Asthma is a common chronic respiratory disease affecting 262 million children and adults worldwide in 2019, with high mortality in low and lower-middle-income countries (Global Initiative For Chronic Obstructive Lung Disease, 2023). Asthma is a heterogeneous noncommunicable disorder characterized by airway inflammation, airway hyperresponsiveness (AHR), bronchoconstriction, wheezing, and mucus hypersecretion (Haldar et al., 2008). It manifests with respiratory symptoms and airflow obstruction that vary in severity and impact on quality of life. Metabolic and cardiovascular conditions, especially obesity, diabetes mellitus, and atrial fibrillation contribute to the heterogeneity of severe asthma (Boulet and Boulay, 2011). Moreover, nearly 60% of patients with severe asthma are experiencing obesity, complicating the diagnosis, pathobiology, and treatment of their asthma (Peters et al., 2018).

While most patients with asthma see improvements in their symptoms through inhaled corticosteroids (ICSs) and long-acting beta2-agonists (LABA), adults and children experiencing obesity have increased recurrent exacerbations despite maximum dose treatment (Henderson et al., 2020). These patients demonstrate glucocorticoid resistance and poor asthma control with increased asthma severity, consuming a disproportionately high amount of healthcare resources for their asthma management (Henderson et al., 2020). These patients are defined as having severe asthma and are under consideration for alternative therapies. Alternative therapies focusing on controlling severe asthma target pathobiological mechanisms contributing to asthma severity and responsiveness to usual therapies (Ernst and Posadzki, 2012). Several pathways have gained attention, but specifically, the use of monoclonal antibodies to target components of Type-2-high (T2-high) airway inflammation have emerged as effective therapies for a subset of asthma patients. The T2-high endotype describes the degree (high) of type 2 lymphocytes (CD4⁺), innate lymphoid cells group 2 (ILC2s) and type 2 cytokines (interleukin [IL]-4, IL-5, and IL-13) that drive airway inflammation through increasing eosinophils, basophils, and mast cells in the airways (Moore et al., 2010; Kuruvilla et al., 2019a; Kaur and Chupp, 2019). Over the last 25 years, biological therapies have revolutionized severe asthma by targeting T2-high severe asthma to reduce asthma exacerbations, but little research has evaluated the efficacy of these therapies in patients with asthma and comorbid obesity.

Given that both asthma and obesity are on the rise, and these patients are relatively unresponsive to standard medications, clinicians are investigating alternative medications such as biological agents. Thus, understanding the effectiveness of using biological agents in patients with asthma with comorbid obesity would impact asthma management in this challenging patient population. This review is aimed to examine and explain the effectiveness of approved biological agents in people with asthma with comorbid obesity and provide an overview to help clinicians select medications to manage T2 severe asthma phenotypes exhibiting comorbid obesity.

Our understanding of T2-high asthma has matured over the last two decades, with key findings for biomarkers representing this phenotype: bronchoalveolar lavage (BAL) fluid, blood and sputum eosinophilia, high levels of serum immunoglobulin-E (IgE), and high fractional exhaled nitric oxide (FeNO) measurements (Dunican and Fahy, 2015a; Fahy, 2015a). Patients presenting with inflammation defined by T2-high immune responses comprise 50%–70% of the severe asthma patient population (AllergyAsthma Network, 2023). In these patients, the airway is characterized by chronic eosinophilic inflammation, excessive T2 cytokine (IL-4, IL-5, and IL-13) release, increased activation of T-helper 2 cells (Th2) and ILC2s, and pathologic interplay of neutrophils, basophils, lymphocytes, dendritic cells, and mast cells (Fahy, 2015a; Gandhi et al., 2016; Busse et al., 2021).

