.
Mayo Clin. Proc.
95
,
2040
2042
[PubMed]
19.
Simonnet
A.
,
Chetboun
M.
,
Poissy
J.
,
Raverdy
V.
,
Noulette
J.
,
Duhamel
A.
et al.
(
2020
)
High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation
.
Obesity (Silver Spring)
28
,
1195
1199
10.1002/oby.22831
20.
Kornum
J.B.
,
Nørgaard
M.
,
Dethlefsen
C.
,
Due
K.M.
,
Thomsen
R.W.
,
Tjønneland
A.
et al.
(
2010
)
Obesity and risk of subsequent hospitalisation with pneumonia
.
Eur. Respir. J.
36
,
1330
1336
[PubMed]
21.
Reis
A.F.N.
,
Lima
J.C.
,
Beccaria
L.M.
,
de CHM Ribeiro
Rita
,
Ribeiro
D.F.
and
Cesarino
C.B.
(
2015
)
Hypertension and diabetes-related morbidity and mortality trends in a municipality in the country side of São Paulo
.
Rev. Lat. Am. Enfermagem
23
,
1157
1164
,
[PubMed]
22.
McMichael
T.M.
,
Clark
S.
,
Pogosjans
S.
,
Kay
M.
,
Lewis
J.
,
Baer
A.
et al.
(
2020
)
COVID-19 in a long-term care facility-King CountyWashington, February 27–March 9, 2020
.
MMWR Morb Mortal Wkly Rep
69
,
339
342
10.15585/mmwr.mm6912e1
23.
Louie
J.K.
,
Acosta
M.
,
Samuel
M.C.
,
Schechter
R.
,
Vugia
D.J.
,
Harriman
K.
et al.
(
2011
)
A novel risk factor for a novel virus: Obesity and 2009 pandemic influenza a (H1N1)
.
Clin. Infect. Dis.
52
,
301
312
24.
Bassetti
M.
,
Parisini
A.
,
Calzi
A.
,
Pallavicini
F.M.B.
,
Cassola
G.
,
Artioli
S.
et al.
(
2011
)
Risk factors for severe complications of the novel influenza A (H1N1): analysis of patients hospitalized in Italy Results Patients presenting with influenza-like illness (temperature
.
Clin. Microbiol. Infect.
17
,
247
250
[PubMed]
25.
Lucas
S.
(
2011
)
Predictive clinicopathological features derived from systematic autopsy examination of patients who died with A/H1N1 influenza infection in the UK 2009-10 pandemic
.
Health Technol. Assess. (Rockv.)
14
,
83
114
26.
Fuhrman
C.
,
Bonmarin
I.
,
Bitar
D.
,
Cardoso
T.
,
Duport
N.
,
Herida
M.
et al.
(
2011
)
Adult intensive-care patients with 2009 pandemic influenza A(H1N1) infection
.
Epidemiol. Infect.
139
,
1202
1209
[PubMed]
27.
Beck
M.A.
,
Zhao
Z.
,
Pence
B.D.
,
Schultz-Cherry
S.
and
Honce
R.
(
2019
)
Impact of obesity on influenza A virus pathogenesis, immune response, and evolution
.
Immune Response Evol. Front. Immunol.
10
,
1071
,
28.
Viasus
D.
,
Paño-Pardo
J.R.
,
Pachón
J.
,
Campins
A.
,
López-Medrano
F.
,
Villoslada
A.
et al.
(
2011
)
Factors associated with severe disease in hospitalized adults with pandemic (H1N1) 2009 in Spain
.
Clin. Microbiol. Infect.
17
,
738
746
[PubMed]
29.
Satterwhite
L.
,
Mehta
A.
and
Martin
G.S.
(
2010
)
Novel findings from the second wave of adult pH1N1 in the United States
.
Crit. Care Med.
38
,
2059
2061
[PubMed]
30.
Coronavirus: latest news and breaking stories | NBC News
.
31.
COVID-19 situation update for the EU/EEA, as of week 3, updated 28 January 2021
.
32.
Dehal
A.
,
Garrett
T.
,
Tedders
S.H.
,
Arroyo
C.
,
Afriyie-Gyawu
E.
and
Zhang
J.
(
2011
)
Body mass index and death rate of colorectal cancer among a national cohort of U.S. adults
.
Nutr. Cancer
63
,
1218
1225
[PubMed]
33.
Sandbakk
S.B.
,
Nauman
J.
,
Lavie
C.J.
,
Wisløff
U.
and
Stensvold
D.
(
2017
)
Combined association of cardiorespiratory fitness and body fatness with cardiometabolic risk factors in older Norwegian adults: The Generation 100 Study
.
34.
Ali
O.
,
Cerjak
D.
,
Kent
J.W.
,
James
R.
,
Blangero
J.
and
Zhang
Y.
(
2014
)
Obesity, central adiposity and cardiometabolic risk factors in children and adolescents: a family-based study
.
Pediatr. Obes.
9
,
e58
e62
[PubMed]
35.
Saetang
J.
and
Sangkhathat
S.
(
2018
)
Role of innate lymphoid cells in obesity and metabolic disease (Review)
.
Mol. Med. Rep.
17
,
1403
1412
[PubMed]
36.
Arroyo-Johnson
C.
and
Mincey
K.D.
(
2016
)
Obesity epidemiology trends by race/ethnicity, gender, and education: National Health Interview Survey, 1997-2012
.
Gastroenterol. Clin. North Am.
45
,
571
579
[PubMed]
37.
Willey
J.Z.
,
Rodriguez
C.J.
,
Carlino
R.F.
,
Moon
Y.P.
,
Paik
M.C.
,
Boden-Albala
B.
et al.
(
2011
)
Race-ethnic differences in the association between lipid profile components and risk of myocardial infarction: The Northern Manhattan Study
.
Am. Heart J.
161
,
886
892
[PubMed]
38.
