Introduction

Explor Asthma Allergy

EAA

Exploration of Asthma & Allergy

2837-5076

Open Exploration Publishing

10.37349/eaa.2025.100991

100991

Review

Evidence-based answers to clinical controversies in the management of severe asthma

https://orcid.org/0000-0003-4837-782X

El-Qutob

David

Writing—original draft Writing—review & editing Conceptualization ¹ ^† ^*

https://orcid.org/0009-0009-5967-0723

Maillo

Martin

² ^† Walsh

Garry M.

Academic Editor University of Aberdeen, UK

¹Unit of Allergy, University Hospital of La Plana, 12540 Vila-Real, Spain ²Instituto del Buen Aire, Santa Fe 2372, Argentina

†

These authors contributed equally to this work.

^*Correspondence: David El-Qutob, Unit of Allergy, University Hospital of La Plana, 12540 Vila-Real, Spain. elqutob@comv.es

2025

21 08 2025

100991

20 05 2025 06 08 2025

This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Asthma is a chronic inflammatory airway disorder characterized by recurrent symptoms, airflow obstruction, and bronchial hyperresponsiveness. Approximately 5–10% of asthma cases are classified as severe, requiring high-dose inhaled corticosteroids (ICS) plus additional controllers, often including systemic corticosteroids. Severe asthma imposes a substantial burden on patients due to frequent exacerbations and reduced quality of life. The pathophysiology of severe asthma involves distinct phenotypic and endotypic variations, primarily classified into high-type 2 (T2) and low-T2 inflammatory profiles. While high-T2 asthma, encompassing eosinophilic and allergic subtypes, benefits from targeted biologic therapies such as monoclonal antibodies against interleukin-5 (IL-5), IL-4/IL-13, thymic stromal lymphopoietin (TSLP), and IgE, treatment options for low-T2 asthma remain limited. The advent of precision medicine has facilitated the identification of novel biomarkers for severe asthma, guiding therapeutic decisions and enabling disease stratification. However, key clinical challenges remain, including selecting the most effective biologic therapy, optimal treatment duration, and safe de-escalation strategies upon achieving remission. This review explores the latest evidence on biological therapies, their immunomodulatory effects, and their potential role in reversing bronchial remodelling. Additionally, it discusses emerging biomarkers that may predict treatment response and remission, ultimately contributing to a more personalized approach to asthma management.

Severe biological airway eosinophilic asthma remodelling biomarkers

Introduction

Asthma is a chronic inflammatory disorder of the airways characterized by variable and recurrent symptoms, airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation. Asthma affects approximately 300 million individuals worldwide and poses a significant public health burden due to its impact on quality of life and healthcare costs [1]. The pathophysiology of asthma involves a complex interaction of genetic, environmental, and immunological factors, resulting in airway inflammation and remodeling [2].

Approximately 17% of asthmatics suffer from “difficult-to-treat asthma”, where poor control is attributed to factors such as suboptimal adherence to treatment, incorrect inhaler technique, smoking, or comorbidities like gastroesophageal reflux, chronic rhinosinusitis, obesity, and obstructive sleep apnea [3]. Severe asthma (SA), a subset of difficult-to-treat asthma, affects about 5–10% of the total asthma population. It is defined by the need for high-dose inhaled corticosteroids (ICS) plus a second controller and/or systemic corticosteroids to prevent it from becoming uncontrolled or that remains uncontrolled despite the high level of treatment [4]. This subset of patients experiences frequent exacerbations, persistent symptoms, and significant limitations in daily activities, often requiring intensive management and specialized care [5]. They need treatment with high-dose ICS plus a second controller with/without oral corticosteroids (OCS).

Despite confirmation of the diagnosis and adequate treatment of comorbidities and confounding factors, such as inhaler technique, adherence, risk factors, and triggers (allergens, air pollution, respiratory infections, and tobacco smoking), the desired outcome is usually not achieved [3]. Multiple phenotypes of SA have been identified, including type 2 (T2; high-T2 and low-T2) (Table 1).

Table 1

Key distinguishing features between type 2 (T2) and no-T2 or low-T2 asthma

High-T2 asthma	Type no-T2 or low-T2 asthma
Associated with eosinophilic inflammation	Associated with neutrophilic or pauci-granulocytic inflammation
Driven by Th2-type cytokines (IL-4, IL-5, IL-13)	Driven by other inflammatory pathways (e.g., IL-17, IL-8)
Often has elevated IgE levels	IgE levels are usually normal or low
More likely to be responsive to corticosteroids	Often resistant or less responsive to corticosteroids
Common in allergic asthma and late-onset eosinophilic asthma	Common in obese patients, smokers, and the elderly
Biomarkers: FeNO, blood eosinophils, periostin	Biomarkers: none well established or under investigation
Targeted by biologic therapies (e.g., anti-IL-5, anti-IL-4R)	Few targeted treatments are currently available
Often diagnosed via biomarker analysis	Diagnosis often relies on clinical assessment and exclusion

FeNO: fractional exhaled nitric oxide; IL-4: interleukin-4

High-T2 asthma is a subtype of SA characterized by a high level of T2 inflammation. This inflammation is primarily driven by eosinophils and allergic responses. High-T2 asthma includes early-onset allergic asthma, late-onset eosinophilic asthma (EA), and non-allergic asthma with aspirin-exacerbated respiratory disease (AERD) [6]. Elevated levels of eosinophils in the blood and sputum are associated with increased asthma severity, exacerbation rate, and airway remodeling [7]. T2 asthma represents approximately 70% of SA cases [8]. On the other hand, low-T2 phenotypes are related to obesity, the elderly, and/or smoking [9]. This phenotype is characterized by a predominance of neutrophilic or paucigranulocytic cellular infiltrates [10]. Currently, no biological therapy is approved for low-T2 asthma, but clinical trials with agents targeting interleukin (IL)-17 are ongoing [11].

The mechanisms involved in the development of asthma could be several and change over time.

Targeted therapies, such as monoclonal antibodies against IL-5 and its receptor, anti-IgE, anti-thymic stromal lymphopoietin (TSLP), and anti-IL-4/IL-13 have shown efficacy in reducing eosinophilic inflammation and improving clinical outcomes in patients with severe EA [12].

Early intervention and personalized treatment strategies are essential for effective management of SA. Identifying specific biomarkers and phenotypes can guide the selection of targeted therapies, optimizing patient outcomes and reducing the disease burden [13]. The integration of molecular diagnostics and precision medicine approaches is promising for advanced asthma management and improving the quality of life in SA patients [14].

Clinical remission is emerging as an important and ambitious goal in asthma management [15], and is a composite endpoint often defined as meeting 3 to 4 key pillars (control of asthma symptoms, optimization/stabilization of lung function, no exacerbations, and no OCS use) over a set period of time [16], and may include the role and definition of biological remission, such as low-T2 biomarkers or normal airway responsiveness [17]. However, its definition remains under construction.

In clinical settings where SA is treated, physicians often face challenges in translating scientific evidence into effective patient management. These difficulties are primarily due to the complex process of applying research findings to real-world practice. Clear, evidence-based answers to common clinical questions are therefore essential to guide asthma care. To address this need, a bibliographic review was conducted in PubMed, focusing on the most widely cited studies and established asthma management guidelines. This review aims to explore current controversies and unresolved questions in the management of SA with biological treatments, including the role of novel biomarkers and strategies for treatment de-escalation following disease remission.

Questions, controversies, and unmet needs Could we compare the efficacy among biologic treatments in high-T2 profiles?

Some studies have compared the efficacy of biological treatments for SA, either directly or indirectly. Although their methodologies and population characteristics may vary, these studies are crucial for identifying the most effective treatments for different patient subgroups. Presented below are representative studies demonstrating these comparisons.

Direct comparison studies

Scientific studies directly compare different biological medications for treating SA in real-world settings [18–20]. Several multicenter retrospective studies have evaluated the efficacy of various biological drugs in patients with SA for at least 12 months. Despite differing data collection methods, the results were generally comparable, with differences based on the drugs included in each study. Although the methods of data collection varied, the studied objectives and their results allow for conclusions about the populations studied.

Indirect comparison studies

These studies use data from existing randomized controlled trials (RCTs) and apply statistical methods for indirect comparisons to obtain comparable results across treatments. A common approach is matched-adjusted indirect comparisons (MAIC), where patient data from one trial are adjusted to match characteristics from another trial, allowing for a more balanced and accurate comparison [21]. Results vary, demonstrating differing efficacies among biologics across populations [22–24].

Systematic reviews and meta-analyses

These are powerful tools for comparing the efficacy of different biological treatments by combining multiple trials; these analyses provide comprehensive efficacy and safety data. Kyriakopoulos et al. [25], analyzed 48 RCTs of approved biologic agents for SA (16,350 participants), showing biologics significantly reduced exacerbations, hospitalizations, and corticosteroid use, with modest improvements in lung function, asthma control, and quality of life, although heterogeneity among studies was noted.

Network meta-analysis

Network meta-analysis (NMA) extends traditional meta-analyses, integrating direct (head-to-head comparisons) and indirect (comparisons via a common comparator) evidence to compare multiple treatments simultaneously [26]. NMAs are powerful tools for comparing multiple biological treatments in SA, providing a more complete and robust view of the relative efficacy and safety of these treatments compared to traditional systematic reviews. Provide relevant information to identify differences among biologics for SA and guide clinical decision-making, in defined clinical scenarios and proposed objectives [27–30].

Due to the lack of extensive comparative studies, there are currently no recommendations for selecting the appropriate treatment among those available. Therefore, the choice is empirical and likely shared between doctor and patient, with previously defined treatment objectives. Table 2 summarises the comparative methods described.

Table 2

Comparative methods between biologics for SA

Method	Description	Key findings
Direct comparison studies	Scientific studies that directly compare different biological medications for treating SA in real-world settings.	These studies generally show that all biological drugs improve various objectives, including the frequency of exacerbations, use of systemic corticosteroids, and asthma control.
Indirect comparison studies	These studies use data from existing randomized controlled trials (RCTs) and apply statistical methods for indirect comparisons, such as matched-adjusted indirect comparisons (MAIC).	They demonstrate variable results with a predominance of the efficacy of one biologic over another in different patient populations.
Systematic reviews and meta-analyses	These studies compile and analyze data from multiple clinical trials, providing a comprehensive view of treatments’ relative efficacy and safety.	They allow a more precise estimate of the treatment effect by increasing the sample size and statistical power. Significant heterogeneity was found in the effect estimates across subgroups and endpoints.
Network meta-analysis (NMA)	NMA extends traditional meta-analyses, allowing for the simultaneous comparison of multiple treatments, even when direct comparisons in clinical trials do not exist.	They provide a comparative view of the efficacy and safety of different biologics for treating SA, integrating data from multiple clinical trials.