Severe asthma is a heterogenous disease, and recent efforts to classify phenotypes of severe asthma have focused on T2 inflammatory markers as defining characteristics. Allergen-sensitized asthma is typically characterized by early age of asthma onset (<12 years of age) and the production of elevated allergen-specific IgE, with the majority of patients being responsive to corticosteroid therapy (Walford and Doherty, 2014). This phenotype causes more severe disease, AHR and eosinophilia through Th2 cell and ILC2 activation, and T2 cytokine secretion (Romanet-Manent et al., 2002). Non-allergic/T2-low sensitized asthma is typically characterized by late age of asthma onset (≥12 years of age) that does not display elevated serum IgE levels (Hurwitz, 1955). T2-low asthma is more arbitrarily defined as asthma without features of T2 cytokine-driven inflammation. Acute severe exacerbations are less responsive to corticosteroids in the non-allergic phenotype (Klain et al., 2022). T2-low asthma has been reported to comprise about 20% of the severe asthma patient population and occurs more frequently in late-onset females with obesity (Ricciardolo et al., 2021a). It is associated with Th1 and Th17 cell-driven, neutrophilic airway inflammation, and elevated quantities of cytokines IL-1β, IL-6, IL-8, IL-17, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) involved in its pathobiology (Hinks et al., 2021; Ji and Li, 2023). T2-low asthma is difficult to define due to the lack of signature biomarkers and is primarily diagnosed based on the absence of or very reduced levels of eosinophils and other T2-driven inflammation markers and relatively high levels of neutrophils in sputum (Rupani et al., 2021). However, recent reports of longitudinal real-world severe asthma cohorts demonstrate that the T2t1-low asthma phenotype may be rare compared to the T2-high phenotype, as the vast majority of severe asthma patients exhibited elevated eosinophilic inflammation and other T2 biomarkers at times over a 10-year period (Azim et al., 2021; Heaney et al., 2021; Rupani et al., 2023). Thus, patients described as T2-low may actually have an underlying T2-high phenotype that is masked at the time of sampling, and the simplified T2-high/T2-low paradigm should be expanded to include other cellular/molecular pathways to define asthma phenotypes.

Infections, bacteria, smoking, and atrial fibrillation can provoke severe non-allergic asthma (Ricciardolo et al., 2021b). Patients with T2-low asthma, compared to the T2-high asthma phenotype, do not respond as well to current standard treatments for asthma, such as ICS, LABAs, and higher-level treatments such as biologics (Ricciardolo et al., 2021b). Knowledge of the various and distinct asthma pathobiology phenotypes is continuously growing; however, the underlying mechanisms of severe asthma pathogenesis are not yet completely understood. Further research is needed to understand the cellular and metabolic processes of all phenotypes of severe asthma and to find specific interventions to best treat patients according to their specific endotypes.

T2 immune responses in the airway are mediated primarily by eosinophils, dendritic cells, mast cells, Th2 cells, ILC2s, and IgE-producing B-cells (Koyasu and Moro, 2011; Walker and McKenzie, 2018). After exposure to an allergen, the T2 immune response is initiated upstream by alarmins, IL-33, IL-25, and thymic stromal lymphopoietin (TSLP) (Koyasu and Moro, 2011; Walker and McKenzie, 2018). They stimulate migration of ILC2s to the airway epithelium and subepithelial mucosa and regulate the differentiation of native Th cells (Th0) into Th2 cells (Barnes, 2001). ILC2s also secrete Type 2 cytokines (IL-4, IL-5, and IL-13) that promote AHR and mucus overproduction (Table 1) (Walker and McKenzie, 2018; Akdis et al., 2020). These T2 cytokines drive a cascade of downstream events, including activating airway epithelial cells, switching B cell-secreted IgG to IgE, and inducing exaggerated responses to inhaled agents, causing remodeling changes in the airway (Fahy, 2015a). The relevant pathological remodeling changes are smooth muscle hypertrophy, goblet cell metaplasia, and subepithelial fibrosis (Dunican and Fahy, 2015a). The distinct functions of T2 cytokines and the interrelationship between asthma exacerbations and airway remodeling in T2-high asthma are of considerable interest and clinical relevance (Figure 1).

The incidence of obesity has tripled in the US in the past 40 years, and body mass indices (BMIs) have nearly doubled from the pre-pandemic rate (Office of the Surgeon General US, 2010). Nearly 70% of adults exhibit either overweight or obesity, with more than 30% of those having obesity (NHLBI Obesity Education Initiative Expert, 1998; National Institute of Diabetes and Digestive and Kidney Diseases, 2021; USAFacts, 2023). Obesity is defined by a BMI greater than 30 kg/m² and is typically characterized by excessive adiposity (Nuttall, 2015). Despite the reliance of this clinical definition of obesity on BMI, the measure has serious limitations for describing body composition, which is influenced not only by adipose tissue, lean muscle and bone mass and does not capture the heterogeneity of obesity phenotypes, including differences in body composition (Bray, 2023). Waist circumference is a more reflective measure of central adiposity than BMI, and body fat distribution may be more accurately measured using dual x-ray absorptiometry (DXA), computed tomography (CT) or magnetic resonance imaging (MRI) (Bray, 2023). Still, BMI provides a standard measure by which to track populations of patients and to serve as a base indicator of individual metabolic health (Bray, 2023).