Hsu
C.Y.
,
McCulloch
C.E.
,
Iribarren
C.
,
Darbinian
J.
and
Go
A.S.
(
2006
)
Body mass index and risk for end-stage renal disease
.
Ann. Intern. Med.
144
,
21
28
[PubMed]
39.
Hales
C.
,
Carroll
M.
,
Fryar
C.
and
Ogden
C.
(
2020
)
Prevalence of obesity and severe obesity among adults: United States, 2017-2018
.
NCHS Data Brief.
360
,
1
8
40.
Ng
C.
(
2012
)
Obesity among off-reserve First Nations, Métis, and Inuit peoples in Canada’s provinces: associated factors and secular trends
.
41.
Martins-Silva
T.
,
dos Santos Vaz
J.
,
de Mola
C.L.
,
Assunção
M.C.F.
and
Tovo-Rodrigues
L.
(
2019
)
Prevalence of obesity in rural and urban areas in Brazil: National health survey, 2013
.
Rev. Bras. Epidemiol.
22
,
e190049
[PubMed]
42.
Ingaramo
R.A.
et al.
(
2016
)
Obesity, diabetes and other cardiovascular risk factors in native populations of South America
.
Curr. Hypertens. Rep.
18
,
1
5
[PubMed]
43.
Uauy
R.
,
Albala
C.
and
Kain
J.
(
2001
)
Obesity trends in Latin America: transiting from under- to overweight
.
J. Nutr.
131
,
893S
899S
[PubMed]
44.
Tavares
E.F.
,
Vieira-Filho
J.P.B.
,
Andriolo
A.
,
Sañudo
A.
,
Gimeno
S.G.A.
and
Franco
L.J.
(
2003
)
Metabolic profile and cardiovascular risk patterns of an Indian tribe living in the Amazon Region of Brazil
.
Hum. Biol.
75
,
31
46
[PubMed]
45.
He
Y.
,
Pan
A.
,
Wang
Y.
,
Yang
Y.
,
Xu
J.
,
Zhang
Y.
et al.
(
2017
)
Prevalence of overweight and obesity in 15.8 million men aged 15-49 years in rural China from 2010 to 2014
.
Sci. Rep.
7
,
5012
[PubMed]
46.
Xu
W.
,
Zhang
H.
,
Paillard-Borg
S.
,
Zhu
H.
,
Qi
X.
and
Rizzuto
D.
(
2016
)
Prevalence of overweight and obesity among Chinese adults: Role of adiposity indicators and age
.
Obes. Facts
9
,
17
28
[PubMed]
47.
Du
P.
,
Wang
H.J.
,
Zhang
B.
,
Qi
S.F.
,
Mi
Y.J.
,
Liu
D.W.
et al.
(
2017
)
Prevalence of abdominal obesity among Chinese adults in 2011
.
J. Epidemiol.
27
,
282
286
[PubMed]
48.
Misra
A.
,
Jayawardena
R.
and
Anoop
S.
(
2019
)
Obesity in South Asia: phenotype, morbidities, and mitigation
.
Curr. Obes. Rep.
8
,
43
52
[PubMed]
49.
Martorell
R.
,
Kettel Khan
L.
,
Hughes
M.L.
and
Grummer-Strawn
L.M.
(
2000
)
Obesity in women from developing countries
.
Eur. J. Clin. Nutr.
54
,
247
252
[PubMed]
50.
Bentham
J.
,
Di Cesare
M.
,
Bilano
V.
,
Bixby
H.
,
Zhou
B.
,
Stevens
G.A.
et al.
(
2017
)
Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults
.
Lancet
390
,
2627
2642
[PubMed]
51.
Banik
S.
and
Rahman
M.
(
2018
)
Prevalence of overweight and obesity in Bangladesh: a systematic review of the literature
.
Curr. Obes. Rep.
7
,
247
253
52.
Rahmani
A.
,
Sayehmiri
K.
,
Asadollahi
K.
,
Sarokhani
D.
,
Islami
F.
and
Sarokhani
M.
(
2015
)
Investigation of the prevalence of obesity in Iran: a systematic review and meta-analysis study
.
Acta Med. Iran.
53
,
596
607
53.
DeNicola
E.
,
Aburizaiza
O.S.
,
Siddique
A.
,
Khwaja
H.
and
Carpenter
D.O.
(
2015
)
Obesity and public health in the kingdom of Saudi Arabia
.
Rev. Environ. Health
30
,
191
205
54.
Al-Qahtani
A.M.
(
2019
)
Prevalence and predictors of obesity and overweight among adults visiting primary care settings in the southwestern region, Saudi Arabia
.
Biomed Res. Int.
2019
,
8073057
[PubMed]
55.
Al-Thani
M.
,
Al-Thani
A.
,
Alyafei
S.
,
Al-Chetachi
W.
,
Khalifa
S.E.
,
Ahmed
A.
et al.
(
2018
)
The prevalence and characteristics of overweight and obesity among students in Qatar
.
Public Health
160
,
143
149
[PubMed]
56.
Toselli
S.
,
Gualdi-Russo
E.
,
Boulos
D.N.K.
,
Anwar
W.A.
,
Lakhoua
C.
,
Jaouadi
I.
et al.
(
2014
)
Prevalence of overweight and obesity in adults from North Africa
.
Eur. J. Public Health
24
,
31
39
[PubMed]
57.
NCD Risk Factor Collaboration (NCD-RisC) - Africa Working Group
(
2017
)
Trends in obesity and diabetes across Africa from 1980 to 2014: an analysis of pooled population-based studies
.
Int. J. Epidemiol.
46
,
1421
1432
[PubMed]
58.
Price
A.J.
,
Crampin
A.C.
,
Amberbir
A.
,
Kayuni-Chihana
N.
,
Musicha
C.
,
Tafatatha
T.
et al.