SA: severe asthma

How long should biological treatment be maintained?

According to GINA 2021, a treatment duration of at least 4 to 6 months is recommended to assess the response to biological treatment in patients with SA, followed by re-evaluation every 3–6 months [3, 31]. Current international guidelines generally recommend continuing biologic therapy for a minimum of 12 months before considering a withdrawal attempt. Such a decision should only be contemplated if the patient’s asthma remains well controlled while receiving, at a minimum, a maintenance regimen that includes medium-dose ICS [1].

If there is no clinically meaningful improvement after 4 to 6 months of treatment with a biologic agent, switching to an alternative biologic with a different mechanism of action should be considered, provided that the eligibility criteria are still met [32]. For patients with incomplete responses, add-on therapy with a second biologic may be considered, but this indication is not currently supported by robust evidence from randomized clinical trials or by international guidelines, and it is not considered a recommended standard practice. This option can be considerably expensive and is usually not covered by insurance companies or healthcare systems.

The duration of biological treatment for SA depends on several factors, including the patient’s response to therapy, disease severity, control of comorbidities, use of OCS, and the presence of clinically relevant side effects.

Clinical response

The primary factor in determining the biological treatment duration is the patient’s clinical response. If the patient shows significant improvement in symptoms, reduced exacerbations, and better lung function, treatment should be continued. Regular monitoring and assessment are essential to evaluate the ongoing effectiveness of the therapy and the achievement of the objectives proposed by physicians and patients.

In recent years, response levels to biological treatments have been established to categorize patients who respond spectacularly, partially, or inadequately to therapy. Although several definitions of clinical response or remission have been proposed, a “clinical response” generally includes a reduction in the annualized exacerbation rate, reduction of OCS dose, and improvement of lung function without clinical bronchial symptoms. Some authors define “clinical remission” as the complete absence of exacerbations and the need for OCS, well-controlled symptoms, and stabilization of lung function [33]. In September 2023 [34], ACAAI, ATS, and AAAAI postulated six mandatory criteria to be reached within one year for clinical remission in asthma: no exacerbations, no missed work or school over 12 months due to asthma-related symptoms, stable and optimized pulmonary, treatment with ICS only at low-medium doses, an asthma control test (ACT) score of > 20 or an asthma control questionnaire (ACQ) score of < 1.5, and symptoms requiring one-time reliever therapy no more than once a month.

A study from the Danish Severe Asthma Register cohort reported that 79% of patients had a clinical response and 19% achieved clinical remission [35]. Certain clinical characteristics were associated with a higher probability of achieving remission, such as earlier initiation of biological therapy (patients with shorter disease duration), fixed airflow obstruction and remodeling, mild forms of the disease, and minimal or no use of OCS. Complete remission goes beyond clinical remission and is defined as the absence of underlying inflammation and structural changes in the airways, demonstrated by negative bronchial hyperresponsiveness [36]. Complete remission should not be defined in asthma patients who still require treatment to control their disease. Another issue is that patients with long-standing disease and/or significant loss of lung function, usually with fixed airway obstruction, cannot achieve all the criteria for a clinical response, even if they meet the other criteria. Predictors of remission include younger age, better previous asthma control, lower previous ICS dose, milder airway hyperresponsiveness (AHR), fewer nasal polyps, and lower levels of blood neutrophils [37]. Remission, as a disease state, should be differentiated from the concept of a super-responder, which refers specifically to the degree of response to treatment [34].

Quantitative assessments of airway function using chest computed tomography (CT) and magnetic resonance imaging (MRI) in clinical trials of tezepelumab (NCT05280418), benralizumab (NCT03976310), and dupilumab (NCT0440318) aim to enhance the understanding of remission in SA by evaluating both large and small airways, as well as mucus plugging scores [38–40]. These imaging-based metrics may support the development of new treatment endpoints.

Although clinical response is a desirable goal, some patients may accept marginal improvements in disease expression and fear losing the benefits obtained during the initial biological treatment.

The NICE guidelines recommend that benralizumab, mepolizumab, and reslizumab be reviewed after 12 months of treatment and discontinued if asthma has not responded adequately [31, 41, 42]. For dupilumab, the NICE guideline recommends interruption if the rate of SA exacerbations has not been reduced by at least 50% after 12 months [43].

Disease severity

Patients with severe, persistent asthma may require long-term biological treatment to maintain symptom control and prevent exacerbations. The decision to continue treatment should be based on disease severity and the risk of exacerbations if treatment is discontinued.

Use of corticosteroids

For patients chronically treated with OCS, reducing the OCS dose is an important consideration and a primary goal of biological treatment in SA [44]. Cessation of maintenance OCS is a major criterion for clinical remission [45].

Control of comorbidities

The ISAR group identified chronic rhinosinusitis, with or without nasal polyposis, as a potential predictor of a positive response to biologics, particularly in reducing exacerbation risk, improving asthma control, and enhancing lung function. Obesity is a common comorbidity associated with poorer asthma control, increased risk of exacerbations, impaired lung function, and reduced quality of life [46].

Side effects

The presence of side effects may influence the duration of biological treatment. If a patient experiences significant adverse effects, the healthcare provider may consider adjusting the dosage or switching to an alternative therapy. Long-term side effects are unknown, but their presence appears anecdotal [47]. A long-term safety review, conducted after over a decade of experimental studies and validated by real-world clinical experience, has not indicated any increase in malignant diseases, such as solid tumours or leukaemia, among patients undergoing treatment [48]. After 5 years of starting treatment with benralizumab, the MELTEMI study confirmed ongoing safety with rates of malignancy and serious infections at less than 2% [49].

Biomarkers

Monitoring biomarkers of high-T2 asthma, such as blood and/or sputum eosinophil counts and fractional exhaled nitric oxide (FeNO) levels, can help guide the duration of treatment [50]. A sustained reduction in these biomarkers may indicate that the treatment is effective and should be continued. High levels predict the risk of more severe exacerbations, poor disease control, and poor response to treatment [51]. Serum IgE is a marker of atopy, but not useful in monitoring response to biological therapies [52].

Anyway, the duration of biological treatment should be individualized based on the patient’s specific needs and circumstances. A personalized approach ensures that the treatment is tailored to achieve the best possible outcomes for each patient. Most SA patients treated with biologic therapies continue in the long term, with only 13% stopping them and 16% switching to another biologic [53].

Once remission of SA is achieved, how do we de-escalate treatment?

Once remission of SA is achieved, the approach to de-escalating treatment should be carefully planned to maintain disease control while minimizing medication use. De-escalation of treatment should be gradual and closely monitored. If the patient is on biological therapy and has achieved remission, the decision to reduce or discontinue biologics should be based on clinical assessment and biomarkers. Some patients may be able to reduce the frequency of biologic administration or switch to a lower dose. However, complete discontinuation should be approached with caution and only considered if the patient has been stable for an extended period. Abrupt discontinuation of biologics or inhalers can lead to a relapse of symptoms. Elevated levels of FeNO after suspension of long-term therapy with omalizumab could predict near-exacerbation [54]. The COMET Study evaluated the effects of stopping versus continuing long-term mepolizumab therapy on asthma control [55]. Patients who stopped mepolizumab had an increased risk and shorter time to first asthma worsening compared to those who continued, largely driven by worsening in rescue medication use and morning PEF. Similar results were observed in another study after a 12-month follow-up following mepolizumab discontinuation [56]. Interestingly, patients who stopped treatment for 3 months between the COSMOS and COSMEX studies showed improvement in ACQ score, lung function, and eosinophil count when therapy was restarted [57].

A step-down protocol for SA patients treated with omalizumab has been published [58]. Patients must have received omalizumab treatment for at least one and a half years, the OCS dose must have reached the lowest tolerated dose, and lung function tests must be equal to or better than at entry. Then, omalizumab can be reduced by half and halved again every 6 months if the patient is clinically stable. Around one-third of the patients tolerated omalizumab withdrawal safely, and this benefit was long-lasting. French authors propose maintaining continuous therapy with omalizumab for a minimum of two years, after which discontinuation may be considered in patients with inactive allergic disease, low peripheral eosinophil counts, reduced FeNO levels, well-controlled asthma, and no history of severe exacerbation for at least one year [59]. A phase 4 study, XPORT, demonstrated persistent improvement in asthma control and reduced risk of exacerbations in patients treated with omalizumab. In this study, the interruption of the therapy could increase IgE levels and basophil expression of FcεRI [55]. In real-life experience, the effects of 6 years of omalizumab treatment may persist for at least 4 years after discontinuation in 60% of asthmatic patients [60].

ICS, long-acting bronchodilator agents (LABAs), long-acting muscarinic antagonists (LAMAs), and leukotriene inhibitor (LI) are often the basis of SA maintenance therapy. Once remission is achieved, the ICS dose can be gradually reduced while monitoring for any signs of worsening symptoms. LABAs should generally be continued as part of a combination therapy with ICS to maintain control. LAMAs and LI can also be withdrawn while monitoring asthma progression. Regular follow-up appointments are essential to monitor the patient’s response to treatment adjustments. Spirometry, peak flow measurements, and assessment of symptoms (validated questionnaires: ACT [61], ACQ [62], global evaluation of treatment effectiveness (GETE) [63], Saint George’s Respiratory Questionnaire (SGRQ) [64]) should be conducted to ensure asthma control is maintained. GINA recommends reducing ICS doses in patients with SA who respond positively to biologics [3]. In the randomized, multicenter, open-label, phase 4 study (SHAMAL), patients who received at least three doses of benralizumab were studied to analyze the effect of ICS reduction. Ninety-two percent of patients successfully reduced their high-dose ICS. However, patients need at least a low-to-moderate dose of ICS to control asthma. These results are important because some patients may experience early benefits, leading them to believe they can reduce ICS, which can increase the risk of exacerbations and poor asthma control.

The education of the patient about the importance of adherence to the adjusted treatment plan and recognizing early signs of exacerbation is crucial. Patients should be instructed on how to use their medications correctly and when to request medical assistance.

Each patient’s treatment plan should be individualized based on their specific needs, asthma severity, and response to previous treatments. Biomarkers such as blood eosinophil counts and FeNO levels can help guide the de-escalation process.