Obesity often exists alongside asthma and within the context of other comorbidities (gastroesophageal reflux disease [GERD], metabolic syndrome, diabetes, cardiovascular disease, obstructive sleep apnea, anxiety and depression, etc.,.) (Pandya et al., 2014). These concurrent conditions may affect long-term clinical presentation of asthma and influence the effect of asthma-focused biologic drug delivery and efficacy. Evidence from both human clinical trials and mouse models of asthma demonstrate bidirectionality of various comorbidities in altering systemic and airway immune responses, including those targeted by biologic therapies (Thomas et al., 2010; Broytman et al., 2015; Tariq et al., 2019; Fernández-Gallego et al., 2022; Wang et al., 2022; Hou et al., 2023). For example, the presence of GERD reduced airway production of several T2 cytokines in a mouse model allergic airway disease and markedly altered airway production of proteins involved in inflammatory responses in patients with severe asthma (Thomas et al., 2010; Tariq et al., 2019). Moreover, chronic intermittent hypoxia, as experienced in obstructive sleep apnea, reduced airway levels of IL-5 and increased Type1 inflammation (Broytman et al., 2015; Ohta et al., 2020). Also, multimorbidity may lead to misdiagnosis, undertreatment or overtreatment of asthma. A recent study found that 36% of patients with obesity were misdiagnosed with asthma by physicians (Scott et al., 2012). In addition, comorbid conditions, including obesity, may lead to polypharmacy with negative effects on efficacy of long-term treatments, such as biologics, by reducing adherence and increasing risk of adverse events (Ye et al., 2022). Thus, the complex interplay of the pathobiology of asthma, obesity and other comorbid conditions that impact immune responses must be considered in aggregate when developing diagnoses and therapeutic strategies.

Indeed, certain asthma treatments increase the risk of developing comorbid conditions, including obesity. Children and adolescents with asthma and comorbid obesity are 24% more likely to be unresponsive to bronchodilators, even when given systemically (Peters et al., 2018). Despite poor response, they are often treated with these drugs for long periods of time, only worsening obesity and metabolic dysfunction. Oral corticosteroids (OCS) are commonly prescribed for severe asthma, but patients on these drugs are at significantly increased risk for weight gain, among other adverse effects (Price et al., 2018; Kulkarni et al., 2022). Initiation of biologic therapies reduces the use of systemic corticosteroids (Chen et al., 2023). Moreover, long-term weight reduction was associated with biologic therapy in patients with severe eosinophilic asthma, an effect that was attributed to reduced OCS use. The greatest weight loss was observed in patients that had the highest exposure to OCS before initiating biologic therapy combined with a reduction in OCS dose during treatment (Ten Have et al., 2023). Therefore, biologic therapies could be particularly beneficial for OCS-treated asthma patients with obesity in mitigating both comorbid conditions.

Asthma is more severe in patients with obesity than in lean patients (Sharma and Cowan, 2021). Patients with asthma and comorbid obesity may be classified in two endotypes according to age of asthma onset: one with early-onset asthma (<12 years of age) with obesity as a complicating factor or even a consequence of asthma and the other with late-onset asthma (≥12 years of age), which is associated with the development of obesity prior to the onset of asthma (Holguin et al., 2011; Sideleva and Dixon, 2014). While mechanisms of asthma pathobiology in patients with comorbid obesity are not fully understood, it may be attributed to altered cell signaling and inflammatory mechanisms inherent in obesity. The manifestation of airway remodeling could be provoked by an abnormal accumulation of T2 cytokine–producing cells and eosinophils in visceral adipose tissue (Figure 2).