(
2018
)
Prevalence of obesity, hypertension, and diabetes, and cascade of care in sub-Saharan Africa: a cross-sectional, population-based study in rural and urban Malawi
.
Lancet Diabetes Endocrinol.
6
,
208
222
[PubMed]
59.
Ng
M.
,
Fleming
T.
,
Robinson
M.
,
Thomson
B.
,
Graetz
N.
,
Margono
C.
et al.
(
2014
)
Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013
.
Lancet
384
,
766
781
[PubMed]
60.
Gibb
S.
,
Shackleton
N.
,
Audas
R.
,
Taylor
B.
,
Swinburn
B.
,
Zhu
T.
et al.
(
2019
)
Child obesity prevalence across communities in New Zealand: 2010-2016
.
Aust. N.Z. J. Public Health
43
,
176
181
[PubMed]
61.
62.
Díaz
E.
,
Rodríguez
A.
,
Martin-Loeches
I.
,
Lorente
L.
,
Del Mar Martín
M.
,
Pozo
J.C.
et al.
(
2011
)
Impact of obesity in patients infected with 2009 influenza A (H1N1)
.
Chest
139
,
382
386
,
[PubMed]
63.
Twig
G.
,
Geva
N.
,
Levine
H.
,
Derazne
E.
,
Goldberger
N.
,
Haklai
Z.
et al.
(
2018
)
Body mass index and infectious disease mortality in midlife in a cohort of 2.3 million adolescents
.
Int. J. Obes.
42
,
801
807
64.
Richardson
S.
,
Hirsch
J.S.
,
Narasimhan
M.
,
Crawford
J.M.
,
McGinn
T.
,
Davidson
K.W.
et al.
(
2020
)
Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area
.
JAMA
323
,
2052
2059
65.
NCIARC
(
2020
)
ICNARC report on COVID-19 in critical care
.
High Holborn
66.
Almerie
M.Q.
and
Kerrigan
D.D.
(
2020
)
The association between obesity and poor outcome after COVID-19 indicates a potential therapeutic role for montelukast
.
Med. Hypotheses
143
,
109883
[PubMed]
67.
Field
A.E.
,
Coakley
E.H.
,
Must
A.
,
Spadano
J.L.
,
Laird
N.
,
Dietz
W.H.
et al.
(
2001
)
Impact of overweight on the risk of developing common chronic diseases during a 10-year period
.
Arch. Intern. Med.
161
,
1581
1586
[PubMed]
68.
Schwarz
P.E.H.
,
Reimann
M.
,
Li
J.
,
Bergmann
A.
,
Licinio
J.
,
Wong
M.L.
et al.
(
2007
)
The metabolic syndrome - A global challenge for prevention
.
Horm. Metab. Res.
39
,
777
780
[PubMed]
69.
Andersen
C.J.
,
Murphy
K.E.
and
Fernandez
M.L.
(
2016
)
Impact of obesity and metabolic syndrome on immunity
.
Adv Nutr.
7
,
66
75
[PubMed]
70.
Maciver
N.J.
,
Shaikh
S.R.
,
Russo
M.A.
,
Nikolajczyk
B.S.
and
Liu
R.
(
2019
)
Tissue Immune cells fuel obesity-associated inflammation in adipose tissue and beyond
.
Front. Immunol.
10
,
1587
,
71.
Kanneganti
T.D.
and
Dixit
V.D.
(
2012
)
Immunological complications of obesity
.
Nat. Immunol.
13
,
707
712
[PubMed]
72.
Yang
H.
,
Youm
Y.H.
,
Vandanmagsar
B.
,
Rood
J.
,
Kumar
K.G.
,
Butler
A.A.
et al.
(
2009
)
Obesity accelerates thymic aging
.
Blood
114
,
3803
3812
[PubMed]
73.
Yang
H.
,
Youm
Y.-H.
,
Vandanmagsar
B.
,
Ravussin
A.
,
Gimble
J.M.
,
Greenway
F.
et al.
(
2010
)
Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance
.
J. Immunol.
185
,
1836
1845
[PubMed]
74.
Yang
H.
,
Youm
Y.-H.
and
Dixit
V.D.
(
2009
)
Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution
.
J. Immunol.
183
,
3040
3052
[PubMed]
75.
Iwasaki
H.
and
Akashi
K.
(
2007
)
Myeloid lineage commitment from the hematopoietic stem cell
.
Immunity
26
,
726
740
[PubMed]
76.
Barbu-Tudoran
L.
,
Gavriliuc
O.I.
,
Paunescu
V.
and
Mic
F.A.
(
2013
)
Accumulation of tissue macrophages and depletion of resident macrophages in the diabetic thymus in response to hyperglycemia-induced thymocyte apoptosis
.
J. Diabetes Complications
27
,
114
122
[PubMed]
77.
Naveiras
O.
,
Nardi
V.
,
Wenzel
P.L.
,
Hauschka
P.V.
,
Fahey
F.
and
Daley
G.Q.
(
2009
)
Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment
.
Nature
460
,
259
263
[PubMed]
78.
Morrison
S.J.
and
Scadden
D.T.
(
2014
)
The bone marrow niche for haematopoietic stem cells
.
Nature
505
,
327
334
[PubMed]
79.
Dixit
V.D.
(
2012
)
Impact of immune-metabolic interactions on age-related thymic demise and T cell senescence
.
Semin. Immunol.
24
,
321
330
[PubMed]
80.
Takahama
Y.
(
2006
)
Journey through the thymus: stromal guides for T-cell development and selection
.
Nat. Rev. Immunol.
6
,
127
135
[PubMed]
81.
Winer
S.
,
Chan
Y.
,
Paltser
G.
,
Truong
D.
,
Tsui
H.
,
Bahrami
J.
et al.
(
2009
)
Normalization of obesity-associated insulin resistance through immunotherapy
.
Nat. Med.
15
,
921
929
[PubMed]
82.
