Association of Obesity and Severe Asthma in Adults

The incidence of obesity and asthma continues to enhance, significantly impacting global public health. Adipose tissue is an organ that secretes hormones and cytokines, causes meta-inflammation, and contributes to the intensification of bronchial hyperreactivity, oxidative stress, and consequently affects the different phenotypes of asthma in obese people. As body weight increases, the risk of severe asthma increases, as well as more frequent exacerbations requiring the use of glucocorticoids and hospitalization, which consequently leads to a deterioration of the quality of life. This review discusses the relationship between obesity and severe asthma, the underlying molecular mechanisms, changes in respiratory function tests in obese people, its impact on the occurrence of comorbidities, and consequently, a different response to conventional asthma treatment. The article also reviews research on possible future therapies for severe asthma. The manuscript is a narrative review of clinical trials in severe asthma and comorbid obesity. The articles were found in the PubMed database using the keywords asthma and obesity. Studies on severe asthma were then selected for inclusion in the article. The sections: ‘The classification connected with asthma and obesity’, ‘Obesity-related changes in pulmonary functional tests’, and ‘Obesity and inflammation’, include studies on subjects without asthma or non-severe asthma, which, according to the authors, familiarize the reader with the pathophysiology of obesity-related asthma.


Introduction
Asthma is a heterogeneous, chronic disease associated with inflammation of the airways, characterized by attacks of wheezing, shortness of breath, coughing, and chest tightness, which vary in time and severity [1].It is one of the most widespread noncommunicable chronic diseases.In 2019, 262 million people worldwide had asthma, and it was the cause of 455,000 deaths [2].
According to numerous studies, the incidence of severe asthma among all asthma patients is estimated at 3-10% in European countries [3][4][5][6].According to GINA, severe asthma is defined as asthma that is uncontrolled despite high doses of ICS-LABA and optimal treatment of underlying factors, or that worsens when high doses of ICS-LABA are reduced [1].It is estimated that severe asthma consumes about 60% of all costs related to the treatment of patients with asthma, including costs of drugs or hospitalization due to exacerbations, which is significant for public health [7].To optimize the treatment of a patient with severe asthma, it is necessary to look for comorbidities, such as obesity, that may affect the control of asthma symptoms and the effectiveness of conventional therapies.The relevance between asthma and obesity, its impact on worsening asthma control, poorer response to treatment, changes in pulmonary functional tests, and deterioration of quality of life have been shown in numerous studies [8][9][10][11][12].However, the exact mechanisms have not been well understood yet.Changes in the biomechanics of the chest and breathing, increased inflammation, and oxidative stress are considered to be fundament of this association.
The aim of the article, in the face of the growing increase in the incidence of asthma and obesity, is to draw attention to the co-occurrence of these two diseases and, consequently, to problems with the optimal treatment of obesity-related asthma due to its more severe course, complicated treatment regimens, and the coexistence of other obesity-related diseases.It also presents clinical trials of other possible therapies for asthma in obese people.

The Classifications Connected with Asthma and Obesity
Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health [13].The most commonly used, low cost, easy to measure, and well correlated with the health risk rate is BMI, calculated as body weight in kilograms divided by the square of height in meters [14].For adults, the WHO defines overweight as a BMI greater than or equal to 25 kg/m 2 and obesity greater than or equal to 30 kg/m 2 , respectively [13].
Since 1975, the number of obese people has nearly tripled to 650 million in 2016.According to the WHO data, approximately 39% of the adult population are obese, while 13% are overweight [13].Many cross-sectional investigations have shown that asthma is more prevalent in obese compared to lean individuals [15][16][17][18].Moreover, recent studies have demonstrated a dose-response relationship between an increased asthma incidence and an increase in BMI.Koebnick et al., in a mixed longitudinal and cross-sectional retrospective study, showed that the hazard of adult-onset asthma is increased by 12% with a BMI of 25.0-29.9kg/m 2 , by 40% with a BMI 30.0-34.9 kg/m 2 , and by almost 250% with a BMI of 50 kg/m 2 and above, compared to individuals with a normal weight BMI < 25 kg/m 2 [16].Furthermore, they proved a positive correlation between BMI and poorly controlled asthma [16].In the Portuguese National Health Survey of 32,644 adults, overweight (25.0-29.9kg/m 2 ) individuals were associated with an odds ratio for severe asthma (defined as an emergency room visit for deterioration of asthma within the last 12 months) of 1.36, class I obesity (30.0-34.9kg/m 2 ) and class II obesity (35.0-39.9kg/m 2 ) with an OR of 1.5, and class III obesity (≥40.0 kg/m 2 ) with an OR of 3.70 [9].Holguin et al., in the study of 1049 adults from the Severe Asthma Project, evaluated obesity as a 4-to 6-fold higher risk of being hospitalized compared with lean asthmatics [19].Moreover, in a retrospective cohort study of 72,086 patients aged 18-54 years hospitalized for asthma exacerbation, 24% were obese and were more likely to require hospitalization > 3 days, which was associated with a significantly higher risk of using mechanical ventilation compared to non-obese subjects [10].
On the other hand, the impact of weight change on asthma control, quality of life, number of courses of steroid therapy, and exacerbations was analyzed in the TENOR study (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) in 2396 adults with asthma [20].This multicenter, observational, prospective cohort study demonstrated poorer asthma control, quality of life, and a greater need for OCS in patients who gained 2.27 kg or more over 12 months of follow-up compared with patients whose weight remained unchanged or decreased by at least 2.27 kg [20].
As shown above, obesity significantly worsens asthma control, so it is worth understanding the mechanisms underlying this change.The following sections present the impact of obesity on functional pulmonary tests and the pathomechanisms of meta-inflammation caused by excess adipose tissue.