The mechanical properties of the lungs and chest are significantly altered in obesity. The mechanisms behind the reduction in the respiratory drive in obesity and asthma have not been clearly elucidated. Obesity causes adipocytes to undergo hypertrophy, resulting in inadequate perfusion of enlarged adipose tissue, hypoxia and apoptosis (Kang et al., 2023; Luk et al., 2023). Various researchers have studied obesity and its relation with lung volumes and found that obesity causes an accumulation of fat in the thoracic and abdominal cavities which is associated with increased pleural pressures secondary to restricted downward movement of the diaphragm and outward movement of the chest wall (Ladosky et al., 2001; Jones and Nzekwu, 2006; Melo et al., 2014; Dixon and Peters, 2018). This fat accumulation alters the breathing pattern resulting in a substantial reduction of functional residual capacity (FRC); the volume remaining in the lungs after a normal, passive exhalation; expiratory reserve volume (ERV); the volume of air that can be forcefully exhaled after a normal resting expiration, and tidal volume (TV); the volume of air that moves in and out of the lungs with each respiration (Ladosky et al., 2001; Jones and Nzekwu, 2006; Melo et al., 2014; Dixon and Peters, 2018). Obesity has very little effect on residual volume (RV); the volume of air remaining in the lungs after maximum forceful expiration; and total lung capacity (TLC); the volume of air in the lungs upon the maximum effort of inspiration (Ladosky et al., 2001; Jones and Nzekwu, 2006; Melo et al., 2014; Dixon and Peters, 2018). Obesity is proposed to cause a substantial increase of inspiratory reserve volume (IRV), the amount of air that can forcefully be inhaled after a normal volume, because of increased workload of the intercostal muscles (Figure 2) (Ladosky et al., 2001; Jones and Nzekwu, 2006; Melo et al., 2014; Dixon and Peters, 2018).

Recent studies have shown increased numbers of proinflammatory macrophages as well as elevated concentrations of the pro-fibrotic adipokine, leptin, TNF-α, and IL-6 in bronchoalveolar lavage fluid (BALF) and blood from adolescents and adults with severe asthma (Stream and Sutherland, 2012; Sutherland et al., 2012; Farzan, 2013), contributing to disease severity and diminished responsiveness to prescribed therapies. Obesity causes rapid adipose tissue expansion, leading to the activation of hypoxia-inducible factor 1-alpha (HIF1-α) (He et al., 2011). Hypoxic death of adipocytes promotes fibrosis and proliferation of M1 macrophages that induce pro-inflammatory activity (Weisberg et al., 2003). The number of adipose macrophages in non-obese patients is 4% but can reach up to 12% in patients with obesity (Weisberg et al., 2003). With the elevation of adipose M1 macrophages, pro-inflammatory cytokines are activated and attract fibroblasts and more pro-inflammatory cells (Boutens and Stienstra, 2016). Notably, Th17 lymphocytes are also elevated in adipose tissue, which release IL-6 and IL-17, inducing the polarization of T cells into Th17 cells and reducing secretion of the anti-inflammatory adipokine, adiponectin (Boutens and Stienstra, 2016). Adiponectin suppresses differentiation and activation of M1 macrophages, contributing to a decreased inflammatory process (Boutens and Stienstra, 2016). Little is known regarding the influence of these obesity-related inflammatory pathways on the efficacy of asthma biologics and whether measurement of serum IL-6, IL-17 or adiponectin levels may predict response to biologic therapies in patients with asthma. These gaps in knowledge represent important areas of future research.

Asthma severity in patients with obesity may be directly addressed through weight loss. Studies have shown that a 5% decrease in body weight can reduce airway inflammation (Johnson et al., 2022). However, obesity is increasing—by 2030, 51% of the US population is expected to exhibit obesity, a significant jump from the 38% population who have obesity in 2022 (Schneider et al., 2010; Finkelstein et al., 2012). In 2018, a higher proportion of adults with obesity had asthma (39%) than did not have asthma (27%) (Centers for Disease Control and Prevention, 2013). Weight loss through dietary modification and exercise is difficult. Bariatric surgery and pharmacologic interventions of patients with asthma result in improvement asthma control; however, long-term consequences are poorly understood, and these approaches must be accompanied by positive lifestyle management strategies to maximize benefits for asthma patients (Reddy et al., 2011). Dietary interventions carry the lowest risk of adverse events and are the core strategy to tackle obesity in a sustainable manner. Therefore, further understanding the interaction between asthma and obesity and its direct treatment options to improve asthma control is increasingly important.