Shaikh
S.R.
,
Haas
K.M.
,
Beck
M.A.
and
Teague
H.
(
2015
)
The effects of diet-induced obesity on B cell function
.
Clin. Exp. Immunol.
179
,
90
99
[PubMed]
83.
Bennett
B.D.
,
Solar
G.P.
,
Yuan
J.Q.
,
Mathias
J.
,
Thomas
G.R.
and
Matthews
W.
(
1996
)
A role for leptin and its cognate receptor in hematopoiesis
.
Curr. Biol.
6
,
1170
1180
[PubMed]
84.
Nguyen
M.T.A.
,
Favelyukis
S.
,
Nguyen
A.K.
,
Reichart
D.
,
Scott
P.A.
,
Jenn
A.
et al.
(
2007
)
A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via toll-like receptors 2 and JNK-dependent pathways
.
J. Biol. Chem.
282
,
35279
35292
[PubMed]
85.
Lumeng
C.N.
,
DeYoung
S.M.
,
Bodzin
J.L.
and
Saltiel
A.R.
(
2007
)
Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity
.
Diabetes
56
,
16
23
[PubMed]
86.
Feuerer
M.
,
Herrero
L.
,
Cipolletta
D.
,
Naaz
A.
,
Wong
J.
,
Nayer
A.
et al.
(
2009
)
Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters
.
Nat. Med.
15
,
930
939
[PubMed]
87.
O'Rourke
R.W.
,
Kay
T.
,
Scholz
M.H.
,
Diggs
B.
,
Jobe
B.A.
,
Lewinsohn
D.M.
et al.
(
2005
)
Alterations in T-cell subset frequency in peripheral blood in obesity
.
Obes. Surg.
15
,
1463
1468
[PubMed]
88.
Ghanim
H.
,
Aljada
A.
,
Hofmeyer
D.
,
Syed
T.
,
Mohanty
P.
and
Dandona
P.
(
2004
)
Circulating mononuclear cells in the obese are in a proinflammatory state
.
Circulation
110
,
1564
1571
[PubMed]
89.
Van Der Weerd
K.
,
Dik
W.A.
,
Schrijver
B.
,
Schweitzer
D.H.
,
Langerak
A.W.
,
Drexhage
H.A.
et al.
(
2012
)
Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype
.
Diabetes
61
,
401
408
[PubMed]
90.
Weitman
E.S.
,
Aschen
S.Z.
,
Farias-Eisner
G.
,
Albano
N.
,
Cuzzone
D.A.
,
Ghanta
S.
et al.
(
2013
)
Obesity impairs lymphatic fluid transport and dendritic cell migration to lymph nodes
.
PLoS ONE
8
,
e70703
[PubMed]
91.
Bredella
M.A.
,
Gill
C.M.
,
Gerweck
A.V.
,
Landa
M.G.
,
Kumar
V.
,
Daley
S.M.
et al.
(
2013
)
Ectopic and serum lipid levels are positively associated with bone marrow fat in obesity
.
Radiology
269
,
534
541
[PubMed]
92.
Cortez
M.
,
Carmo
L.S.
,
Rogero
M.M.
,
Borelli
P.
and
Fock
R.A.
(
2013
)
A high-fat diet increases IL-1, IL-6, and TNF-α production by increasing NF-κb and attenuating PPAR-γ expression in bone marrow mesenchymal stem cells
.
Inflammation
36
,
379
386
[PubMed]
93.
Howard
J.K.
,
Lord
G.M.
,
Matarese
G.
,
Vendetti
S.
,
Ghatei
M.A.
,
Ritter
M.A.
et al.
(
1999
)
Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice
.
J. Clin. Invest.
104
,
1051
1059
,
[PubMed]
94.
Chae
J.S.
,
Paik
J.K.
,
Kang
R.
,
Kim
M.
,
Choi
Y.
,
Lee
S.H.
et al.
(
2013
)
Mild weight loss reduces inflammatory cytokines, leukocyte count, and oxidative stress in overweight and moderately obese participants treated for 3 years with dietary modification
.
Nutr. Res.
33
,
195
203
[PubMed]
95.
Smith
A.G.
,
Sheridan
P.A.
,
Tseng
R.J.
,
Sheridan
J.F.
and
Beck
M.A.
(
2009
)
Selective impairment in dendritic cell function and altered antigen-specific CD8+ T-cell responses in diet-induced obese mice infected with influenza virus
.
Immunology
126
,
268
279
[PubMed]
96.
Chandra
R.K.
(
1980
)
Cell-mediated immunity in genetically obese (C57BL/6J ob/ob) mice | The American Journal of Clinical Nutrition | Oxford Academic
.
Am. J. Clin. Nutr.
33
,
13
16
,
[PubMed]
97.
Mori
A.
,
Sakurai
H.
,
Choo
M.K.
,
Obi
R.
,
Koizumi
K.
,
Yoshida
C.
et al.
(
2006
)
Severe pulmonary metastasis in obese and diabetic mice
.
Int. J. Cancer
119
,
2760
2767
[PubMed]
98.
Eliakim
A.
,
Swindt
C.
,
Zaldivar
F.
,
Casali
P.
and
Cooper
D.M.
(
2006
)
Reduced tetanus antibody titers in overweight children
.
Autoimmunity
39
,
137
141
[PubMed]
99.
Visness
C.M.
,
London
S.J.
,
Daniels
J.L.
,
Kaufman
J.S.
,
Yeatts
K.B.
,
Siega-Riz
A.M.
et al.
(
2009
)
Association of obesity with IgE levels and allergy symptoms in children and adolescents: results from the National Health and Nutrition Examination Survey 2005-2006
.
J. Allergy Clin. Immunol.
123
,
1163
1169
[PubMed]
100.
Sheridan
P.A.
,
Paich
H.A.
,
Handy
J.
,
Karlsson
E.A.