Obesity-Related Changes in Pulmonary Functional Tests
Better understanding of functional and molecular changes related to obesity is important to find associations and clinical implications, which could lead to distinct therapeutic options for obese asthmatics.Obesity causes alterations in lung mechanics independently of asthma, which determines difficulty in distinguishing physiological changes associated with obesity from those caused by asthma.Many studies have demonstrated diminution in all lung volumes, predominantly in the functional residual capacity (FRC) and expiratory reserve volume (ERV) as a result of excess adipose tissue inside thoracic cavity, around the trunk and abdomen [21][22][23][24][25][26].Richard L Jones and Mary-Magdalene U Nzekwu showed an exponential decrease in FRC and ERV with increasing BMI, with the greatest rates of change presented in overweight and mild obesity.Moreover, they found a linear connection between BMI and vital capacity (VC) and total lung capacity (TLC); however, the group mean values remained within normal limits even among patients with obesity in class III [22].These alterations lead morbidly obese individuals to breathe near residual volume with a low tidal volume and more frequent respiratory rates, which may contribute to their self-reported dyspnea [27].In addition, investigations have shown a significant, uniform reduction in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), leading to a slight increase or maintenance of the FEV1/FVC ratio, which indicates a restrictive dysfunction pattern [11,21,28].This phenomenon is probably related to the reduction in parenchymal binding forces on the attached airways, which causes expiratory dynamic closure of airways, increasing their resistance, leading to limitation of expiratory flow, air trapping, and hyperinflation [8], causing a mismatch of ventilation and perfusion [29].All these changes occurring in the respiratory tract in obese people may cause asthma-like symptoms and, consequently, lead to an incorrect diagnosis.On the other hand, patients diagnosed with asthma may experience greater shortness of breath, and this may lead to overtreatment.
Nevertheless, despite the obesity-related reduction in peripheral airway diameter, clinical observations regarding airway hyperresponsivity (AHR) are contradictory.Many researchers have demonstrated a link between the development of AHR and increased BMI [30][31][32][33][34].For example, Litonjua et al., in longitudinal research with 2280 men, found a non-linear association with obesity and greater AHR and a positive linear relationship between change in BMI and the subsequent development of AHR [30].Badier et al., in a cohort study of 60 lean, 84 overweight, and 360 class I-III obese non-asthmatic individuals, noted that overweight and obese adults presented AHR about twice as often as lean individuals [31].Moreover, weight reduction in obese asthmatics undergoing bariatric surgery resulted in an improvement in AHR [35].Other human studies have negated this association between bronchial hyperresponsivity and higher BMI [36][37][38][39].
A summary of the changes in the respiratory system and the clinical characteristics of obesity-related asthma is presented in Figure 1.
capacity (FRC) and expiratory reserve volume (ERV) as a result of excess adipose tis inside thoracic cavity, around the trunk and abdomen [21][22][23][24][25][26].Richard L Jones and Ma Magdalene U Nzekwu showed an exponential decrease in FRC and ERV with increas BMI, with the greatest rates of change presented in overweight and mild obes Moreover, they found a linear connection between BMI and vital capacity (VC) and to lung capacity (TLC); however, the group mean values remained within normal limits ev among patients with obesity in class III [22].These alterations lead morbidly ob individuals to breathe near residual volume with a low tidal volume and more frequ respiratory rates, which may contribute to their self-reported dyspnea [27].In additi investigations have shown a significant, uniform reduction in forced expiratory volu in one second (FEV1) and forced vital capacity (FVC), leading to a slight increase maintenance of the FEV1/FVC ratio, which indicates a restrictive dysfunction patt [11,21,28].This phenomenon is probably related to the reduction in parenchymal bind forces on the attached airways, which causes expiratory dynamic closure of airwa increasing their resistance, leading to limitation of expiratory flow, air trapping, a hyperinflation [8], causing a mismatch of ventilation and perfusion [29].All these chan occurring in the respiratory tract in obese people may cause asthma-like symptoms a consequently, lead to an incorrect diagnosis.On the other hand, patients diagnosed w asthma may experience greater shortness of breath, and this may lead to overtreatmen Nevertheless, despite the obesity-related reduction in peripheral airway diame clinical observations regarding airway hyperresponsivity (AHR) are contradictory.Ma researchers have demonstrated a link between the development of AHR and increa BMI [30][31][32][33][34].For example, Litonjua et al., in longitudinal research with 2280 men, foun non-linear association with obesity and greater AHR and a positive linear relations between change in BMI and the subsequent development of AHR [30].Badier et al., i cohort study of 60 lean, 84 overweight, and 360 class I-III obese non-asthmatic individu noted that overweight and obese adults presented AHR about twice as often as le individuals [31].Moreover, weight reduction in obese asthmatics undergoing baria surgery resulted in an improvement in AHR [35].Other human studies have negated t association between bronchial hyperresponsivity and higher BMI [36][37][38][39].
A summary of the changes in the respiratory system and the clinical characteris of obesity-related asthma is presented in Figure 1.

Obesity and Inflammation
Adipose tissue both participates in energy storage and acts as an endocrine organ by secreting hormones and adipokines that modulate the immune response.Obesity causes low-grade systemic inflammation, called meta-inflammation [40].As adipose tissue grows and the distance between adipocytes and capillaries increases, leading to hypoxia, the number of macrophages activated by fatty acids released from dead adipocytes increases [41,42].This results in a burst of pro-inflammatory cytokines, such as IL-6, TNF-α, IL-1β, and leptin [40,42], which drain from adipose tissue via portal circulation to the pulmonary vasculature and, consequently, may affect the development and course of asthma [35].The most important cytokines and their impact on asthma are presented in a Table 1.
Table 1.Chemokines and cytokines secreted by adipose tissue, their systemic effects, and their impact on the respiratory system.