T2-high asthma constitutes 60% of patients with severe asthma (AllergyAsthma Network, 2023). Patients with severe uncontrolled asthma have increased hospitalizations, poor quality of life, and impaired lifestyles compared to patients with controlled asthma (Johnson et al., 2022). Although T2-high asthma is generally a corticosteroid-responsive endotype, a substantial proportion of patients with asthma and comorbid obesity (44%) have persistent symptoms despite more than a year of ICS and LABA usage (Tashiro and Shore, 2019). Although ICS remains essential for managing acute exacerbations, the overuse of systemic corticosteroids is associated with adverse effects, including osteoporosis, immunosuppression, obesity, sleep apnea, arrhythmias, glaucoma, and depression (Yasir et al., 2023). Therefore, patients receiving the standard of care for severe asthma may remain poorly controlled.

However, over the past decade, this unmet need to improve severe asthma outcomes has led to a greater understanding of our knowledge of the complex pathophysiological mechanisms of severe asthma, leading to the development of new treatment options. Today, patients with uncontrolled severe T2-high asthma are routinely considered candidates for biologics, monoclonal antibody-based cytokine-targeted therapies (Votto et al., 2021). Unlike corticosteroids which target an unspecified range of cells, biological therapies specifically target inflammatory cytokines (IL-4, IL-5, and IL-13), of T2-high asthma (Votto et al., 2021). Biologics have the potential to modify the natural course of the disease without the collateral damages associated with ICS and LABA (Dragonieri and Carpagnano, 2021). While ICS inhibits IL-13, a high proportion of uncontrolled asthma patients have elevated levels of IL-13 in their sputum despite treatment with high dosage ICS (Saha et al., 2008). The impact of biological therapies on asthma control and corticosteroid dependence has led researchers to consider asthma remission as a possibility. Recent evidence has identified a new phenotype, super-responders, for patients taking biologic treatments. Super responders are defined by a group of patients with a more rapid response to a certain treatment leading to better asthma control and quality of life (Portacci et al., 2023). The super responder rate is estimated to be between 14% and 44% and more commonly is observed in patients with male sex, no smoking history, a lower BMI, higher T2 biomarker levels, and a later age of disease onset (Jane McDowell et al., 2023; Portacci et al., 2023). Obesity influences potential for asthma remission on biological therapies, with a 47% lower frequency of remission in patients with obesity compared to patients without obesity (Jane McDowell et al., 2023).

As mentioned above, biologic therapies influence long-term (2-year) weight loss through sparing of OCS, which contributes to weight gain as a side effect (Ten Have et al., 2023). Significant weight loss following initiation of anti-IL-5 therapies in the short-term (6–11 months) has been reported, but these findings were not replicated in a separate study (Kuruvilla et al., 2019b; Cusack et al., 2021). Regardless, a subgroup of asthma patients has been identified that gained a significant amount of weight at the short- or long-term time points in the studies (Kuruvilla et al., 2019b; Cusack et al., 2021; Ten Have et al., 2023). The factors contributing to this weight gain in the subgroup are likely complex and postulated to be due to depletion of eosinophils by anti-IL-5-targeted biologics, influencing adipose tissue homeostasis and body weight (Calco et al., 2020). More research is needed to understand the mechanisms driving weight gain and loss in association with biologics in asthma with comorbid obesity.

Biological therapies were first introduced with an anti-IgE monoclonal antibody, omalizumab, and now have subsequent biological agents aimed at different inflammatory modulators, including IL-4 receptor alpha (IL-4Rα), IL-5, IL-5 receptor alpha (IL-5Rα), IL-13, and TSLP (Pelaia et al., 2018a; Guntern and Eggel, 2020). These drugs block specific immunological pathways triggering allergic airway inflammation (Pelaia et al., 2018a; Guntern and Eggel, 2020). To date, the United States Food and Drug Administration (FDA) has approved six biologics for use in selected severe asthma patients: Omalizumab (anti-IgE); Mepolizumab, Benralizumab, Reslizumab (anti-IL5/anti-IL5R α ); Dupilumab (anti-IL4R α ); and Tezepelumab (anti-TSLP) (Guntern and Eggel, 2020).