,
Hudgens
M.G.
,
Sammon
A.B.
et al.
(
2012
)
Obesity is associated with impaired immune response to influenza vaccination in humans
.
Int. J. Obes.
36
,
1072
1077
101.
Charland
K.M.
,
Buckeridge
D.L.
,
Hoen
A.G.
,
Berry
J.G.
,
Elixhauser
A.
,
Melton
F.
et al.
(
2013
)
Relationship between community prevalence of obesity and associated behavioral factors and community rates of influenza-related hospitalizations in the United States
.
Influenza Other Respir. Viruses
7
,
718
728
102.
O’Brien
K.B.
,
Vogel
P.
,
Duan
S.
,
Govorkova
E.A.
,
Webby
R.J.
,
McCullers
J.A.
et al.
(
2012
)
Impaired wound healing predisposes obese mice to severe influenza virus infection
.
J. Infect. Dis.
205
,
252
261
[PubMed]
103.
Jung
S.H.
,
Kwon
J.M.
,
Shim
J.W.
,
Kim
D.S.
,
Jung
H.L.
,
Park
M.S.
et al.
(
2013
)
Effects of diet-induced mild obesity on airway hyperreactivity and lung inflammation in mice
.
Yonsei Med. J.
54
,
1430
1437
[PubMed]
104.
Easterbrook
J.D.
,
Dunfee
R.L.
,
Schwartzman
L.M.
,
Jagger
B.W.
,
Sandouk
A.
,
Kash
J.C.
et al.
(
2011
)
Obese mice have increased morbidity and mortality compared to non-obese mice during infection with the 2009 pandemic H1N1 influenza virus
.
Influenza Other Respir. Viruses
5
,
418
425
105.
Warren
K.J.
,
Olson
M.M.
,
Thompson
N.J.
,
Cahill
M.L.
,
Wyatt
T.A.
,
Yoon
K.J.
et al.
(
2015
)
Exercise improves host response to influenza viral infection in obese and non-obese mice through different mechanisms
.
PLoS ONE
10
,
e0129713
[PubMed]
106.
Kim
Y.H.
,
Kim
J.K.
,
Kim
D.J.
,
Nam
J.H.
,
Shim
S.M.
,
Choi
Y.K.
et al.
(
2012
)
Diet-induced obesity dramatically reduces the efficacy of a 2009 pandemic H1N1 vaccine in a mouse model
.
J. Infect. Dis.
205
,
244
251
[PubMed]
107.
Zhang
A.J.X.
,
To
K.K.W.
,
Li
C.
,
Lau
C.C.Y.
,
Poon
V.K.M.
,
Chan
C.C.S.
et al.
(
2013
)
Leptin mediates the pathogenesis of severe 2009 pandemic influenza A(H1N1) infection associated with cytokine dysregulation in mice with diet-induced obesity
.
J. Infect. Dis.
207
,
1270
1280
[PubMed]
108.
Smith
A.G.
,
Sheridan
P.A.
,
Harp
J.B.
and
Beck
M.A.
(
2007
)
Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus 1,2
.
J. Nutr.
137
,
1236
1243
,
[PubMed]
109.
Khan
S.H.
,
Hemann
E.A.
,
Legge
K.L.
,
Norian
L.A.
and
Badovinac
V.P.
(
2014
)
Diet-induced obesity does not impact the generation and maintenance of primary memory CD8 T cells
.
J. Immunol.
193
,
5873
5882
[PubMed]
110.
Milner
J.J.
,
Rebeles
J.
,
Dhungana
S.
,
Stewart
D.A.
,
Sumner
S.C.J.
,
Meyers
M.H.
et al.
(
2015
)
Obesity increases mortality and modulates the lung metabolome during pandemic H1N1 Influenza virus infection in mice
.
J. Immunol.
194
,
4846
4859
[PubMed]
111.
Karlsson
E.A.
,
Meliopoulos
V.A.
,
van de Velde
N.C.
,
van de Velde
L.A.
,
Mann
B.
,
Gao
G.
et al.
(
2017
)
A perfect storm: Increased colonization and failure of vaccination leads to severe secondary bacterial infection in influenza virus-infected obese mice
.
mBio
8
,
e00889
e00917
[PubMed]
112.
Milner
J.J.
,
Sheridan
P.A.
,
Karlsson
E.A.
,
Schultz-Cherry
S.
,
Shi
Q.
and
Beck
M.A.
(
2013
)
Diet-induced obese mice exhibit altered heterologous immunity during a secondary 2009 pandemic H1N1 infection
.
J. Immunol.
191
,
2474
2485
[PubMed]
113.
Karlsson
E.A.
,
Sheridan
P.A.
and
Beck
M.A.
(
2010
)
Diet-Induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells
.
J. Nutr.
140
,
1691
1697
[PubMed]
114.
Sartipy
P.
and
Loskutoff
D.J.
(
2003
)
Monocyte chemoattractant protein 1 in obesity and insulin resistance
.
Proc. Natl. Acad. Sci. U.S.A.
100
,
7265
7270
[PubMed]
115.
Lagathu
C.
,
Yvan-Charvet
L.
,
Bastard
J.P.
,
Maachi
M.
,
Quignard-Boulangé
A.
,
Capeau
J.
et al.
(
2006
)
Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes
.
Diabetologia
49
,
2162
2173
[PubMed]
116.
Na
H.N.
and
Nam
J.H.
(
2012
)
Adenovirus 36 as an obesity agent maintains the obesity state by increasing MCP-1 and inducing inflammation
.
J. Infect. Dis.
205
,
914
922
[PubMed]
117.
Watanabe
M.
,
Risi
R.
,
Tuccinardi
D.
,
Baquero
C.J.
,
Manfrini
S.
and
Gnessi
L.
(
2020
)
Obesity and SARS-CoV-2: a population to safeguard
.
Diabetes Metab. Res. Rev.