New biomarkers for SA

While phenotyping/endotyping asthma and identifying relevant biomarkers offer opportunities to target treatments toward the underlying causes of the disease, there are also challenges and issues associated with using precision medicine via biomarkers [65]. These challenges partly explain why biomarker measurements are not yet routinely used in clinical practice. Blood and/or sputum eosinophils, FeNO, and serum total IgE are the most widely used biomarkers for the diagnosis of both high-T2 and low-T2 asthma in clinical practice. Currently, there is a significant lack of biomarkers predictive of disease remission and safe step-down of treatment. There are several new biomarkers, both in high-T2 and low-T2, are being investigated for the monitoring of SA. These biomarkers can help in understanding the disease’s pathophysiology, in the prediction of risk of exacerbations, and in tailoring personalized treatment strategies. Here are some of the emerging biomarkers.

YKL-40 is a chitinase-like protein that is elevated in patients with SA. It is associated with airway remodeling and inflammation, making it a potential biomarker for disease severity and progression. YKL-40 promotes allergen sensitization, IgE production [66], bronchial smooth muscle cell proliferation, and bronchial remodeling [67]. A systematic meta-analysis showed that the level of YKL-40 was significantly higher in asthmatic patients than in the normal group, regardless of age and residential location, and it also increases with severity and acute exacerbation (p < 0.05) [68]. Some studies linked YKL-40 to high-T2 inflammation [69] and others to severe neutrophilic and obesity-associated asthma [70]. YKL-40 has low specificity, as high levels are also found in chronic obstructive pulmonary disease (COPD), malignancies, and other diseases, and this is the main limitation of its use as a biomarker. Despite this, YKL-40 could be useful in phenotyping when combined with other biomarkers.

Patients with late-onset asthma (LOA) tend to have poor clinical outcomes. Osteopontin (OPN) is a matricellular protein that mediates diverse biological functions and is linked to eosinophilic airway inflammation and remodeling [71]. A study compared serum OPN levels between 131 adult asthma patients, 48 with LOA and 83 with early-onset asthma (EOA) and 226 healthy controls (HCs) [72]. The study found that serum OPN levels were significantly higher in asthma patients compared to HCs, and in LOA patients compared to EOA patients (p < 0.05). The authors concluded that aging and exposure to viral infections may induce OPN release, modulating inflammation and contributing to the development of LOA. Despite the investigation of OPN as a biomarker in various diseases, including asthma, and its association with disease severity, its clinical application remains limited due to its lack of specificity. OPN is a diverse protein with a broad range of functions [73].

The endogenously produced cannabinoid oleoylethanolamide (OEA) has immunomodulatory effects by binding to cannabinoid receptors (CB1 and CB2) on immune cells such as eosinophils and monocytes. Recent studies have reported higher serum OEA levels in patients with SA or non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD). Additionally, OEA induces IL-33 secretion in airway epithelial cells (AECs), which increases T2 cytokine levels by activating T2 innate lymphoid cells (ILC2s) and eosinophils, promoting T2 airway inflammation [74]. Notably, surface CB2 receptor expression on eosinophils was significantly higher in patients with EA compared to those with non-EA. Blocking CB2 receptors reduces the release of alarmins and T2 cytokines, as well as the recruitment of eosinophils and ILC2s to the airways. This suggests that serum OEA levels may serve as a novel biomarker for classifying high-T2 asthma, which is associated with ILC2 activation and reduced steroid responsiveness [75].

MicroRNAs (miRNAs) are small non-coding RNA molecules, formed by approximately 18–22 nucleotides, which negatively regulate gene expression at the post-transcriptional level [76]. The abnormal regulation of gene expression by miRNAs has been associated with the development and progression of numerous lung diseases, making miRNAs potential new biomarkers for SA. Approximately 90% of circulating miRNAs form complexes with proteins, and the remaining 10% is secreted in exosomes [77], vesicles conferring miRNAs stability and resistance to degradation by endogenous RNases, characteristics that predispose miRNAs in exosomes to be useful as diagnostic biomarkers, predictors of disease progression, and a helpful tool for decision-making strategies. A study evaluated a group of miRNAs (miR-21, miR-223, and Let-7a) both in serum and in exosomes isolated from the serum of asthma subjects and compared with a group of HCs [78]. Only differences were observed at the exosomal level, and no differences were observed in the serum of the patients. The miRNA expression was dependent on the severity of asthma (severe or mild-to-moderate). Another study analyzed blood serum from 60 subjects (mild asthma, moderate-to-severe, and HC) with a total of 365 miRNAs expressed [79]. Plasma miR-140-5p and miR-107 could be useful as diagnostic biomarkers to distinguish asthma patients from HCs.

For predicting the effect of dupilumab, 17 patients with SA treated with dupilumab were studied [80] (10 responders and 7 non-responders), where serum T2 cytokines were equivalent between responders and non-responders based on decreased ACQ by > 0.5 points. However, the baseline serum IL-18 level was significantly lower in responders than in non-responders (responders, 194.9 ± 51.0 pg/mL; non-responders, 323.4 ± 122.7 pg/mL, p = 0.013). The authors concluded that a low baseline serum IL-18 level may be a useful predictor of an unfavourable response to dupilumab in terms of the ACQ-6.

A study identifies that serum levels of lysophosphatidylglycerol (LPG) 18:0 are generally elevated in asthmatics and serve as a biomarker for asthma. LPG 18:0 impairs regulatory T cells (Tregs) function via the NAD⁺/SIRT1/FOXP3 pathway, revealing its potential as a biomarker for asthma.

In low-T2 asthma, although neutrophils are the predominant cells in the airway, their quantification has not been defined as a good biomarker [81]. A study investigated the relationship between myeloperoxidase (MPO) and human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin (HNL/NGAL) with inflammation in the airways [82]. The study included 86 children with asthma and 59 control subjects. The results showed that MPO and HNL/NGAL concentrations in sputum were significantly higher in children with asthma compared to controls. Additionally, these concentrations were positively correlated with each other and with asthma severity. Children with moderate-to-severe persistent asthma had higher levels of MPO and HNL/NGAL compared to those with intermittent and mild persistent asthma. A positive correlation was also found between sputum neutrophil counts and MPO and HNL/NGAL concentrations, as well as with FeNO levels. MPO and HNL/NGAL concentrations in sputum could be a good tool for assessing asthma severity in children. However, another study evaluated the levels of serum MPO as a biomarker for assessing asthma control [83]. The study included 94 asthmatic adult patients and 86 HCs. Asthma severity was assessed using the “Global Initiative for Asthma guidelines”, and participants were divided into three groups: good control (n = 22), partial control (n = 28), and poor control (n = 44). MPO levels were significantly higher in asthmatic patients. However, MPO levels did not significantly differ from asthma control levels but showed significant differences with treatment history. There was a non-significant negative correlation between MPO levels and spirometry variables. ROC curves revealed sensitivity, specificity, and accuracy for MPO (80.9%, 72.1%, and 84.3%, respectively) in predicting asthma severity. In conclusion, serum MPO levels were significantly higher in asthmatic patients compared to HCs. While MPO levels had a non-significant positive correlation with asthma control levels, they showed a non-significant negative correlation with spirometric results. Finally, another study measured the serum level of MPO and its correlation with respiratory function [84]. The study included 130 patients with asthma and 130 age- and sex-matched HCs. MPO levels were significantly higher in the asthmatic group compared to the control group. Serum MPO levels were positively correlated with asthma severity, all cellular content in bronchoalveolar lavage (BAL), and body mass index (BMI), but inversely correlated with respiratory function. MPO levels were significantly higher in SA compared to non-severe forms. The ROC curve also demonstrated good predictive potential of MPO for asthma diagnosis and its severity. In conclusion, serum MPO levels can be used as a good biomarker for the diagnosis of asthma and its severity. However, results should be interpreted with caution, and MPO should be used alongside a panel of biomarkers until further evidence confirms its role in future studies.

S100 calcium-binding protein A9 (S100A9) has been shown to correlate with neutrophil activation in neutrophilic asthma (NA) by activating Toll-like receptor 4 and increasing IL-8 production [85]. A study found that serum levels of S100A9 were higher in NA patients than in non-NA patients, with a positive correlation between serum S100A9 levels and sputum neutrophil counts (r = 0.340, p = 0.005) [86]. Asthmatic patients with higher S100A9 levels had lower PC20 methacholine values and a higher prevalence of SA (p < 0.05). Higher S100A9 levels were observed in sera, BAL fluid, and lung tissues in the mouse model of NA, but not in other mouse models. These findings suggest that S100A9 is a potential serum biomarker and therapeutic target for the NA phenotype in adult asthmatics.

Olfactomedin 4 (OLFM4) is endogenously expressed in mature neutrophils and gastric. intestinal epithelial cells and the prostate [87]. OLFM4 is involved in innate immunity, inflammation, and carcinogenesis [88]. OLFM4 is a neutrophil-specific granule protein, solely expressed in bone marrow and peripheral blood, but serum could be used to evaluate augmented neutrophilic inflammation in the airway of asthmatic subjects [89]. Therefore, serum OLFM4 levels may be useful as a biomarker for NA.

Over the past two decades, omics approaches, such as genomics [90, 91], transcriptomics [92], epigenomics [93], proteomics [94, 95], metabolomics [96, 97], and microbiomics [98], have emerged as valuable tools for precisely endotyping asthma [99]. Continuous research has demonstrated their effectiveness in distinguishing asthma patients from healthy individuals, increasing our understanding of asthma heterogeneity and pathophysiology. These approaches have also provided insights into the biological mechanisms that may influence treatment responses.

In the U-BIOPRED cohort study, 110 proteins were significantly different, mostly elevated, in SA compared to MMA (mild-to-moderate asthma) and HCs [100]. Ten proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR [alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, IL-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor (TGF)-β, and glutathione S-transferase]. OCS treatment decreased most proteins, yet differences between SA and MMA remained following adjustment for OCS use. The plasma proteomic panel revealed previously unexplored yet potentially useful type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.

A study used lipidomics to profile serum glycerophospholipids in asthmatic patients and controls [101]. The potential as a biomarker for the concentration of LPG 18:0 was assessed as being notably higher in asthmatic patients. These levels correlated with asthma severity and control levels.

Early-life alterations in gut microbiome composition may be involved in asthma pathogenesis and microbial metabolites may also potentially serve as valuable biomarkers in asthma [102].

Five exhaled breath volatile organic compounds (VOCs), benzothiazole, acetophenone, 2-pentyl-furan, methylene chloride, and 2-methyl-butane, predicted early improvement as measured by GETE score, whereas another set of VOCs (2-ethyl-1-hexanol, toluene, 2-pentene, nonanal, and an unidentified compound) predicted a decrease in exacerbations higher than 50% over 12 months [103].