Adipokine Systemic Effect Effect on Asthma
Leptin ■ is a mediator of appetite and energy expenditure-anorexigenic effect (inhibits hunger) [43] ■ is increased in obesity, aggravates insulin resistance [44] ■ stimulates adipocytes to secrete pro-inflammatory cytokines, such as TNF-α, Il-6, IL-12 [45], and MCP-1 [46] ■ facilitates phagocytosis [45] ■ activates peripheral blood mononuclear cells (PBMC) to induce the secretion of Il-6 and TNF-α [47,48] ■ enhances the formation of oxygen radicals in neutrophils [49] ■ promotes the production of T lymphocytes and their differentiation toward cells producing cytokines for Th1, inhibits the functions of regulatory Treg lymphocytes [50], and affects the activity of pro-inflammatory Th17 cells [51] ■ leptin and leptin receptor are expressed in the airway epithelium [35,52] ■ leptin level is significantly higher in obese asthmatics compared to obese controls and is associated with greater AHR [35] ■ is positively associated with asthma severity, asthma control, and lung function [53] Adiponectin ■ is involved in the stimulation of food intake (anorexigenic hormone) [54] ■ is decreased in obesity [55] ■ negatively correlates with insulin resistance by activating AMPK in muscle and liver [54] ■ stimulates expression of anti-inflammatory cytokines, such as IL-10, an endogenous antagonist of the IL-1 receptor [56] ■ inhibits production of pro-inflammatory cytokines TNF-α, IL-6, and INF and the expression of the transcription factor NF-κB in macrophages [56,57] ■ promotes the differentiation of monocytes into M1 macrophages and inhibits differentiation into M2 macrophages [58] ■ adiponectin receptors (adipoR1, adipoR2, and T-cadherin) are present in bronchial airways, lung parenchyma, and alveolar fluid [54,59] ■ reduces AHR in lean people; in obese people, lowering the concentration of adiponectin leads to an increase in AHR [60] ■ inversely relates with asthma control [61] Resistin ■ is increased in obesity [62] ■ induces insulin resistance [63] ■ stimulates macrophages to produce TNF-α and IL-12 [64] ■ plays a role in the differentiation of monocytes and macrophages [65] ■ augments mucin expression in airway epithelial cells [66] ■ plays a role in a dose-dependent effect on asthma severity [67] ■ induce airway remodeling [68] TNF-α ■ serum concentration of TNF-α is elevated in obesity [69] ■ induces insulin resistance by reducing the expression of insulin-regulated glucose transporter type 4 and by impairing the insulin signaling through serine phosphorylation [70] ■ causes an increase in the level of reactive oxygen species (ROS) because of mitochondrial dysfunction [71] ■ stimulates PAI-1 expression in the adipose tissue [72] ■ In normal subjects, it induces AHR and augments neutrophil infiltration to airways [73] ■ expression of membrane-bound TNF-α, TNF-α receptor 1, and TNF-α-converting enzyme by PBMC in patients with refractory asthma [74] TGF-β1 ■ promotes the browning of white adipose tissue [75] ■ induces PAI-1 secretion [72] ■ is positively associated with asthma severity [76] ■ contributes to upregulation of PAI-1 expression in airway epithelial cells [77] Table 1.Cont.