Recent developments in therapeutic strategies and improved understanding of asthma pathogenesis have provided alternatives to corticosteroids as the cornerstone treatment for asthma control. The past two decades have witnessed a heightened development of novel biological anti-cytokine monoclonal antibodies therapies to target eosinophilic inflammation for the management of severe asthma. Even so, new biological agents are being developed especially focusing on non-eosinophilic asthma and alternative, non-T2 inflammatory pathways. While immense improvements in clinical outcomes are observed with the currently FDA approved biologics, a significant disease burden remains from limited understanding of the mechanisms that underly the association between asthma and obesity. While most of the FDA-approved biological therapies target pathways of T2 inflammation downstream of T-helper 2 cell activation, modest asthma control has led researchers to study upstream alarmin cytokines, including IL-25, IL-33, and TSLP. For example, a recent phase II trial showed that Ipetekimab, an anti-IL-33 monoclonal antibody, improved asthma control, lung function, quality of life, and lowered blood eosinophil count (Wechsler et al., 2021). Additionally, in a recent phase IIb randomized control trial (RCT) of patients with moderate-to-severe asthma, amlitelimab, a fully human monoclonal antibody that binds to OX40 receptor and its cognate ligand OX40L, impedes T2 polarization of naive T cells (Lé and Torres, 2022; ClinicalTrials.gov, 2023). In a study done by Arestides et al, they found that Tnfsf4 ^−/− ovalbumin-sensitized mice (null for OX40L) had a significant reduction in total serum IgE, pulmonary eosinophils, cytokines, and pulmonary inflammation compared with wild-type control mice (Arestides et al., 2002). Thus, continued research to increase understanding of the type 2 immune response in the airways of asthma patients will reveal promising targets for development of new biologic therapies.

Additionally, alternative methods to deliver biologic therapies are being evaluated. To increase the bioavailability of drugs in the body, researchers are studying nebulized biologic therapy. In a study conducted by Hacha et al, the authors evaluated the efficacy of an anti-IL-13 monoclonal antibody in a mouse model of allergic asthma (Hacha et al., 2012). They found that nebulization significantly decreased bronchial hyperresponsiveness and BALF eosinophilia (Hacha et al., 2012). Moreover, inhaled anti-TSLP has been proposed as an alternative administration route. Ecleralimab (CSJ117) represents the first inhaled anti-TSLP antibody that prevents TSLP receptor activation inhibiting downstream inflammatory signaling cascades (Hacha et al., 2012). It is formulated as powder in hard capsules for administration in the airways through a Diskus^® (Dry-powder inhaler) (Novartis Pharmaceuticals, 2021). In a Phase IIa trial, ecleralimab reduced allergen-induced bronchoconstriction with mild asthma (NCT04410523) (Novartis Pharmaceuticals, 2021). Nebulizing biological therapies could represent a novel and effective therapy for the treatment of asthma; however, further research needs to be done to investigate the efficacy of these delivery methods in patients with severe uncontrolled asthma.

With rising rates of obesity in the United States, epidemiological data indicates that obesity increases the prevalence and incidence of asthma (Centers for Disease Control and Prevention, 2013). Patients in this subgroup will exhibit more severe, poorly controlled asthma, significantly burdening the healthcare system (Henderson et al., 2020). However, the underlying pathophysiologic mechanisms in which obesity changes asthma are not well understood.

The field of asthma has undergone a radical transformation over the past two decades. Obesity-induced asthma is known to disrupt routine treatments, causing these patients to be resistant to corticosteroids. However, the advent of monoclonal biological therapies has revolutionized the management of severe asthma. Important research has shown the clinical benefits of currently approved monoclonal antibodies on altering levels of biomarkers of type 2 inflammation in lean patients. These patients exhibit significant improvements in asthma exacerbations, lung function, and blood eosinophil count following biologic therapies. Biologics offer a safe, highly effective treatment plan for patients with significant unmet needs through routine treatment. The success of biological therapies deepens our understanding of type 2 airway inflammation and its importance in the pathobiology of asthma.