These biomarkers are part of ongoing research and clinical trials aimed at improving the management of SA through more precise and personalized treatment approaches. See Table 3.

Table 3

New biomarkers for SA

Biomarker	Description	Clinical relevance
YKL-40	A chitinase-like protein elevated in SA	Associated with airway remodeling and inflammation
Osteopontin (OPN)	A matricellular protein linked to eosinophilic airway inflammation and remodeling	Higher levels of late-onset asthma compared to early-onset asthma
Oleoylethanolamide (OEA)	An endocannabinoid with immunomodulatory effects	Induces IL-33 secretion, promoting T2 airway inflammation
MicroRNAs (miRNAs)	Small non-coding RNA molecules, regulates gene expression	Potential biomarkers for SA based on their expression in exosomes
IL-18	A cytokine involved in the immune response	Lower baseline levels may predict a favourable response to dupilumab
LPG 18:0	A glycerophospholipid	Elevated levels in asthmatics, impairs Treg function
Myeloperoxidase (MPO)	An enzyme found in neutrophils	Higher levels of SA, correlated with inflammation
S100A9	A protein associated with neutrophil activation	Higher levels in neutrophilic asthma, correlated with sputum neutrophil counts
Olfactomedin 4 (OLFM4)	A protein expressed in neutrophils	Potential biomarker for neutrophilic asthma

IL-33: interleukin-33; LPG: lysophosphatidylglycerol; S100A9: S100 calcium-binding protein A9; SA: severe asthma; T2: type 2; Treg: regulatory T cell

Despite the identification of several promising biomarkers for SA, there remains a significant gap in identifying relevant biomarkers specific to each phenotype and endotype. Additionally, these biomarkers could prove useful in predicting therapeutic responses and improving clinical outcomes in the long-term management of asthma.

Do biologics have immunomodulatory effects in SA?

Biologics exert significant immunomodulatory effects in the treatment of SA. These therapies target specific pathways involved in the inflammatory process, modulating the immune response. Some effects are directly related to the drug’s mechanism of action and the modulated immunological target, while others are not originally related but contribute to the therapeutic benefits. Here are some key points.

IL-5 pathway: Mepolizumab (anti-IL-5 IgG1), reslizumab (anti-IL-5 IgG4), and benralizumab (anti-IL-5Ra IgG1) target IL-5 or its receptor, reducing eosinophil differentiation, survival, and activation [104]. Benralizumab uniquely induces apoptosis of IL-5Ra-expressing cells via antibody-dependent cellular cytotoxicity. These agents effectively lower blood and airway eosinophil counts, mitigating eosinophilic inflammation, a hallmark of SA.

IgE inhibition: Omalizumab binds to free IgE, preventing its interaction with mast cells and basophils, thereby reducing mediator release and allergic inflammation. Beyond its primary mechanism, omalizumab decreases high-affinity IgE receptor expression on mast cells, basophils, and dendritic cells (DCs), stabilizes mast cells, increases Tregs, and reduces epithelial-derived cytokines (IL-33, IL-25, and TSLP) and IL-13 levels [105]. Notably, in super-responders, its immunomodulatory effects may persist after discontinuation, although high baseline IgE levels can predict the need for retreatment [106].

IL-4 and IL-13 blockade: Dupilumab targets IL-4Ra, inhibiting IL-4 and IL-13 signalling, reducing T2 inflammation. Clinical effects include decreased FeNO and serum levels of thymus activation-regulated chemokine (TARC), periostin, eotaxin-3, and total IgE in moderate-to-SA [107–110]. Transient blood eosinophilia with dupilumab has been attributed to impaired tissue migration rather than increased production [108].

TSLP inhibition: Tezepelumab inhibits TSLP, an epithelial cytokine that can trigger different endotypes of asthma inflammation. TSLP is produced mainly by epithelial cells in response to various stimuli (e.g., viruses, pollutants, and allergens) but is also secreted by eosinophils, mast cells, macrophages, fibroblasts, and ILC2 cells. Multiple immune cells, including progenitor cells, eosinophils, basophils, mast cells, ILC2, DCs, and monocytes/macrophages, express TSLP receptors [111, 112]. By blocking TSLP, tezepelumab suppresses upstream signaling, reducing activation of downstream inflammatory pathways.

AHR: AHR is a core treatable trait in EA, driven by inflammatory phenotypes and endotypes [113–115]. Airway smooth muscle cells (ASMC) are the main effectors, not only through their contractile properties but also via proinflammatory and immunomodulatory functions, secreting cytokines and chemokines [116–118]. ASMC express receptors for TSLP [119], IL-4/IL-13 [120], and IgE [121], but not IL-5R [122]. Thus, omalizumab, dupilumab, and tezepelumab can modulate AHR directly via ASMC and indirectly via eosinophilic inflammation and neural pathways, whereas mepolizumab and benralizumab reduce AHR predominantly through their anti-eosinophilic effects [115]. Overall, these immunomodulatory effects of biologics lead to reduced exacerbation rates, improved lung function, and enhanced quality of life in patients with SA.

Could biologics reverse bronchial remodeling?

Airway remodeling is a fundamental feature of asthma, present in both severe and mild forms [123]. It involves structural changes in the large and small airways and lung parenchyma [122, 124], clinically manifesting as airway hyperreactivity and fixed airflow obstruction. Key remodeling features include epithelial barrier damage [125, 126], subepithelial matrix and collagen deposition [127–129], infiltration, cell infiltration and activation [130–132], goblet cell metaplasia [133], inflammatory angiogenesis [134, 135], and airway smooth muscle (ASM) hyperplasia and hypertrophy [136–139]. Subepithelial fibrosis results from fibroblast-to-myofibroblast transition (FMT) induced mainly by TGF-β [140]. Table 4 summarizes the changes in remodeling in SA.

Table 4

Remodeling in SA

Aspect	Description	Clinical relevance
Epithelial barrier	Damaged epithelial barrier stimulates ECM production by airway epithelial and smooth muscle cells.	Leads to subepithelial fibrosis and reduced airway compliance.
Subepithelial fibrosis	Increased deposition of ECM components, including fragmented and disorganized fibrillar collagen.	Associated with asthma severity and inversely correlated with FEV₁.
Airway smooth muscle (ASM)	ASM cell hyperplasia and hypertrophy contribute to airway remodeling.	ASM cells have proinflammatory and immunomodulatory functions.
Goblet cell metaplasia	Overexpression of inflammatory angiogenesis and goblet cell metaplasia.	Leads to mucus hyperproduction and airway obstruction.
Angiogenesis	Overexpression of vascular endothelial growth factor and basic fibroblast growth factor.	Contributes to airway remodeling and inflammation.
Inflammatory cells	Persistent airway infiltration/activation of immune cells, including eosinophils.	Contributes to airway alterations and fixed airflow obstruction.
Fibroblast-to-myofibroblast transition (FMT)	Enhanced differentiation of bronchial fibroblasts into myofibroblasts induced by TGF-β.	Key aspects of subepithelial fibrosis.

ECM: extracellular matrix; SA: severe asthma; TGF: transforming growth factor

The combination of inflammatory and structural changes in airway remodeling causes the fixed airflow obstruction observed in clinical settings [141]. While biologics primarily target inflammatory pathways in asthma, there is promising evidence that they may also help reverse or reduce bronchial remodeling.

Persistent airway inflammation reduces epithelial barrier integrity, stimulating extracellular matrix (ECM) production by epithelial and ASM cells, promoting collagen and fibronectin deposition by fibroblasts and myofibroblasts [142, 143]. Subepithelial fibrosis results from an imbalance in ECM synthesis and degradation, leading to scarring and reduced airway compliance [144], correlating with disease severity and inversely with FEV₁ [145].

Structural alterations are typically assessed histologically [146], but imaging modalities such as high-resolution CT (HRCT), endobronchial ultrasonography (EBUS), and hyperpolarized gas MRI provide non-invasive evaluation [147]. HRCT has been used to assess treatment response by measuring airway wall thickness [148], airway wall area [149], luminal area [56, 150, 151], and ventilation changes [152]. Studies demonstrate that omalizumab [148], mepolizumab [56, 150], benralizumab [152], and tezepelumab [151] improve structural airway variables, with EBUS showing reduced wall thickening with mepolizumab [153].

Biologic agents reduce eosinophilic and inflammatory cell infiltration, potentially mitigating remodeling [141]. Bronchial biopsies from patients treated with benralizumab and tezepelumab showed decreased eosinophils and ASM mass, though not myofibroblast counts, suggesting effects via depletion of local TGF-β1⁺ eosinophils [122].

Clinically, biologics improve airflow obstruction that resists OCS in many SA patients [109, 154–158], with benralizumab [159], mepolizumab [160, 161], omalizumab [162], and dupilumab [108], enhancing lung function and reducing exacerbations, while allowing OCS dose reductions. Tezepelumab rapidly improves FEV₁ by decreasing airway eosinophils and matrix metalloproteinase (MMP)-10 and MMP-3 [163], though OCS-sparing effects remain unproven [164].

Treatment discontinuation studies (e.g., mepolizumab) show lung function deterioration upon stopping, reversed with re-treatment, while some patients maintain improvements post-discontinuation, suggesting lasting anti-inflammatory or anti-remodeling effects [54].

While FEV₁ improvements reflect multiple factors beyond remodeling (e.g., inflammation, AHR, and autonomic modulation) [140], mucus plugs have emerged as key targets. They correlate with goblet cell hyperplasia/metaplasia, galectin-10 activity, ciliated cell dysfunction, and increased MUC5AC/MUC5B expression, leading to airway obstruction [165–168]. Biologics may reduce mucus plugging, contributing to long-term remodeling improvements.

Overall, by modulating eosinophils, mast cells, macrophages, fibroblasts, ASM cells, and cytokine-mediated pathways, biologics can slow or reverse airway remodeling, with efficacy depending on treatment timing and established endpoints.

Conclusions

Some studies directly or indirectly compare the efficacy of different biological treatments for SA. These studies are essential to determine which treatments may be more effective for various subgroups of patients. The duration of biological treatment for SA depends on several factors, including the patient’s response to therapy, the severity of the disease, the control of comorbidities, the use of OCS, and the presence of clinically relevant side effects. The de-escalation of treatment should be gradual and closely monitored. If the patient has achieved remission with biological therapy, reducing or discontinuing biologics should be based on clinical evaluation and biomarkers. Biologics have significant immunomodulatory effects in the treatment of SA. These therapies target specific pathways involved in the inflammatory process, thus modulating the immune response. Emerging biomarkers can help understand the disease’s pathophysiology, predict the risk of exacerbations, and tailor personalized treatment strategies. Although biologics primarily target inflammatory pathways in asthma, there is promising evidence that they may also contribute to reversing or reducing bronchial remodeling.