PAI-1
■ is elevated in obesity and associated with insulin resistance [72,78] ■ plays a key role in proinflammatory, profibrotic, and mitogenic mechanisms [79] ■ contributes to an increase in AHR [80,81] ■ plays a role as a mediator of airway inflammation and remodeling [81,82] ■ inhibits tissue plasminogen activator (tPA) and urokinase (uPA), which suppress fibrinolysis [83] ■ elevated level of PAI-1 plays a key role in atherosclerosis and cardiovascular disease, thrombosis, tumor invasion, and metastasis [84] IL-6 ■ positively correlates with BMI [85] ■ mediates the suppression of food intake by stimulating the glucagon-like peptide-1 (GLP-1) receptor [86] ■ increases insulin secretion by stimulating the production of GLP-1 [86] ■ stimulates neutrophils to produce IL-17 [87] ■ adipose tissue-derived dendritic cells (ATDCs) express higher levels of IL-6, TGF-β, and IL-23, which promote differentiation of Th17 cells [88] ■ associates with diminished FEV1 [89], more frequent asthma exacerbations [89,90], blood eosinophilia, submucosal infiltration of T-cells, and macrophages [90] IL-17A ■ is elevated in obesity [91]; IL-17A receptor C (IL-17RC) is expressed in mature adipocytes [92] ■ induces production of TNF-α, IL-6, and IL-1β [93] ■ plays a key role in pathogenesis of lupus, psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and cancers [94,95] ■ increases the influx of neutrophils into airways by affecting the synthesis of chemokines (CXC) and growth factors G-CSF and GM-CSF [96] ■ airway neutrophilia and sputum level of IL-17 positively correlates with asthma control and negatively correlates with FEV1 and serum IL-17 levels [97] ■ induces MUC5B expression in bronchial epithelial cells via the NF-κB pathway, which affects airway remodeling [98] IL-1β ■ is a major endogenous pyrogen [99] ■ is increased in obesity [100] ■ induces impaired insulin signal transduction by reducing the expression of signaling proteins and glucose transport proteins (GLUT4) [101] ■ fatty acids via toll-like receptor 4 (TLR4) activate the inflammasome of nucleotide oligomerization domain-like receptor protein 3 (NLRP3), which then activates caspase-1, resulting in release of IL-1β and neutrophil influx [12] ■ affects the activation of T lymphocytes, proliferation of B cells, and increasing the synthesis of immunoglobulins [102] ■ the level of IL-1β in the sputum positively correlates with neutrophilic inflammation and obesity by enhanced expression of the NLRP3 genes [103] ■ plays a key role in airway remodeling by regulating airway smooth-muscle responses [104,105], increasing AHR [105], and inducing MUC5B expression in bronchial epithelial cells via the NF-κB pathway [98] ■ is associated with an increased risk of asthma exacerbations [106] ■ positively correlates with asthma severity [106] IL-8 ■ is increased in obesity [100,107] ■ promotes insulin resistance by inhibition of insulin-induced Akt phosphorylation in adipocytes [108] ■ activates neutrophils [109] ■ induces the migration of cells and fibroblasts to the wound, and hence promotes healing [110] ■ supports angiogenesis [111] ■ plays a key role in pathogenesis of psoriasis rheumatoid arthritis, chronic obstructive pulmonary disease, endometriosis, inflammatory bowel disease, development of cancers, and signaling in cystic fibrosis [112] ■ correlates with number of neutrophils in BALF and the level of myeloperoxidase (MPO), which proves the role of IL-8 in inducing neutrophil chemotaxis to the airways [113] ■ IL-8 gene and protein expression is upregulated in the bronchial epithelium of patients with symptomatic asthma [114] ■ positively correlates with asthma severity [115] ■ an increase in IL-8 sputum levels precedes an exacerbation of asthma [116] IL-10 ■ is negatively correlated with BMI [117] ■ inhibits adipogenesis in preadipocytes [118] ■ is associated with insulin sensitivity [117] ■ is a major anti-inflammatory cytokine that reduces TNF-α, IL-6, and IL-8 [119] ■ IL-10 level in sputum is significantly lower in asthmatic individuals [120] A schematic summary of the pathophysiology of airway remodeling induced by meta-inflammation present in obesity is shown in Figure 2.

Endotypes and Phenotypes
Taking into account the pathophysiological mechanisms at the cellular and molecular levels, there are two main endotypes of asthma: Th2 high and Th2 low [121].In the high Th2 endotype, eosinophilic and mixed subtypes can be distinguished, while in the low Th2 endotype-neutrophilic and paucigranulocytic.All these subtypes, except paucigranulocytic, may occur in severe asthma.Moreover, recent studies based on cluster analysis of obesity-related asthma have identified two distinct phenotypes: late-onset asthma due to obesity and early-onset asthma, in which pre-existing symptoms worsen with weight gain [122,123].Understanding the characteristic features of individual endotypes and phenotypes is important in selecting appropriate, effective asthma therapy, and these are presented in the sections below.

Late-Onset Asthma (LOA)
Haldar et al., in the cluster analysis, identified a group of predominantly obese women (81.5%) with later onset of asthma (35 ± 19 years), reduced atopy, and a higher level of symptoms' expression in the low Th2 inflammation (decreased blood and sputum eosinophils, and less FeNO) and enhanced neutrophilic inflammation [122].Similar observations were performed by Moore et al. within the study of 726 subjects with persistent asthma from the NIH Severe Asthma Research Program (SARP).They distinguished a LOA phenotype (all had asthma diagnosed > 23 years), predominating in older women (mean age 50) with the highest BMI (58% > 30 kg/m 2 ) and lower baseline lung function (71% of FEV1 < 80% predicted), despite the relatively short duration of the disease.Compared to other clusters, the lowest bronchial hyperresponsiveness and reduced atopy were characteristic for that group (64% of patients had ≥1 positive SPT and lower total IgE) [123].
In a comparative study for both phenotypes of obesity-related asthma, obese individuals with LOA predominated in severe disease and required more complicated treatment regimens [19].Moreover, regardless of using ≥ 3 asthma control medications, including high-dose ICS (54% of patients) and more frequent use of oral steroids (17% of patients used them regularly, 36% required ≥ 3 OCS, burst/year), they reported greater daily symptoms and high care utilization associated with exacerbations.The representatives of this cluster were also more likely to have comorbidities, such as sinus disease, gastroesophageal reflux, and hypertension [123].

Early-Onset Asthma (EOA)
In a cluster analysis, Haldar et al. [122], in addition to LOA, distinguished a group of predominantly male patients (54%) with early-onset asthma (14.6 ± 15.5 years), which was characterized by atopy (95%), eosinophilic inflammation (higher percentage of eosinophils in sputum, and increased FeNO), more frequent exacerbations requiring oral corticosteroids, and hospitalization, compared to other clusters treated in primary care.In secondary care, this phenotype was dominant in females (75.7%) and was characterized by a lower quality of life due to poorer control of symptoms, greater eosinophilic inflammation, and airway obstruction, despite the use of the highest doses of ICS and more frequent treatment with oral glucocorticoids [122].
In a study comparing LOA and EOA, the latter showed greater airway obstruction, which was positively correlated with BMI, greater bronchial hyperresponsiveness, and elevated IgE.Moreover, obese EOA individuals had a higher risk of pneumonia and exacerbation-related hospitalization, ICU admission, and mechanical ventilation compared with obese LOA subjects.Obese patients with EOA were three and six times more likely to be hospitalized and admitted to the ICU than their lean counterparts [19].
Furthermore, representatives of this phenotype showed a linear increase in BMI with the duration of asthma, also after taking into account its severity.This phenomenon was not observed among LOA subjects.The results may suggest that in early-onset asthma, pre-existing symptoms worsen with weight gain, whereas in late-onset asthma, the severity of asthma and BMI may be due to a cause-and-effect relationship [19].