36
,
e3325
118.
Michalakis
K.
and
Ilias
I.
(
2020
)
SARS-CoV-2 infection and obesity: common inflammatory and metabolic aspects
.
Diab. Metab. Syndr. Clin. Res. Rev.
14
,
469
471
119.
Ahn
S.Y.
,
Sohn
S.H.
,
Lee
S.Y.
,
Park
H.L.
,
Park
Y.W.
,
Kim
H.
et al.
(
2015
)
The effect of lipopolysaccharide-induced obesity and its chronic inflammation on influenza virus-related pathology
.
Environ. Toxicol. Pharmacol.
40
,
924
930
[PubMed]
121.
2017-2018 Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths and Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths Averted by Vaccination in the United States|CDC
.
122.
Chiu
C.
,
Ellebedy
A.H.
,
Wrammert
J.
and
Ahmed
R.
(
2015
)
B cell responses to influenza infection and vaccination
.
Curr. Top. Microbiol. Immunol.
386
,
381
398
[PubMed]
123.
Kreijtz
J.H.C.M.
,
Fouchier
R.A.M.
and
Rimmelzwaan
G.F.
(
2011
)
Immune responses to influenza virus infection
.
Virus Res.
162
,
19
30
[PubMed]
124.
Iwasaki
A.
and
Pillai
P.S.
(
2014
)
Innate immunity to influenza virus infection
.
Nat. Rev. Immunol.
14
,
315
328
[PubMed]
125.
Watanabe
T.
and
Kawaoka
Y.
(
2011
)
Pathogenesis of the 1918 pandemic influenza virus
.
PLoS Pathog.
7
,
e1001218
126.
Taubenberger
J.K.
and
Morens
D.M.
(
2006
)
1918 Influenza: the mother of all pandemics
.
Emerg. Infect. Dis.
12
,
15
22
127.
Morens
D.M.
and
Fauci
A.S.
(
2007
)
The 1918 influenza pandemic: insights for the 21st century
.
J. Infect. Dis.
195
,
1018
1028
[PubMed]
128.
Garten
R.J.
,
Davis
C.T.
,
Russell
C.A.
,
Shu
B.
,
Lindstrom
S.
,
Balish
A.
et al.
(
2009
)
Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans
.
Science (80-)
325
,
197
201
129.
Smith
G.J.D.
,
Vijaykrishna
D.
,
Bahl
J.
,
Lycett
S.J.
,
Worobey
M.
,
Pybus
O.G.
et al.
(
2009
)
Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza a epidemic
.
Nature
459
,
1122
1125
[PubMed]
130.
Simonsen
L.
,
Spreeuwenberg
P.
,
Lustig
R.
,
Taylor
R.J.
,
Fleming
D.M.
,
Kroneman
M.
et al.
(
2013
)
Global mortality estimates for the 2009 influenza pandemic from the GLaMOR Project: a modeling study
.
PLoS Med.
10
,
e1001558
[PubMed]
131.
Louie
J.K.
,
Acosta
M.
,
Samuel
M.C.
,
Schechter
R.
,
Vugia
D.J.
,
Harriman
K.
et al.
(
2011
)
A novel risk factor for a novel virus: Obesity and 2009 pandemic influenza a (H1N1)
.
Clin. Infect. Dis.
52
,
301
312
[PubMed]
132.
Kwong
J.C.
,
Campitelli
M.A.
and
Rosella
L.C.
(
2011
)
Obesity and respiratory hospitalizations during influenza seasons in Ontario, Canada: a cohort study
.
Clin. Infect. Dis.
53
,
413
421
[PubMed]
133.
Alpert
M.A.
,
Lavie
C.J.
,
Agrawal
H.
,
Aggarwal
K.B.
and
Kumar
S.A.
(
2014
)
Obesity and heart failure: epidemiology, pathophysiology, clinical manifestations, and management
.
Transl. Res.
164
,
345
356
[PubMed]
134.
Alpert
M.A.
(
2001
)
Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome
.
Am. J. Med. Sci.
321
,
225
236
[PubMed]
135.
Wong
C.
and
Marwick
T.H.
(
2007
)
Obesity cardiomyopathy: pathogenesis and pathophysiology
.
Nat. Clin. Pract. Cardiovasc. Med.
4
,
436
443
[PubMed]
136.
Blokhin
I.O.
and
Lentz
S.R.
(
2013
)
Mechanisms of thrombosis in obesity
.
Curr. Opin. Hematol.
20
,
437
444
[PubMed]
137.
Zhou
F.
,
Yu
T.
,
Du
R.
,
Fan
G.
,
Liu
Y.
,
Liu
Z.
et al.
(
2020
)
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study
.
Lancet
395
,
1054
1062
[PubMed]
138.
Ruan
Q.
,
Yang
K.
,
Wang
W.
,
Jiang
L.
and
Song
J.
(
2020
)
Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China
.
Intensive Care Med.
46
,
846
848
[PubMed]
139.
Xu
Z.
,
Shi
L.
,
Wang
Y.
,
Zhang
J.
,
Huang
L.
,
Zhang
C.
et al.
(
2020
)
Pathological findings of COVID-19 associated with acute respiratory distress syndrome
.
Lancet Respir. Med.
8
,
420
422
[PubMed]
140.
Littleton
S.W.
(
2012
)
Impact of obesity on respiratory function
.
Respirology
17
,
43
49
[PubMed]
141.
Bokov
P.
and
Delclaux
C.
(
2019
)
The impact of obesity on respiratory function
.
Rev. des Mal. Respir.
36
,
1057
1063
142.
Sharp
J.T.
,
Henry
J.P.
,
Sweany
S.K.
,
Meadows
W.R.
and
Pietras
R.J.
(
1964
)
The total work of breathing in normal and obese men
.
J. Clin. Invest.
43
,
728
739
[PubMed]
143.
Naimark
A.
and
Cherniack
R.M.