Abbreviations

ACQ

asthma control questionnaire

ACT

asthma control test

AECs

airway epithelial cells

AERD

aspirin-exacerbated respiratory disease

AHR

airway hyperresponsiveness

ASM

airway smooth muscle

ASMC

airway smooth muscle cells

BAL

bronchoalveolar lavage

BMI

body mass index

COPD

chronic obstructive pulmonary disease

computed tomography

DCs

dendritic cells

eosinophilic asthma

EBUS

endobronchial ultrasonography

ECM

extracellular matrix

EOA

early-onset asthma

FeNO

fractional exhaled nitric oxide

FMT

fibroblast-to-myofibroblast transition

GETE

global evaluation of treatment effectiveness

HCs

healthy controls

HNL/NGAL

human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin

HRCT

high-resolution computed tomography

ICS

inhaled corticosteroids

IL-5

interleukin-5

ILC2s

type 2 innate lymphoid cells

LABAs

long-acting bronchodilator agents

LAMAs

long-acting muscarinic antagonists

leukotriene inhibitor

LOA

late-onset asthma

LPG

lysophosphatidylglycerol

MAIC

matched-adjusted indirect comparisons

miRNAs

microRNAs

MMA

mild-to-moderate asthma

MMP

matrix metalloproteinase

MPO

myeloperoxidase

MRI

magnetic resonance imaging

neutrophilic asthma

NMA

network meta-analysis

NSAID

non-steroidal anti-inflammatory drug

OCS

oral corticosteroids

OEA

oleoylethanolamide

OLFM4

olfactomedin 4

OPN

osteopontin

RCTs

randomized controlled trials

S100A9

S100 calcium-binding protein A9

severe asthma

SGRQ

Saint George’s Respiratory Questionnaire

type 2

TARC

thymus activation-regulated chemokine

TGF

transforming growth factor

Tregs

regulatory T cells

TSLP

thymic stromal lymphopoietin

VOCs

volatile organic compounds

Declarations Author contributions

DEQ and MM have contributed equally to: Writing—original draft, Writing—review & editing, Conceptualization.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

Reddel

Bacharier

Bateman

Brightling

Brusselle

Buhl

et al.

Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes

Am J Respir Crit Care Med 2022 205 17 35

10.1164/rccm.202109-2205PP

34658302

PMC8865583

Holgate

Pathogenesis of asthma

Clin Exp Allergy 2008 38 872 97

10.1111/j.1365-2222.2008.02971.x

18498538

ginasthma.org [Internet]

Global Initiative for Asthma – GINA; c2025 [cited 2025 Jan 3]. Available from: https://ginasthma.org/

Chung

Wenzel

Brozek

Bush

Castro

Sterk

et al.

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Eur Respir J 2014 43 343 73

10.1183/09031936.00202013

24337046

Wenzel

Asthma phenotypes: the evolution from clinical to molecular approaches

Nat Med 2012 18 716 25

10.1038/nm.2678

22561835

Opina

Moore

Phenotype-Driven Therapeutics in Severe Asthma

Curr Allergy Asthma Rep 2017 17

10.1007/s11882-017-0678-1

28233153

Loutsios

Farahi

Porter

Lok

Peters

Condliffe

et al.

Biomarkers of eosinophilic inflammation in asthma

Expert Rev Respir Med 2014 8 143 50

10.1586/17476348.2014.880052

24460178

Perez-de-Llano

Tran

Al-ahmad

Alacqua

Bulathsinhala

Busby

et al.

Characterization of Eosinophilic and Non-Eosinophilic Severe Asthma Phenotypes and Proportion of Patients with These Phenotypes in the International Severe Asthma Registry (ISAR)

Am J Respir Crit Care Med 2020 201

A4525

10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A4525

Chheang

Guinand

von Garnier

Sartori

New perspectives of biological therapy for severe asthma in adults and adolescents

Swiss Med Wkly 2022 152

w30176

10.4414/smw.2022.w30176

35748315

Busse

Biological treatments for severe asthma: A major advance in asthma care

Allergol Int 2019 68 158 66

10.1016/j.alit.2019.01.004

30792118

Hinks

TSC

Levine

Brusselle

Treatment options in type-2 low asthma

Eur Respir J 2021 57

2000528

10.1183/13993003.00528-2020

32586877

PMC7116624

FitzGerald

Bleecker

Nair

Korn

Ohta

Lommatzsch

et al. CALIMA study investigators

Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial

Lancet 2016 388 2128 41

10.1016/S0140-6736(16)31322-8

27609406

Pavord

Beasley

Agusti

Anderson

Bel

Brusselle

et al.

After asthma: redefining airways diseases

Lancet 2018 391 350 400

10.1016/S0140-6736(17)30879-6

28911920

Agusti

Bel

Thomas

Vogelmeier

Brusselle

Holgate

et al.

Treatable traits: toward precision medicine of chronic airway diseases

Eur Respir J 2016 47 410 9

10.1183/13993003.01359-2015

26828055

Lommatzsch

Buhl

Canonica

Ribas

Nagase

Brusselle

et al.

Pioneering a paradigm shift in asthma management: remission as a treatment goal

Lancet Respir Med 2024 12 96 9

10.1016/S2213-2600(23)00415-0

38071999

Canonica

Blasi

Carpagnano

Guida

Heffler

Paggiaro

et al.

Severe Asthma Network Italy Definition of Clinical Remission in Severe Asthma: A Delphi Consensus

J Allergy Clin Immunol Pract 2023 11 3629 37

10.1016/j.jaip.2023.07.041

37558162

Lommatzsch

Virchow

Asthma remission: a call for a globally standardised definition

Lancet Respir Med 2025 13 2 3

10.1016/S2213-2600(24)00304-7

39549711

Valverde-Monge

Sánchez-Carrasco

Betancor

Barroso

Rodrigo-Muñoz

Mahillo-Fernández

et al.

Comparison of Long-term Response and Remission to Omalizumab and Anti-IL-5/IL-5R Using Different Criteria in a Real-life Cohort of Severe Asthma Patients

Arch Bronconeumol 2024 60 23 32. English, Spanish

10.1016/j.arbres.2023.11.011

38042707

Pham

Lee

Kwon

Song

Cho

Kim

et al.

Prospective direct comparison of biologic treatments for severe eosinophilic asthma: Findings from the PRISM study

Ann Allergy Asthma Immunol 2024 132 457 62.e2

10.1016/j.anai.2023.11.005

37977324

Kearney

Sangani

Shankar

O’Connor

Law

Walkey

et al.

Comparative Effectiveness of Mepolizumab, Benralizumab, and Dupilumab among Patients with Difficult-to-Control Asthma: A Multicenter Retrospective Propensity-matched Analysis

Ann Am Thorac Soc 2024 21 866 74

10.1513/AnnalsATS.202306-566OC

38241013

PMC11160126

Signorovitch

Sikirica

Erder

Xie

Hodgkins

et al.

Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research

Value Health 2012 15 940 7

10.1016/j.jval.2012.05.004

22999145

Busse

Chupp

Nagase

Albers

Doyle

Shen

et al.

Anti-IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: Indirect treatment comparison

J Allergy Clin Immunol 2019 143 190 200.e20

10.1016/j.jaci.2018.08.031

30205189

Bateman

Khan

Guyot

Chao

Kamat

et al.

Pairwise indirect treatment comparison of dupilumab versus other biologics in patients with uncontrolled persistent asthma

Respir Med 2022 191

105991

10.1016/j.rmed.2020.105991

35090688

Mareque

Climente

Martinez-Moragon

Padilla

Oyagüez

Touron

et al.

Cost-effectiveness of benralizumab versus mepolizumab and dupilumab in patients with severe uncontrolled eosinophilic asthma in Spain

J Asthma 2023 60 1210 20

10.1080/02770903.2022.2139718

36322679

Kyriakopoulos

Gogali

Markozannes

Kostikas

Biologic agents licensed for severe asthma: a systematic review and meta-analysis of randomised controlled trials

Eur Respir Rev 2024 33

230238

10.1183/16000617.0238-2023

38657997

PMC11040390

Chu

Brignardello-Petersen

Guyatt

Ricci

Genuneit

Method’s corner: Allergist’s guide to network meta-analysis

Pediatr Allergy Immunol 2022 33

e13609

10.1111/pai.13609

34324742

Akenroye

Lassiter

Jackson

Keet

Segal

Alexander

et al.

Comparative efficacy of mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: A Bayesian network meta-analysis

J Allergy Clin Immunol 2022 150 1097 105.e12

10.1016/j.jaci.2022.05.024

35772597

PMC9643621

Nopsopon

Lassiter

Chen

Alexander

Keet

Hong

et al.

Comparative efficacy of tezepelumab to mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: A Bayesian network meta-analysis

J Allergy Clin Immunol 2023 151 747 55

10.1016/j.jaci.2022.11.021

36538979

PMC9992307

Pitre

Jassal

Angjeli

Jarabana

Nannapaneni

Umair

et al.

A comparison of the effectiveness of biologic therapies for asthma: A systematic review and network meta-analysis

Ann Allergy Asthma Immunol 2023 130 595 606

10.1016/j.anai.2022.12.018

36563746

Phinyo

Krikeerati

Vichara-Anont

Thongngarm

Efficacy and Safety of Biologics for Oral Corticosteroid-Dependent Asthma: A Systematic Review and Network Meta-Analysis

J Allergy Clin Immunol Pract 2024 12 409 20

10.1016/j.jaip.2023.11.007

37972921

Mepolizumab for treating severe eosinophilic asthma [Internet]

NICE; c2024 [cited 2025 Jan 3]. Available from: https://www.nice.org.uk/guidance/ta671/resources/mepolizumab-for-treating-severe-eosinophilic-asthma-pdf-82609314548677

Chapman

Albers

Chipps

Muñoz

Devouassoux

Bergna

et al.

The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma

Allergy 2019 74 1716 26

10.1111/all.13850

31049972

PMC6790683

Busse

Chupp

Corbridge

Stach-Klysh

Oppenheimer

Targeting Asthma Remission as the Next Therapeutic Step Toward Improving Disease Control

J Allergy Clin Immunol Pract 2024 12 894 903

10.1016/j.jaip.2024.01.044

38320720

Lommatzsch

Remission in asthma

Curr Opin Pulm Med 2024 30 325 9

10.1097/MCP.0000000000001068

38441430

PMC10990011

Hansen

Baastrup

Søndergaard M

von Bülow

Bjerrum

Schmid

Rasmussen

et al.