Neutrophilic Phenotype of Severe Asthma
The most common manifestation of severe asthma seen in adults, with onset predominantly > 12 years of age [123,124], is neutrophilic asthma, characterized by a sputum neutrophil count of 500 × 10 4 /mL [125] or 40% to 76% of all sputum cells [124][125][126][127], with a reduced eosinophil count (usually less than 1.9% to 3%) [122,128].However, sputum analysis has limited availability and requires advanced training, which makes its clinical use difficult.The diagnosis of neutrophilic asthma can also be complicated by high doses of inhaled or oral steroids that increase neutrophil counts in tissues and peripheral blood [129].
Previous studies have shown that the neutrophilic phenotype is more likely to occur in obese than in lean women (42.9% vs. 16.2%)[130], non-atopic [123,131], with persistent remodeling airway obstruction [127,132,133] and lower AHR compared with eosinophilic asthma [123,131].
Furthermore, it was associated with poorer quality of life and prognosis [123,128,134,135] due to more severe steroid-resistant asthma [136,137], poorer symptom control [123] with recurrent nocturnal attacks [138], frequent non-infectious exacerbations requiring urgent emergency room visits, hospitalization, and mechanical ventilation [139,140].A higher risk of exacerbations may also be associated with chronic atypical bacterial inflammation, as seen in patients with severe neutrophilic asthma [141].

Mixed Granulocytic Asthma
Scott proposed distinguishing the obesity-related neutrophilic asthma as a subgroup of late-onset asthma, but it may also include patients with mixed granulocytic inflammation [130].Moore et al. [123], in cluster 5, observed a group of mostly elderly (49 ± 11 years), obese (51% with a BMI > 30 kg/m 2 ) women (63%) with late-onset asthma (21 ± 15 years) and longer duration (29 ± 15), accompanied by mixed inflammation: eosinophilic and neutrophilic.This phenotype was also characterized by less atopy (66% of patients had ≥1 positive SPT), greater airway limitation (FEV1 pred.43 ± 14%), more severe disease manifested by complicated treatment regimens (95% taking ≥2 and ≥3 controller drugs were taken by 95% and 67%, respectively), and frequent use of high-dose ICS and oral corticosteroids.Moreover, representatives of this group had worse disease control, with recurrent exacerbations requiring oral steroid bursts, admission to ED, or hospitalization, including ICU [123].Further research is needed to improve the clinical characteristics of this mixed granulocytic endotype [130].
A summary of the endotypes and phenotypes of obesity-related asthma is presented in Table 2.

Comorbidities
More than mild-to-moderate, severe asthma predisposes to various pulmonary and extrapulmonary comorbidities [142,143].Obesity, together with female gender, older age, former smoking, or steroid resistance, are factors of their more frequent occurrence [144].Due to the significant impact of comorbidities on the course and severity of asthma [143], prompt diagnosis and appropriate treatment are crucial to improve asthma and avoid overtreatment.Below, the diseases comorbid with asthma and obesity are presented, the appropriate treatment of which significantly improves the control of asthma symptoms.

Chronic Rhinosinusitis and Nasal Polypus
Most asthmatics have symptoms of seasonal or perennial allergic rhinitis [142]; therefore, these two entities are considered to constitute one complex syndrome of asthma and allergic rhinitis, characterized by Th2 inflammation [145].Rhinitis is also common in nonallergic asthma [146].Chronic rhinosinusitis (CRS) occurs in 1/3 of patients with severe asthma [147], predominantly neutrophilic (>64%) [148], and 20% additionally have nasal polyps [149].The evidence has shown that chronic rhinosinusitis worsens asthma symptom control, increases the frequency of exacerbations, and impairs quality of life [150], while medical and surgical treatment improves the clinical course of severe asthma [142].The use of monoclonal antibodies, including omalizumab, mepolizumab, and dupilumab, in the treatment of CRS with polyps is promising, which in randomized clinical trials has been shown to be effective in reducing the size of polyps and, consequently, symptoms [151].

Obstructive Sleep Apnea (OSA)
Both obesity [152] and severe asthma increase the risk of obstructive sleep apnea, with an odds ratio of 4.36 for severe and difficult-to-control asthma [153].OSA was more likely to occur in the neutrophilic phenotype and was associated with more self-reported asthma symptoms, more frequent use of β2-agonists [154], and a higher risk of exacerbations [155].There is evidence that treating OSA with continuous positive airway pressure (CPAP) reduces systemic inflammation and asthma symptoms, thereby improving both asthma control and obesity [156,157].

Gastroesophageal Reflux Disease (GERD)
The prevalence of GERD in patients with asthma increases with severity and accounts for 21% and 46-63% of mild-to-moderate and severe asthma, respectively [142].Moreover, obesity was associated with a higher incidence of GERD among patients with severe asthma [123].Gastric acid micro-aspirations present in reflux contribute to increased bronchoconstriction by activating the vagus response [158] and increasing AHR indirectly by inducing airway chronic neutrophilic inflammation [159], which may lead to poorer asthma control and more frequent exacerbations [142].On the other hand, bronchodilators, including beta-agonists, anticholinergics, and methylxanthines, reduce the tone of the lower esophageal sphincter, worsening reflux symptoms [160].Evidence has demonstrated conflicting results regarding clinical improvement of asthma with proton pump inhibitors (PPIs), with most showing little or no treatment effect, although none of the studies focused on obese asthmatics [157].
For this reason, GINA does not recommend the systematic use of PPIs in uncontrolled asthma with asymptomatic GERD [1].In addition, the evidence supporting the effectiveness of surgery in adults with GERD and concomitant asthma is currently insufficient [161].
In summary, it seems clinically important to treat GERD with proton pump inhibitors only when symptoms of reflux disease occur.