While biological therapies are an important treatment of asthma patients, none of them are heavily studied or directed specifically toward asthma patients with obesity. Weight-based dosing may improve efficacy of biologics in the population of patients with obesity by optimizing the safety and bioavailability of the drug compared to standard dosing. Research shows that tissue composition is likely to affect drug tissue distribution, absorption, and elimination; therefore weight-based dosing may be beneficial (Cheymol, 1993). Since the roles of IL-4/-13 are pleiotropic with effects on eosinophil transmigrations across endothelium, mucus secretion, B-cell immunoglobulin E production, and enhanced contractility of airway smooth muscle cells, biologic treatment targeting IL-4/-13 may effectively improve asthma in a broader population, not necessarily solely in patients with significant airway eosinophilia (Greenfeder et al., 2001; Castro et al., 2020; Ricciardolo et al., 2021c). Also, in patients with asthma and obesity, anti-IL-5 biologics may have limited effectiveness due to their specific effects on eosinophil maturation, activation, survival, and recruitment to the airway (Padilla Galo et al., 2018; Cinqair, 2023). These drugs to be more effective with weight-based dosing as the effectiveness of IL-5/IL-5R-targeted biologics is maximal in patients with airflow obstruction driven by luminal eosinophils (Pelaia et al., 2019a). Twenty-five percent of non-obese BMI patients with severe T2 asthma are non-responders to the fixed mepolizumab dosage (Özyiğit et al., 2020). Therefore, weight-based dosage may be beneficial as the fixed dose could be under-dosing patients with obesity.

Biologics targeting the alarmins, upstream pathways that initiate events of airway inflammatory and immune responses, have the potential to treat a broader subgroup of patients than the other currently approved biologics. Additionally, it is the only biologic that significantly reduces asthma exacerbations irrespective of key T2 biomarkers and does not target a specific phenotype (eosinophilic or allergic). Findings across clinical trials have shown that tezepelumab inhibits inflammatory biomarkers across diverse pathways causing more effective asthma control (Corren et al., 2017). Since researchers are not fully aware of the cellular and metabolic differences in the airway between lean patients with asthma and patients with asthma and obesity, the ability of tezepelumab to block a broader profile of inflammatory biomarkers may allow for greater reduction in asthma exacerbations in patients with obesity than other biologic therapies. A more precise understanding of patient characteristics and predictive biomarkers could help clinicians decide which biologics lead to the most beneficial response in patients with asthma and obesity. To do so, biomarker responses, asthma control questionnaire scores, and FEV1 should be measured monthly over the course of 2 years to evaluate short- and long-term benefits. These clinical indicators measured by asthma specialists will allow clinicians to execute a course of treatment for this subgroup of patients.

Another concern for biologic treatment of asthma patients with obesity is drug delivery. Efficacy of intramuscularly injected biologic therapies may be compromised in asthma patients with comorbid obesity if needle length is too short to penetrate through excess subcutaneous adipose tissue. Several studies point to significant differences in skin-to-deltoid-muscle distance depending on BMI, sex, injection site and arm circumference (Doppen et al., 2023a; Doppen et al., 2023b). Currently the CDC Guidelines on immunization practices recommend using a 5/8” needle, 23–25 gauge for all patients (Centers for Disease Control and Prevention, 2023). However, use of a standard needle length for all patients does not account for variations in body tissue composition. These differences are crucial because deposition of drug in adipose tissue could result in slower mobilization and processing of the drug, reducing drug bioavailability. In addition, obesity has the potential to affect the rate and extent of drug absorption (Erstad and Barletta, 2022). Further research is needed to evaluate the impact of needle length on efficacy of injected biological drugs in asthma patients with obesity.

While it is clear that the treatment of asthma patients with obesity must include weight control, future research is necessary to fully understand the complex interrelation between obesity and asthma. Many questions remain to be investigated and answered, especially with regard to understanding the efficacy of biological therapies in patient populations with asthma and comorbid obesity (Box 1). More explorations on the metabolic functions of airway cells in asthma patients with obesity, how weight gain affects treatment, and how weight-loss interventions, including medical interventions and bariatric surgery, affect efficacy of therapy are needed. By studying the interaction between the pathogenesis of both disorders, new therapeutic treatments can address the unmet needs of this patient population. Research on asthma and comorbid obesity is especially relevant today and will continue to be in the future as obesity rates are on the rise.