Clinical Response and Remission in Patients With Severe Asthma Treated With Biologic Therapies

Chest 2024 165 253 66

10.1016/j.chest.2023.10.046

37925144

Mailhot-Larouche

Celis-Preciado

Heaney

Couillard

Identifying super-responders: A review of the road to asthma remission

Ann Allergy Asthma Immunol 2025 134 31 45

10.1016/j.anai.2024.09.023

39383944

Westerhof

Coumou

de Nijs

Weersink

Bel

Clinical predictors of remission and persistence of adult-onset asthma

J Allergy Clin Immunol 2018 141 104 9.e3

10.1016/j.jaci.2017.03.034

28438546

Niedbalski

Choi

Hall

Castro

Imaging in Asthma Management

Semin Respir Crit Care Med 2022 43 613 26

10.1055/s-0042-1743289

35211923

Svenningsen

Haider

Boylan

Mukherjee

Eddy

Capaldi

DPI

et al.

CT and Functional MRI to Evaluate Airway Mucus in Severe Asthma

Chest 2019 155 1178 89

10.1016/j.chest.2019.02.403

30910637

Pompe

Kwee

Tejwani

Siddharthan

Mohamed

Hoesein FA

Imaging-derived biomarkers in Asthma: Current status and future perspectives

Respir Med 2023 208

107130

10.1016/j.rmed.2023.107130

36702169

Benralizumab for treating severe eosinophilic asthma [Internet]

NICE; c2025 [cited 2025 Jan 3]. Available from: https://www.nice.org.uk/guidance/ta565

Reslizumab for treating severe eosinophilic asthma [Internet]

NICE; c2025 [cited 2025 Jan 3]. Available from: https://www.nice.org.uk/guidance/ta479

Dupilumab for treating severe asthma with type 2 inflammation [Internet]

NICE; c2025 [cited 2025 Jan 3]. Available from: https://www.nice.org.uk/guidance/ta751

Rogers

Jesenak

Bjermer

Hanania

Seys

Diamant

Biologics in severe asthma: A pragmatic approach for choosing the right treatment for the right patient

Respir Med 2023 218

107414

10.1016/j.rmed.2023.107414

37776915

Farinha

Heaney

Barriers to clinical remission in severe asthma

Respir Res 2024 25

178

10.1186/s12931-024-02812-3

38658975

PMC11044532

McDowell

Busby

Eastwood

Patel

Jackson

et al. UK Severe Asthma Registry

Clinical remission in severe asthma with biologic therapy: an analysis from the UK Severe Asthma Registry

Eur Respir J 2023 62

2300819

10.1183/13993003.00819-2023

37857423

PMC10719453

Bourdin

Chupp

Jackson

Cohen

Emerath

Shavit

et al.

MELTEMI and COLUMBA: 5-Year Comparative Safety Analysis of Benralizumab and Mepolizumab

J Allergy Clin Immunol Pract 2024 12

2074-83.e4

10.1016/j.jaip.2024.04.033

38677588

Licari

Marseglia

Caimmi

Castagnoli

Foiadelli

Barberi

et al.

Omalizumab in children

Paediatr Drugs 2014 16 491 502

10.1007/s40272-014-0107-z

25404353

PMC4250568

Korn

Bourdin

Chupp

Cosio

Arbetter

Shah

et al.

Integrated Safety and Efficacy Among Patients Receiving Benralizumab for Up to 5 Years

J Allergy Clin Immunol Pract 2021 9 4381 92.e4

10.1016/j.jaip.2021.07.058

34487870

Kuruvilla

Lee

Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease

Clin Rev Allergy Immunol 2019 56 219 33

10.1007/s12016-018-8712-1

30206782

PMC6411459

Nair

O’Byrne

Measuring Eosinophils to Make Treatment Decisions in Asthma

Chest 2016 150 485 7

10.1016/j.chest.2016.07.009

27613975

Jackson

Humbert

Hirsch

Newbold

Garcia

Gil E

Ability of Serum IgE Concentration to Predict Exacerbation Risk and Benralizumab Efficacy for Patients with Severe Eosinophilic Asthma

Adv Ther 2020 37 718 29

10.1007/s12325-019-01191-2

31836949

PMC7004419

Panettieri

RA Jr

Ledford

Chipps

Soong

Lugogo

Carr

et al.

Biologic use and outcomes among adults with severe asthma treated by US subspecialists

Ann Allergy Asthma Immunol 2022 129 467 74.e3

10.1016/j.anai.2022.06.012

35728746

Ledford

Busse

Trzaskoma

Omachi

Rosén

Chipps

et al.

A randomized multicenter study evaluating Xolair persistence of response after long-term therapy

J Allergy Clin Immunol 2017 140 162 9.e2

10.1016/j.jaci.2016.08.054

27826098

Liu

Bel

Kornmann

Moore

Kaneko

Smith

et al.

Health outcomes after stopping long-term mepolizumab in severe eosinophilic asthma: COMET

ERJ Open Res 2022 8

00419-2021

10.1183/23120541.00419-2021

35036420

PMC8752942

Haldar

Brightling

Singapuri

Hargadon

Gupta

Monteiro

et al.

Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis

J Allergy Clin Immunol 2014 133 921 3

10.1016/j.jaci.2013.11.026

24418480

Khurana

Brusselle

Bel

FitzGerald

Masoli

Korn

et al.

Long-term Safety and Clinical Benefit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: The COSMEX Study

Clin Ther 2019 41 2041 56.e5

10.1016/j.clinthera.2019.07.007

31447130

Domingo

Pomares

Navarro

Amengual

Montón

Sogo

et al.

A step-down protocol for omalizumab treatment in oral corticosteroid-dependent allergic asthma patients

Br J Clin Pharmacol 2018 84 339 48

10.1111/bcp.13453

29044640

PMC5777444

Licari

Castagnoli

Denicolò

Rossini

Seminara

Sacchi

et al. Omalizumab in Childhood Asthma Italian Study Group

Omalizumab in Children with Severe Allergic Asthma: The Italian Real-Life Experience

Curr Respir Med Rev 2017 13 36 42

10.2174/1573398X13666170426094536

29213221

PMC5684803

Vennera

MDC

Sabadell

Picado

Spanish Omalizumab Registry

Duration of the efficacy of omalizumab after treatment discontinuation in ‘real life’ severe asthma

Thorax 2018 73 782 4

10.1136/thoraxjnl-2017-210017

29079610

Thomas

Kay

Pike

Williams

Rosenzweig

Hillyer

et al.

The Asthma Control Test (ACT) as a predictor of GINA guideline-defined asthma control: analysis of a multinational cross-sectional survey

Prim Care Respir J 2009 18 41 9

10.4104/pcrj.2009.00010

19240948

PMC6619040

Hermosa

Sánchez

Rubio

Mínguez

Walther

Factors associated with the control of severe asthma

J Asthma 2010 47 124 30

10.3109/02770900903518835

20170317

Panettieri

RA Jr

Chipps

Moore

Soong

Carr

Kreindler

et al.

Differing perceptions of asthma control and treatment effectiveness by patients with severe asthma and treating subspecialists in the United States

J Asthma 2022 59 1859 68

10.1080/02770903.2021.1963766

34374622

Soong

Chipps

Carr

Trevor

Patel

Clarke

et al.

Quality of Life Improvements with Biologic Initiation Among Subspecialist-Treated US Patients with Severe Asthma

J Asthma Allergy 2024 17 441 8

10.2147/JAA.S452386

38745837

PMC11093117

Bonnesen

Jensen

JUS

Mathioudakis

Corlateanu

Sivapalan

Promising treatment biomarkers in asthma

Front Drug Saf Regul 2023 3

1291471

10.3389/fdsfr.2023.1291471

Kim

Shim

Park

Ahn

Min

Increased serum YKL-40: a new potential marker for airway allergic responses in adult patients with food allergy

Allergy 2011 66 979 80

10.1111/j.1398-9995.2011.02547.x

21496058

Bara

Ozier

Girodet

Carvalho

Cattiaux

Begueret

et al.

Role of YKL-40 in bronchial smooth muscle remodeling in asthma

Am J Respir Crit Care Med 2012 185 715 22

10.1164/rccm.201105-0915OC

22281830

Jin

Song

Zhang

Zheng

et al.

Association between YKL-40 and asthma: a systematic meta-analysis

Sleep Breath 2022 26 1011 22

10.1007/s11325-021-02495-w

34657273

Zhang

Zhou

Tang

Liang

et al.

Association of serum YKL-40 and DPP4 with T2-high asthma in Chinese adults

Medicine (Baltimore) 2024 103

e37169

10.1097/MD.0000000000037169

38335422

PMC10860958

Specjalski

Romantowski

Niedoszytko

YKL-40 as a possible marker of neutrophilic asthma

Front Med (Lausanne) 2023 10

1115938

10.3389/fmed.2023.1115938

36844232

PMC9945318

Lund

Giachelli

Scatena

The role of osteopontin in inflammatory processes

J Cell Commun Signal 2009 3 311 22

10.1007/s12079-009-0068-0

19798593

PMC2778587

Trinh

HKT

Nguyen

TVT

Kim

Cao

TBT

Luu

Kim

et al.

Osteopontin contributes to late-onset asthma phenotypes in adult asthma patients

Exp Mol Med 2020 52 253 65

10.1038/s12276-020-0376-2

32009132

PMC7062758

Barkas

Kotsiou

The Role of Osteopontin in Respiratory Health and Disease

J Pers Med 2023 13

1259

10.3390/jpm13081259

37623509

PMC10455105

Kwon

Choi

Yoon

Won

Sim

Lee

et al.

Oleoylethanolamide induces eosinophilic airway inflammation in bronchial asthma

Exp Mol Med 2021 53 1036 45

10.1038/s12276-021-00622-x

34079051

PMC8257664

Kwon

Choi

Sim

Shin

Park

et al.

Cannabinoid receptor 2 as a regulator of inflammation-induced oleoylethanolamide in eosinophilic asthma

J Allergy Clin Immunol 2024 153 998 1009.e9

10.1016/j.jaci.2023.09.043

38061443

Ratti

Lampis

Ghidini

Salati

Mirchev

Valeri

et al.

MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside

Target Oncol 2020 15 261 78

10.1007/s11523-020-00717-x

32451752

PMC7283209

Fabbiano

Corsi

Gurrieri

Trevisan

Notarangelo

D’Agostino

RNA packaging into extracellular vesicles: An orchestra of RNA-binding proteins?

J Extracell Vesicles 2020 10

e12043

10.1002/jev2.12043

33391635

PMC7769857

Soccio

Moriondo

Lacedonia

Tondo

Pescatore

Quarato

CMI

et al.