Diabetes Mellitus Type 2 and Metabolic Syndrome
Abdominal obesity is one of the components of metabolic syndrome (MetS), and the others include: dyslipidemia (hypertriglyceridemia or low HDL), hyperglycemia or treated diabetes, and elevated blood pressure > 130/85 mmHg or treated hypertension, and ≥3 of the above features must be present to be diagnosed [162].The incidence of MetS is high in asthmatic patients; however, there was no significant relationship between the incidence of the syndrome and the severity of asthma [163,164].Asthmatics with metabolic syndrome after bariatric surgery had less improvement in asthma control compared to those without metabolic syndrome, which may be due to greater systemic inflammation caused by metabolic dysregulation [165].
Lipid disorders often accompany obesity [162].A study of 85,555 people found that wheezing was positively related to BMI, waist circumference, a high TG level, high blood pressure, and metabolic syndrome, but inversely related to s-HDL [166].Moreover, it has been observed that low HDL levels in childhood may be associated with an increased risk of asthma in adolescence [167].Previous analyses found no effect of statins on improving asthma [166]; however, a more recent meta-analysis of 11 randomized and 8 observational studies showed improved asthma control on the ACT and ACQ questionnaires and a reduction in asthma-related ED visits in patients taking statins compared to placebo.No improvement in lung function (FEV1 and PEF) was observed [168].
There is evidence that asthma was associated with a 31% higher risk of DMt2 (OR = 1.31); however, this relationship weakened when BMI was adjusted for (OR = 1.25) [169], suggesting that chronic inflammation is involved in the pathogenesis.Insulin resistance, a characteristic feature of obesity, may also contribute to worsening of asthma by blocking M2 muscarinic receptors, and increasing the release of acetylcholine from parasympathetic airway neurons causes bronchospasm [170].In addition, due to higher use of OCS and insulin resistance, severe asthma is associated with an enhanced incidence of diabetes compared to mild and moderate asthma [171].Concomitant diabetes worsens asthma control.Studies have shown a positive correlation between Hb1Ac levels and the risk of exacerbation [172] and hospitalizations [173].Hyperglycemia was associated with longer hospital stays due to exacerbations [174] and higher mortality [175].Moreover, taking metformin reduced the risk of asthma exacerbations and hospitalization [176].
The use of glucagon-like peptide receptor 1 (GLP-1R) analogues seems promising, as lower rates of asthma exacerbations and symptoms have been observed compared to other diabetic treatment [177].This may be related to their effect on weight loss, improvement of insulin sensitivity, and reduction of systemic inflammation [178].In an obese mouse model of asthma, the GLP-1R agonist reduced both eosinophilic airway inflammation through a decrease in the cytokines IL-4, 5, and 33, and neutrophilic inflammation through inhibition of NLRP3 inflammasome activity and suppression of IL-1β [179].In addition, a study using isolated human bronchi found GLP-1 receptors in the airway epithelium, mucous glands, inflammatory cells, and ASM of the mid-bronchial airways and observed a positive effect of GLP-1 agonists in modulating ASM contraction and improving AHR [180].Further investigations are needed to evaluate the benefits of using GLP-1 agonists in the treatment of asthma with comorbid obesity or diabetes.
In conclusion, treating obesity as one of the components of metabolic syndrome is important not only to improve asthma control and quality of life, but it may also reduce or eliminate other diseases that are part of metabolic syndrome.The use of GLP-1 analogues seems particularly promising in the therapy of diabetes and obesity.

Influence of Obesity on Asthma Management
In addition to exacerbating self-reported symptoms and worsening asthma control, obesity also affects the response to controller medications.A review of clinical trials on the effectiveness of conventional treatments for obesity-related asthma is discussed below.

Montelukast
Peters-Golden et al. showed a negative correlation between asthma control days (ACD) and increasing BMI, while the response to montelukast, as measured by ACD, was stable across all BMI categories, also after adjusting for placebo [181].This phenomenon may be due to the leptin-stimulated regulation of the production of leukotrienes, as demonstrated in studies on rats [182].In human observations, a positive correlation has been seen between BMI and an increase in leukotriene synthesis [183].On the other hand, a retrospective study comparing the response to treatment with fluticasone propionate plus salmeterol and montelukast alone showed higher FEV1 and better asthma control in the FP/SAL arm than montelukast across the BMI range [184].Further research is needed to determine the role of montelukast in the treatment of obesity-related asthma.