(
1960
)
Compliance of the respiratory system and its components in health and obesity
.
J. Appl. Physiol.
15
,
377
382
[PubMed]
144.
Sugerman
H.
,
Windsor
A.
,
Bessos
M.
and
Wolfe
L.
(
1997
)
Intra-abdominal pressure, sagittal abdominal diameter and obesity comorbidity
.
J. Intern. Med.
241
,
71
79
[PubMed]
145.
Behazin
N.
,
Jones
S.B.
,
Cohen
R.I.
and
Loring
S.H.
(
2010
)
Respiratory restriction and elevated pleural and esophageal pressures in morbid obesity
.
J. Appl. Physiol.
108
,
212
218
146.
Jones
R.L.
and
Nzekwu
M.M.U.
(
2006
)
The effects of body mass index on lung volumes
.
Chest
130
,
827
833
[PubMed]
147.
Sampson
M.G.
and
Grassino
A.E.
(
1983
)
Load compensation in obese patients during quiet tidal breathing
.
J. Appl. Physiol. Respir. Environ. Exerc. Physiol.
55
,
1269
1276
[PubMed]
148.
Burki
N.K.
and
Baker
R.W.
(
1984
)
Ventilatory regulation in eucapnic morbid obesity
.
Am. Rev. Respir. Dis.
130
,
1188
149.
Pellegrino
R.
,
Gobbi
A.
,
Antonelli
A.
,
Torchio
R.
,
Gulotta
C.
,
Pellegrino
G.M.
et al.
(
2014
)
Ventilation heterogeneity in obesity
.
J. Appl. Physiol.
116
,
1175
1181
150.
Polotsky
V.Y.
,
Smaldone
M.C.
,
Scharf
M.T.
,
Li
J.
,
Tankersley
C.G.
,
Smith
P.L.
et al.
(
2004
)
Impact of interrupted leptin pathways on ventilatory control
.
J. Appl. Physiol.
96
,
991
998
151.
Sideleva
O.
,
Suratt
B.T.
,
Black
K.E.
,
Tharp
W.G.
,
Pratley
R.E.
,
Forgione
P.
et al.
(
2012
)
Obesity and asthma: An inflammatory disease of adipose tissue not the airway
.
Am. J. Respir. Crit. Care Med.
186
,
598
605
[PubMed]
152.
Bulló
M.
,
García-Lorda
P.
and
Salas-Salvadó
J.
(
2002
)
Plasma soluble tumor necrosis factor alpha receptors and leptin levels in normal-weight and obese women: Effect of adiposity and diabetes
.
Eur. J. Endocrinol.
146
,
325
331
[PubMed]
153.
Bulló
M.
,
García-Lorda
P.
,
Megias
I.
and
Salas-Salvadó
J.
(
2003
)
Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression
.
Obes. Res.
11
,
525
531
[PubMed]
154.
Poglio
S.
,
De Toni-Costes
F.
,
Arnaud
E.
,
Laharrague
P.
,
Espinosa
E.
,
Casteilla
L.
et al.
(
2010
)
Adipose tissue as a dedicated reservoir of functional mast cell progenitors
.
Stem Cells
28
,
2065
2072
[PubMed]
155.
Zaldivar
F.
,
McMurray
R.G.
,
Nemet
D.
,
Galassetti
P.
,
Mills
P.J.
and
Cooper
D.M.
(
2006
)
Body fat and circulating leukocytes in children
.
Int. J. Obes.
30
,
906
911
156.
Periyalil
H.A.
,
Wood
L.G.
,
Wright
T.A.
,
Karihaloo
C.
,
Starkey
M.R.
,
Miu
A.S.
et al.
(
2018
)
Obese asthmatics are characterized by altered adipose tissue macrophage activation
.
Clin. Exp. Allergy
46
,
641
649
157.
Chen
N.
,
Zhou
M.
,
Dong
X.
,
Qu
J.
,
Gong
F.
,
Han
Y.
et al.
(
2020
)
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study
.
Lancet
395
,
507
513
[PubMed]
158.
Chan
J.F.W.
,
Yuan
S.
,
Kok
K.H.
,
To
K.K.W.
,
Chu
H.
,
Yang
J.
et al.
(
2020
)
A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster
.
Lancet
395
,
514
523
[PubMed]
159.
Jia
H.P.
,
Look
D.C.
,
Shi
L.
,
Hickey
M.
,
Pewe
L.
,
Netland
J.
et al.
(
2005
)
ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia
.
J. Virol.
79
,
14614
14621
[PubMed]
160.
Xu
H.
,
Zhong
L.
,
Deng
J.
,
Peng
J.
,
Dan
H.
,
Zeng
X.
et al.
(
2020
)
High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa
.
Int. J. Oral Sci.
12
,
8
[PubMed]
161.
Walls
A.C.
,
Park
Y.J.
,
Tortorici
M.A.
,
Wall
A.
,
McGuire
A.T.
and
Veesler
D.
(
2020
)
Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein
.
Cell
181
,
281.e6
292.e6
[PubMed]
162.
Sanchis-Gomar
F.
,
Lavie
C.J.
,
Mehra
M.R.
,
Henry
B.M.
and
Lippi
G.
(
2020
)
Obesity and outcomes in COVID-19: when an epidemic and pandemic collide
.
Mayo Clin. Proc.
95
,
1445
1453
[PubMed]
163.
Wong
S.K.
,
Li
W.
,
Moore
M.J.
,
Choe
H.
and
Farzan
M.
(
2004
)
A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2
.
J. Biol. Chem.
279
,
3197
3201
[PubMed]
164.
Xiao
X.
,
Chakraborti
S.
,
Dimitrov
A.S.
,
Gramatikoff
K.
and
Dimitrov
D.S.
(
2003
)
The SARS-CoV S glycoprotein: expression and functional characterization
.
Biochem. Biophys. Res. Commun.
312
,
1159
1164
[PubMed]
165.
Simmons
G.
,
Gosalia
D.N.
,
Rennekamp
A.J.
,
Reeves
J.D.
,
Diamond
S.L.
and
Bates
P.
(
2005
)
Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry
.
Proc. Natl. Acad. Sci. U.S.A.
102
,
11876
11881
[PubMed]
166.
Bosch
B.J.
,
Martina
B.E.E.
,
Van Der Zee
R.
,
Lepault
J.
,
Haijema
B.J.
,
Versluis
C.
et al.
(
2004
)
Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides
.
Proc. Natl. Acad. Sci. U.S.A.
101
,
8455
8460
[PubMed]
167.
Liu
S.
,
Xiao
G.
,
Chen
Y.
,
He
Y.
,
Niu
J.
,
Escalante
C.R.
et al.
(
2004
)
Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: Implications for virus fusogenic mechanism and identification of fusion inhibitors
.
Lancet
363
,
938
947
[PubMed]
168.
Hoffmann
M.
,
Kleine-Weber
H.
,
Schroeder
S.
,
Krüger
N.
,
Herrler
T.
,
Erichsen
S.
et al.
(
2020
)
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor
.
Cell
181
,
271.e8
280.e8
[PubMed]
169.
Wrapp
D.
,
Wang
N.
,
Corbett
K.S.
,
Goldsmith
J.A.
,
Hsieh
C.-L.
,
Abiona
O.
et al.
(
2020
)
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
.
bioRxiv
367
,
1260
1263
170.
Park
W.B.
,
Kwon
N.J.
,
Choi
S.J.
,
Kang
C.K.
,
Choe
P.G.
,
Kim
J.Y.
et al.
(
2020
)
Virus isolation from the first patient with SARS-CoV-2 in Korea
.
J. Korean Med. Sci.
35
,
e84
171.
Zhang
Y.
,
Gao
Y.
,
Qiao
L.
,
Wang
W.
and
Chen
D.
(
2020
)
Inflammatory response cells during acute respiratory distress syndrome in patients with coronavirus disease 2019 (COVID-19)
.
Ann. Intern. Med.
173
,
402
404
[PubMed]
172.
Chen
I.Y.
,
Moriyama
M.
,
Chang
M.F.
and
Ichinohe
T.
(
2019
)
Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome
.
Front. Microbiol.
10
,
50
[PubMed]
173.
Fink
S.L.
and
Cookson
B.T.
(
2005
)
Apoptosis, pyroptosis, and necrosis: Mechanistic description of dead and dying eukaryotic cells
.
Infect. Immun.
73
,
1907
1916
[PubMed]
174.
Yang
M.
(
2020
)
Cell pyroptosis, a potential pathogenic mechanism of 2019-nCoV infection
.
SSRN Electron. J.
175.
Di Stadio
A.
,
Ricci
G.
,
Greco
A.
,
de Vincentiis
M.
and
Ralli
M.
(
2020
)
Mortality rate and gender differences in COVID-19 patients dying in Italy: a comparison with other countries
.
Eur. Rev. Med. Pharmacol. Sci.
24
,
4066
4067
176.
Klang
E.
,
Kassim
G.
,
Soffer
S.
,
Freeman
R.
,
Levin
M.A.
and
Reich
D.L.
(
2020
)
Severe obesity as an independent risk factor for COVID-19 mortality in hospitalized patients younger than 50
.
Obesity
28
,
1595
1599
[PubMed]
178.
Stachel
A.
,
Johnson
D.
,
Francois
F.
,
Lighter
J.
,
Phillips
M.
,
Hochman
S.
et al.
(
2020
)
Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission
.
Clin. Infect. Dis.
71
,
896
897
,
[PubMed]
179.
Kruglikov
I.L.
and
Scherer
P.E.
(
2020
)
The role of adipocytes and adipocyte-like cells in the severity of COVID-19 infections
.
Obesity
28
,
1187
1190
180.
Kassir
R.
(
2020
)
Risk of COVID-19 for patients with obesity
.
Obes. Rev.
21
,
e13034
181.
Bombardini
T.
and
Picano
E.
(
2020
)
Angiotensin-converting enzyme 2 as the molecular bridge between epidemiologic and clinical features of COVID-19
.
Canadian J. Cardiol.
36
,
784.e1
784.e2
182.
Sattar
N.
,
McInnes
I.B.
and
McMurray
J.J.V.
(
2020
)
Obesity a risk factor for severe COVID-19 infection: multiple potential mechanisms
.
Circulation
142
,
4
6
[PubMed]
183.
Green
W.D.
and
Beck
M.A.
(
2017
)
Obesity impairs the adaptive immune response to influenza virus
.
Ann. Am. Thorac. Soc.
14
,
S406
S409
[PubMed]
184.
Salehi
S.
,
Abedi
A.
,
Balakrishnan
S.
and
Gholamrezanezhad
A.
(
2020
)
Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients
.
Am. J. Roentgenol.
215
,
87
93
185.
Mehta
P.
,
McAuley
D.F.
,
Brown
M.
,
Sanchez
E.
,
Tattersall
R.S.
and
Manson
J.J.
(
2020
)
COVID-19: consider cytokine storm syndromes and immunosuppression
.
Lancet
395
,
1033
1034
186.
Kerrigan
D.J.
,
Brawner
C.A.
,
Ehrman
J.K.
and
Keteyian
S.
(
2021
)
Cardiorespiratory fitness attenuates the impact of risk factors associated with COVID-19 hospitalization
.
Mayo Clin. Proc.
96
,
822
823
[PubMed]
187.
Lavie
C.J.
,
Sanchis-Gomar
F.
and
Arena
R.
(
2021
)
Fit is it in COVID-19, future pandemics, and overall healthy living
.
Mayo Clin. Proc.
96
,
7
9
[PubMed]
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).