ICS and LABA/LAMA
Obese asthmatics, compared to lean individuals, are more likely to have severe persistent asthma, a significantly lower chance of achieving well-controlled asthma [185] despite the use of higher doses of ICS [186] and, therefore, more frequent use of controller medications, including ICS, LABA, and oral GCs [185].Obesity was also associated with a worse response to ICS and ICS + LABA in terms of FEV1 and the FEV1/FVC ratio, as well as less improvement in FeNO levels after ICS [187].In addition, Camargo et al. showed that obese asthmatics required longer treatment with ICS+LABA to achieve peak FEV1 compared to their lean counterparts [184].Additive tiotropium therapy improved peak FEV1 and trough FEV1 across all BMI categories in both moderate and severe symptomatic asthma patients; however, the most significant increase in FEV1 was observed in the former [188].
There is also evidence of significant differences in response to ICS treatment between eosinophilic and neutrophilic phenotypes, which can be used as a predictive factor.McGrath et al. showed an improvement in airway obstruction only in a group of patients with eosinophilic asthma after two weeks of intensive combined anti-inflammatory therapy with prednisone, inhaled budesonide, and zafirlukast [189].Similar results were obtained in another study where obese patients with uncontrolled eosinophilic asthma responded well to an increase in ICS, while their non-eosinophil/neutrophil counterparts experienced a worsening of control after intensification of ICS treatment [190].
Steroid hypo-responsiveness in the neutrophilic phenotype of obese asthmatics may be related to dysregulation of glucocorticoid receptors.It has been shown that the cytokine IL-17, the concentration of which increases in obesity and responses to neutrophil inflammation, upregulates the glucocorticoid-beta receptor (GR-β), which is a negative regulator of active GR-α [191].In addition, a decrease in the GRα/GRβ ratio was observed after incubation of adipocytes taken from obese patients in the IL-17A environment, compared to adipocytes obtained from lean individuals whose GR-α/GR-β ratio was enhanced after stimulation with IL-17A and IL-17F [192].
Another possible mechanism of GCS resistance is the reduced induction of MAP kinase phosphatase-1 gene expression in PBMC and BAL cells in response to dexamethasone, associated with enhanced TNF-α synthesis, which significantly decreased with increasing BMI.This effect was not seen in the non-asthmatic control group [193].

Biological Treatment
For two decades, a new biological therapy has been available, mainly aimed at the treatment of Th2 inflammation, including anti-IgE agents, such as omalizumab; antibodies directed against IL-5 receptors or anti-IL-5, such as benralizumab, mepolizumab, and reslizumab; anti-IL-4Rα agents, such as dupilumab, and anti-thymic stromal lymphopoietin antibodies, such as tezepelumab [1].However, conventional Th2 inflammation biomarkers are altered in obesity, with an inverse relationship between FeNO and BMI associated with increased oxidative stress in obese individuals [194].In addition, poor correlation was observed between serum eosinophilia, total IgE, FeNO, and sputum eosinophilia [195].This may cause difficulties in the diagnosis of Th2 inflammation in obese asthmatics, and thus delay the implementation of appropriate biological treatment.
Concerning the heterogeneity of pathogenesis of the obesity-related asthma, it might be expected that the biological treatment may not be as effective in obese asthmatics; however, the evidence is conflicting.GuC et al. [196] showed an improvement in asthma control, as measured by the Asthma Control Test (ACT), after omalizumab administration in all BMI groups, but they observed that the BMI among responders was significantly lower than among non-responders, most of whom were obese.Moreover, an increase in FEV1% predicted and FVC% predicted was found only in non-obese patients [196].Similar observations were performed on a larger group of 340 people by Sposato et al., noting a reduced response of omalizumab to FEV1, FVC, ACT, and FeNO in obesity [197].In contrast, a prospective study of patients treated for 12 months with omalizumab demonstrated significant improvements in asthma control, lung function, a reduction in the daily dose of budesonide, and statistically significant weight loss, but the evidence was limited due to the small cohort (32 subjects, including 19 obese) [198].Furthermore, omalizumab dosing is individualized based on serum IgE concentration and body weight according to a specific drug registration table, which may be problematic in obese patients with high IgE concentrations, as the lack of sufficient data precludes dosing in this group of patients [199].
Another biological drug dosed depending on body weight is reslizumab.Unfortunately, there is still no data on the relationship between its effectiveness and BMI.In an observational study of 134 patients with severe eosinophilic asthma, 30.5% of whom were obese, only a minority of patients (13.6%) did not improve with reslizumab, while the rest showed reduced asthma exacerbations, use of OCS, and reliever medication, and improved lung function [200].
Conflicting reports also apply to mepolizumab.The DREAM study in cluster 4 of patients with the late-onset asthma phenotype (mean age of diagnosis 32 years, with the highest BMI, number of exacerbations, and airway reversibility, and the lowest FEV1) showed a 67% diminution in exacerbations, significantly greater than non-obese counter-parts in other clusters [201].On the contrary, a more recent post hoc analysis of data from the Phase IIb/III trials DREAM, MENSA, SIRIUS, and MUSCA showed a reduction in exacerbation rates and improvements in lung function, asthma control, and quality of life notwithstanding comorbidities, including obesity [202].
Regarding the anti-IL5 receptor antibody, a poorer response to benralizumab was observed in reducing annual exacerbations in patients with a BMI > 35 kg/m 2 [203].Interestingly, in the study comparing reslizumab, mepolizumab, and benralizumab, a statistically significant decrease in body weight was demonstrated after six months of all the above treatments, more pronounced in people with an initial BMI > 30 kg/m 2 .This may have been related to the reduction in exacerbations and the use of OCS; however, due to the small sample size, the clinical relevance of this study is unclear [204].
A post hoc analysis of the QUEST phase III study of dupilumab, including 1584 patients with elevated biomarkers of Th2 inflammation, showed a reduction in the annual rate of asthma exacerbations, regardless of demographics, such as age of onset or BMI, with the greatest treatment effects in those with higher serum eosinophils and FeNO [205].
The latest therapy registered by the European Union in September 2022 is an antibody against thymic stromal lymphopoietin (TSLP), a cytokine that is involved in both driving Th2 inflammation and Th2-independent mechanisms [206].Its concentration is positively correlated with the severity of asthma, the degree of airway obstruction, and resistance to glucocorticoids [206,207].The PATHWAY and NAVIGATOR studies have demonstrated a reduction in the annual rate of exacerbations, blood eosinophils, FeNO, and IgE, and improvement in FEV1 and quality of life, regardless of the baseline blood eosinophil level (also in the group < 300 cells/µL), which may be a promising treatment in the non-eosinophilic asthma phenotype [208,209].Unfortunately, there are no large studies assessing the effects of tezepelumab in patients with obesity-related asthma.
A summary of clinical studies on the effectiveness of conventional treatments for obesity-related asthma is provided in Table 3.

Other Approaches to Severe Asthma Management
Current treatment strategies for asthma in obese patients are mainly based on maximizing therapy with inhaled glucocorticoids and bronchodilators.In severe asthma, biological treatment and the use of systemic glucocorticoids are also possible.Targeted treatment strategies for obesity-related asthma are still lacking.The research results of possible other treatments for severe asthma are presented below and summarized in Table 4.

Macrolide Antibiotics
In the guidelines, GINA recommends considering adding azithromycin to ICS-LABA therapy in persistent symptomatic asthma, administered three times a week for at least six months, after checking the status of mycobacteria in the sputum [1].Evidence from the AMAZES study showed that in patients with both eosinophilic and non-eosinophilic asthma on medium to high doses of ICS plus LABA, azithromycin reduced exacerbation rates and improved quality of life [210].In contrast, in the AZISAST study, a diminution in the risk of exacerbations and lower respiratory tract infections was observed only in the severe non-eosinophilic asthma, while an improvement in quality of life was reported in both phenotypes [211].Macrolides, apart from anti-infective activity, also have antiinflammatory effects: they inhibit the activation of NF-κB and secretion of IL-8 [234], promote phagocytosis [235], and suppress the dysregulation of the TNF pathway [236], contributing to the reduction of neutrophilic inflammation [212].

Roflumilast
Roflumilast is a type 4 cAMP phosphodiesterase inhibitor included in the treatment regimen for chronic obstructive pulmonary disease.However, its anti-inflammatory effect, inhibiting subepithelial fibrosis and ASM hypertrophy, and thus positively affecting remodeling of the airways and reducing AHR, may be used as an additive therapy in asthma [237].Evidence has shown that roflumilast reduces both eosinophilic and neutrophilic allergen-induced inflammation [213], and in combination with montelukast, improves lung function and symptom control in mild-to-moderate, inadequately controlled asthma.However, this study did not evaluate efficacy in moderate-to-severe asthma, which would be worth investigating in future studies [214].

Bronchial Thermoplasty
An alternative form of treatment for adults with severe asthma that remains uncontrolled despite optimal treatment with high doses of ICS + LABA, available in some countries and included in the GINA guidelines, is bronchial thermoplasty (BT) [1].This is a method aimed at reducing ASM hypertrophy, consisting of three sessions of targeted local radiofrequency pulse performed during bronchoscopy at three-to four-week intervals in specialized centers [238].Patients qualified for this procedure should be in a stable period of the disease, without exacerbations within two weeks before the procedure and recurrence of lower respiratory tract infections a year before BT, due to the increased risk of infection and deterioration of the condition and hospitalization during the three-month treatment period.Despite these limitations, studies evaluating the safety and effectiveness of BT have shown that this procedure was associated with significant improvements in ACQ and AQLQ [228,229], and a reduction in the incidence of severe exacerbations and emergency department visits [229][230][231][232].However, data regarding the increase in FEV1 are contradictory [228][229][230][231][232].
A recent study assessing the effect and safety of BT ≥ 10 years after BT, which enrolled 192 of 429 patients from the AIR, RISA, and AIR2 research, showed a similar frequency of severe exacerbations at the BT10+ visit as at one year post-procedure [233].Likewise, quality of life and lung function were similar at one, five, and ten years after BT.In the AIR2 study, an additional HRCT examination was performed, which showed that six (7%) participants were diagnosed with new bronchiectasis (five participants mild and one moderate) [233].
In summary, bronchial thermoplasty may be considered in special cases of patients with severe asthma, uncontrolled by conventional treatment methods, performed in selected centers with experience in its implementation.

Conclusions
Asthma and obesity are two diseases whose coexistence aggravates each other's course.Their incidence is constantly increasing, posing a serious burden to public health.Our understanding of the pathogenetic mechanisms of asthma and obesity and their interaction is expanding, but there are still many unexplored areas.Future research should focus on better detailing the clinical and molecular features of obesity-related asthma phenotypes and finding specific biomarkers, especially in low Th2 inflammation.Despite the paradigm of the increasingly popular approach to treatment according to precision medicine and the observed lower effectiveness of anti-asthmatic drugs in obese patients, individualized treatment regimens for obesity-related asthma are still lacking.This is certainly a challenge for the future.

Figure 1 .
Figure 1.Obesity and its impact on the course of asthma.up arrow-increase; down arrow-decrease.

Figure 2 .
Figure 2. Pathophysiology of airway remodeling related to cytokine secretion by adipose tissue.up arrow-stimulation of cytokine/cell production; down arrow-suppression of cytokine/cell secretion.

Figure 2 .
Figure 2. Pathophysiology of airway remodeling related to cytokine secretion by adipose tissue.up arrow-stimulation of cytokine/cell production; down arrow-suppression of cytokine/cell secretion.

Table 2 .
Asthma phenotypes in obesity and a summary of their characteristic features.

Table 3 .
Summary of clinical trial results regarding the effectiveness of conventional methods of treating asthma with comorbid obesity.

Table 4 .
Summary of research findings on other possible treatments for severe asthma.