MiRNA and Exosomal miRNA as New Biomarkers Useful to Phenotyping Severe Asthma

Biomolecules 2023 13

1542

10.3390/biom13101542

37892224

PMC10605226

Xie

Chen

Shi

Circulating miRNAs act as potential biomarkers for asthma

Front Immunol 2023 14

1296177

10.3389/fimmu.2023.1296177

38173723

PMC10762778

Watanabe

Suzukawa

Tashimo

Ohshima

Asari

Takada

et al.

Low Serum IL-18 Levels May Predict the Effectiveness of Dupilumab in Severe Asthma

Intern Med 2024 63 179 87

10.2169/internalmedicine.1808-23

37225484

PMC10864083

Sardon-Prado

Diaz-Garcia

Corcuera-Elosegui

Korta-Murua

Valverde-Molina

Sanchez-Solis

Severe Asthma and Biological Therapies: Now and the Future

J Clin Med 2023 12

5846

10.3390/jcm12185846

37762787

PMC10532431

Kim

Shim

Kim

Cha

Hwang

Park

et al.

Increased levels of human myeloperxidase (MPO) and neutrophil lipocalin (HNL/NGAL) in childhood asthma. In: Conference: ERS International Congress 2019 abstracts. 2019. p. PA530.

10.1183/13993003.congress-2019.PA530

Obaid

Abdullah S

Ramadan

Makki

Al-Hindy HA

Mousa

Al-Mumin

Jihad

et al.

Serum Myeloperoxidase as a Biomarker of Asthma Severity Among Adults: A Case Control Study

Rep Biochem Mol Biol 2022 11 182 9

10.52547/rbmb.11.1.182

35765520

PMC9208555

Hassan

KAE

Kinawy

SAE

Mahmoud

The Role of Serum Myeloperoxidase in Prediction of Severe Bronchial Asthma

IJMA 2023 5 3373 8

Kim

Lee

Yang

Kashif

Hong

et al.

Suppressive effects of S100A8 and S100A9 on neutrophil apoptosis by cytokine release of human bronchial epithelial cells in asthma

Int J Med Sci 2020 17 498 509

10.7150/ijms.37833

32174780

PMC7053304

Quoc

Choi

Thi

Bich TC

Yang

Shin

Park

S100A9 in adult asthmatic patients: a biomarker for neutrophilic asthma

Exp Mol Med 2021 53 1170 9

10.1038/s12276-021-00652-5

34285336

PMC8333352

Jang

Olfactomedin 4 as a circulating biomarker for asthma

Ann Transl Med 2022 10

1085

10.21037/atm-22-3983

36388787

PMC9652564

Zhang

Liu

Tang

Chen

Wang

Pack

et al.

Identification and characterization of a novel member of the olfactomedin-related protein family, hGC-1, expressed during myeloid lineage development

Gene 2002 283 83 93

10.1016/s0378-1119(01)00763-6

11867215

Chen

Khalid

Chen

Qiu

Serum levels of olfactomedin 4: a biomarker for asthma control state in asthmatics

Ann Transl Med 2020 8

494

10.21037/atm.2020.03.213

32395538

PMC7210139

Espuela-Ortiz

Martin-Gonzalez

Poza-Guedes

González-Pérez

Herrera-Luis

Genomics of Treatable Traits in Asthma

Genes (Basel) 2023 14

1824

10.3390/genes14091824

37761964

PMC10531302

Shou

Wei

Wang

Zheng

Identification of TXN and F5 as novel diagnostic gene biomarkers of the severe asthma based on bioinformatics and machine learning analysis

Autoimmunity 2024 57

2427085

10.1080/08916934.2024.2427085

39531229

Park

Weiss

Understanding the Molecular Mechanisms of Asthma through Transcriptomics

Allergy Asthma Immunol Res 2020 12 399 411

10.4168/aair.2020.12.3.399

32141255

PMC7061151

Sheikhpour

Maleki

Ebrahimi

Vargoorani M

Amiri

A review of epigenetic changes in asthma: methylation and acetylation

Clin Epigenetics 2021 13

10.1186/s13148-021-01049-x

33781317

PMC8008616

Riccio

Mauri

Ferrari L

Rossi

Silvestre D

Bartezaghi

et al. PROXIMA sub-study centers

Plasma Galectin-3 and urine proteomics predict FEV₁improvement in omalizumab-treated patients with severe allergic asthma: Results from the PROXIMA sub-study

World Allergy Organ J 2020 13

100095

10.1016/j.waojou.2019.100095

32015785

PMC6992845

Suzuki

Cole

Konno

Makita

Kimura

Nishimura

et al.

Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma

Clin Transl Allergy 2021 11

e12091

10.1002/clt2.12091

34962717

PMC8686766

Maniscalco

Fuschillo

Paris

Cutignano

Sanduzzi

Motta

Clinical metabolomics of exhaled breath condensate in chronic respiratory diseases

Adv Clin Chem 2019 88 121 49

10.1016/bs.acc.2018.10.002

30612604

Kachroo

Sordillo

Lutz

Weiss

Kelly

McGeachie

et al.

Pharmaco-Metabolomics of Inhaled Corticosteroid Response in Individuals with Asthma

J Pers Med 2021 11

1148

10.3390/jpm11111148

34834499

PMC8622526

Galeana-Cadena

Gómez-García

Lopez-Salinas

Irineo-Moreno

Jiménez-Juárez

Tapia-García

et al.

Winds of change a tale of: asthma and microbiome

Front Microbiol 2023 14

1295215

10.3389/fmicb.2023.1295215

38146448

PMC10749662

Ivanova

Richards

Vijverberg

Neerincx

Sinha

Sterk

et al.

What did we learn from multiple omics studies in asthma?

Allergy 2019 74 2129 45

10.1111/all.13833

31004501

100

Sparreman

Mikus M

Kolmert

Andersson

Östling

Knowles

Gómez

et al. U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Eur Respir J 2022 59

2100142

10.1183/13993003.00142-2021

34737220

PMC8850689

101

Aili

Wang

Shang

Zhang

Liu

et al.

LPG 18:0 is a general biomarker of asthma and inhibits the differentiation and function of regulatory T-cells

Eur Respir J 2024 64

2301752

10.1183/13993003.01752-2023

39147414

PMC11618814

102

Fouka

Domvri

Gkakou

Alevizaki

Steiropoulos

Papakosta

et al.

Recent insights in the role of biomarkers in severe asthma management

Front Med (Lausanne) 2022 9

992565

10.3389/fmed.2022.992565

36226150

PMC9548530

103

Girodet

Strategies for Identifying Biomarkers in Severe Asthma

Am J Respir Crit Care Med 2024 210 251 2

10.1164/rccm.202404-0707ED

38701409

PMC11348967

104

Akdis

Arkwright

Brüggen

Busse

Gadina

Guttman-Yassky

et al.

Type 2 immunity in the skin and lungs

Allergy 2020 75 1582 605

10.1111/all.14318

32319104

105

Harada

Ito

Takahashi

Clinical effects and immune modulation of biologics in asthma

Respir Investig 2021 59 389 96

10.1016/j.resinv.2021.03.003

33893067

106

Arslan

Paçacı

Çetin G

Türk

Gülmez

Yılmaz

Discontinuing Omalizumab Treatment in Super-Responder Patients with Allergic Severe Asthma: Can the Baseline Total IgE Level Be Used as a Biological Marker to Decide Discontinuing Omalizumab Treatment?

Int Arch Allergy Immunol 2022 183 1071 7

10.1159/000525723

35917798

107

Wenzel

Castro

Corren

Maspero

Wang

Zhang

et al.

Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial

Lancet 2016 388 31 44

10.1016/S0140-6736(16)30307-5

27130691

108

Castro

Corren

Pavord

Maspero

Wenzel

Rabe

et al.

Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma

N Engl J Med 2018 378 2486 96

10.1056/NEJMoa1804092

29782217

109

Rabe

Nair

Brusselle

Maspero

Castro

Sher

et al.

Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma

N Engl J Med 2018 378 2475 85

10.1056/NEJMoa1804093

29782224

110

Huang

Pansare

New Treatments for Asthma

Pediatr Clin North Am 2019 66 925 39

10.1016/j.pcl.2019.06.001

31466682

111

Gauvreau

Sehmi

Ambrose

Griffiths

Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma

Expert Opin Ther Targets 2020 24 777 92

10.1080/14728222.2020.1783242

32567399

112

Miralles-López

Antolín-Amérigo

García-Moguel

Domínguez-Ortega

Delgado-Romero

Quirce

Positioning of Tezepelumab in Severe Asthma

J Investig Allergol Clin Immunol 2024 34 1 11

10.18176/jiaci.0949

37812191

113

Pelaia

Crimi

Benfante

Caiaffa

Calabrese

Carpagnano

et al.

Therapeutic Effects of Benralizumab Assessed in Patients with Severe Eosinophilic Asthma: Real-Life Evaluation Correlated with Allergic and Non-Allergic Phenotype Expression

J Asthma Allergy 2021 14 163 73

10.2147/JAA.S297273

33654413

PMC7910091

114

Kardas

Kuna

Panek

Biological Therapies of Severe Asthma and Their Possible Effects on Airway Remodeling

Front Immunol 2020 11

1134

10.3389/fimmu.2020.01134

32625205

PMC7314989

115

Calzetta

Aiello

Frizzelli

Bertorelli

Ritondo

Rogliani

et al.

The Impact of Monoclonal Antibodies on Airway Smooth Muscle Contractility in Asthma: A Systematic Review

Biomedicines 2021 9

1281

10.3390/biomedicines9091281

34572466

PMC8468486

116

Bossé

Smooth muscle in abnormal airways

Curr Opin Physiol 2021 21 1 8

10.1016/j.cophys.2021.03.002

117

Siddiqui

Redhu

Ojo

Liu

Irechukwu

Billington

et al.

Emerging airway smooth muscle targets to treat asthma

Pulm Pharmacol Ther 2013 26 132 44

10.1016/j.pupt.2012.08.008

22981423

118

Rutting

Xenaki

Reddy

Baraket

Chapman

King

et al.

Airway smooth muscle cells from severe asthma patients with fixed airflow obstruction are responsive to steroid and bronchodilator treatment in vitro

ERJ Open Res 2021 7

00117-2021

10.1183/23120541.00117-2021

34084782

PMC8165371

119

Smelter

Sathish

Thompson

Pabelick

Vassallo

Prakash

Thymic stromal lymphopoietin in cigarette smoke-exposed human airway smooth muscle

J Immunol 2010 185 3035 40

10.4049/jimmunol.1000252

20660708

PMC3681514

120

Laporte

Moore

Baraldo

Jouvin

Church

Schwartzman

et al.

Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells

Am J Respir Crit Care Med 2001 164 141 8

10.1164/ajrccm.164.1.2008060

11435252

121

Gounni

Wellemans

Yang

Bellesort

Kassiri

Gangloff

et al.

Human airway smooth muscle cells express the high affinity receptor for IgE (Fc epsilon RI): a critical role of Fc epsilon RI in human airway smooth muscle cell function

J Immunol 2005 175 2613 21

10.4049/jimmunol.175.4.2613

16081836

122

Chachi

Diver

Kaul

Rebelatto

Boutrin

Nisa

et al.

Computational modelling prediction and clinical validation of impact of benralizumab on airway smooth muscle mass in asthma

Eur Respir J 2019 54

1900930

10.1183/13993003.00930-2019

31391226

123

Elliot

Jones

Abramson

Green

Mauad

McKay

et al.

Distribution of airway smooth muscle remodelling in asthma: relation to airway inflammation

Respirology 2015 20 66 72

10.1111/resp.12384

25257809

124

Liu

Philp

Corte

Travis

Schilter

Hansbro

et al.

Therapeutic targets in lung tissue remodelling and fibrosis

Pharmacol Ther 2021 225

107839

10.1016/j.pharmthera.2021.107839

33774068

125

Laitinen

Haahtela

Airway mucosal inflammation even in patients with newly diagnosed asthma

Am Rev Respir Dis 1993 147 697 704

10.1164/ajrccm/147.3.697

8442607

126

Holgate

Wenzel

Postma

Weiss

Renz

Sly

Asthma

Nat Rev Dis Primers 2015 1

15025

10.1038/nrdp.2015.25

27189668

PMC7096989

127

Hough

Curtiss

Blain

Liu

Trevor

Deshane

et al.

Airway Remodeling in Asthma

Front Med (Lausanne) 2020 7

191

10.3389/fmed.2020.00191

32509793

PMC7253669

128

Bourdin

Neveu

Vachier

Paganin

Godard

Chanez

Specificity of basement membrane thickening in severe asthma

J Allergy Clin Immunol 2007 119 1367 74

10.1016/j.jaci.2007.01.055

17481707

129

Liu

Cooley

Nair

Donovan

Hsu

Jarnicki

et al.

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c

J Pathol 2017 243 510 23

10.1002/path.4979

28862768

130

Flood-Page

Menzies-Gow

Phipps

Ying

Wangoo

Ludwig

et al.

Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics

J Clin Invest 2003 112 1029 36

10.1172/JCI17974

14523040

PMC198522

131

Ventura

Vega

Chacón

Chamorro

Aroca

Gómez

et al.

Neutrophils from allergic asthmatic patients produce and release metalloproteinase-9 upon direct exposure to allergens

Allergy 2014 69 898 905

10.1111/all.12414

24773508

132

Vieira

Braga FA

Kar

Berg

Carpaij

Polanski

Simon

et al.

A cellular census of human lungs identifies novel cell states in health and in asthma

Nat Med 2019 25 1153 63

10.1038/s41591-019-0468-5

31209336

133

Hauber

Foley

Hamid

Mucin overproduction in chronic inflammatory lung disease

Can Respir J 2006 13 327 35

10.1155/2006/901417

16983448

PMC2683320

134

Hoshino

Takahashi

Aoike

Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis

J Allergy Clin Immunol 2001 107 295 301

10.1067/mai.2001.111928

11174196

135

Chetta

Zanini

Foresi

Del

Donno M

Castagnaro

D’Ippolito

et al.

Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone

Am J Respir Crit Care Med 2003 167 751 7

10.1164/rccm.200207-710OC

12468439

136

Yick

Ferreira

Annoni

von der Thüsen

Kunst

Bel

et al.

Extracellular matrix in airway smooth muscle is associated with dynamics of airway function in asthma

Allergy 2012 67 552 9

10.1111/j.1398-9995.2011.02773.x

22229658

137

Howarth

Knox

Amrani

Tliba

Panettieri

RA Jr

Johnson

Synthetic responses in airway smooth muscle

J Allergy Clin Immunol 2004 114 S32 50

10.1016/j.jaci.2004.04.041

15309017

138

Boulet

Airway remodeling in asthma: update on mechanisms and therapeutic approaches

Curr Opin Pulm Med 2018 24 56 62

10.1097/MCP.0000000000000441

29076828

139

Fehrenbach

Wagner

Wegmann

Airway remodeling in asthma: what really matters

Cell Tissue Res 2017 367 551 69

10.1007/s00441-016-2566-8

28190087

PMC5320023

140

Paw

Wnuk

Madeja

Michalik

PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients

Int J Mol Sci 2023 24

7721

10.3390/ijms24097721

37175437

PMC10178673

141

Varricchi

Poto

Lommatzsch

Brusselle

Braido

Virchow

et al.

Biologics and airway remodeling in asthma: early, late, and potential preventive effects

Allergy 2025 80 408 22

10.1111/all.16382

39520155

PMC11804314

142

Reeves

Kolstad

Lien

Elliott

Ziegler

Wight

et al.

Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components

J Allergy Clin Immunol 2014 134 663 70.e1

10.1016/j.jaci.2014.04.007

24875618

PMC4149938

143

Mostaço-Guidolin

Osei

Ullah

Hajimohammadi

Fouadi

et al.

Defective Fibrillar Collagen Organization by Fibroblasts Contributes to Airway Remodeling in Asthma

Am J Respir Crit Care Med 2019 200 431 43

10.1164/rccm.201810-1855OC

30950644

144

Lam

Royce

Samuel

Bourke

Serelaxin as a novel therapeutic opposing fibrosis and contraction in lung diseases

Pharmacol Ther 2018 187 61 70

10.1016/j.pharmthera.2018.02.004

29447958

145

Chakir

Shannon

Molet

Fukakusa

Elias

Laviolette

et al.

Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression

J Allergy Clin Immunol 2003 111 1293 8

10.1067/mai.2003.1557

12789232

146

Bergeron

Tulic

Hamid

Tools used to measure airway remodelling in research

Eur Respir J 2007 29 596 604

10.1183/09031936.00019906

17329494

147

Stewart

Smith

Chan

Eaden

Rajaram

Swift

et al.

Lung MRI with hyperpolarised gases: current & future clinical perspectives

Br J Radiol 2022 95

20210207

10.1259/bjr.20210207

34106792

PMC9153706

148

Hoshino

Ohtawa

Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma

Respiration 2012 83 520 8

10.1159/000334701

22236804

149

Tajiri

Niimi

Matsumoto

Ito

Oguma

Otsuka

et al.

Comprehensive efficacy of omalizumab for severe refractory asthma: a time-series observational study

Ann Allergy Asthma Immunol 2014 113 470 5.e2

10.1016/j.anai.2014.06.004

24994694

150

Haldar

Brightling

Hargadon

Gupta

Monteiro

Sousa

et al.

Mepolizumab and exacerbations of refractory eosinophilic asthma

N Engl J Med 2009 360 973 84

10.1056/NEJMoa0808991

19264686

PMC3992367

151

Diver

Khalfaoui

Emson

Wenzel

Menzies-Gow

Wechsler

et al. CASCADE study investigators

Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial

Lancet Respir Med 2021 9 1299 312

10.1016/S2213-2600(21)00226-5

34256031

152

McIntosh

Kooner

Eddy

Wilson

Serajeddini

Bhalla

et al.

CT Mucus Score and ¹²⁹Xe MRI Ventilation Defects After 2.5 Years’ Anti-IL-5Rα in Eosinophilic Asthma

Chest 2023 164 27 38

10.1016/j.chest.2023.02.009

36781102

153

Przybyszowski

Gross-Sondej

Zarychta

Bazan-Socha

Bochenek

Soja

et al.

Late Breaking Abstract - The impact of treatment with mepolizumab on airway remodeling in patients with severe eosinophilic asthma

In: ERS International Congress 2021 abstracts. 2021.

10.1183/13993003.congress-2021.PA894

154

Corren

Parnes

Wang

Roseti

Griffiths

et al.

Tezepelumab in Adults with Uncontrolled Asthma

N Engl J Med 2017 377 936 46

10.1056/NEJMoa1704064

28877011

155

Paganin

Mangiapan

Proust

Prudhomme

Attia

Marchand-Adam

et al.

Lung function parameters in omalizumab responder patients: An interesting tool?

Allergy 2017 72 1953 61

10.1111/all.13202

28517027

156

Corren

Castro

O’Riordan

Hanania

Pavord

Quirce

et al.

Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Allergic Asthma

J Allergy Clin Immunol Pract 2020 8 516 26

10.1016/j.jaip.2019.08.050

31521831

157

Busse

Bleecker

FitzGerald

Ferguson

Barker

Sproule

et al. BORA study investigators

Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial

Lancet Respir Med 2019 7 46 59

10.1016/S2213-2600(18)30406-5

30416083

158

Castro

Papi

Corren

Pavord

Tohda

Mao

et al.

Effect of dupilumab on lung function parameters in oral corticosteroid-dependent patients with asthma enrolled in liberty asthma traverse

Chest 2021 160 A1877 81

159

Chipps

Hirsch

Trudo

Alacqua

Zangrilli

Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma

Ann Allergy Asthma Immunol 2020 124 79 86

10.1016/j.anai.2019.10.006

31626906

160

Chupp

Bradford

Albers

Bratton

Wang-Jairaj

Nelsen

et al.

Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial

Lancet Respir Med 2017 5 390 400

10.1016/S2213-2600(17)30125-X

28395936

161

Bel

Wenzel

Thompson

Prazma

Keene

Yancey

et al. SIRIUS Investigators

Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma

N Engl J Med 2014 371 1189 97

10.1056/NEJMoa1403291

25199060

162

Menzella

Fontana

Galeone

D’Amato

Canonica

Ghidoni

et al.

A Real-World Evaluation of Clinical Outcomes of Biologicals and Bronchial Thermoplasty for Severe Refractory Asthma (BIOTERM)

J Asthma Allergy 2021 14 1019 31

10.2147/JAA.S324099

34413654

PMC8370487

163

Pham

Cook

Parnes

Colice

Griffiths

Tezepelumab Reduces Biomarkers of Airway Remodeling, MMP-10 and MMP-3: Exploratory Results from the Phase 3 NAVIGATOR Study

Am J Respir Crit Care Med 2022 205

A2359

10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A2359

164

Wechsler

Menzies-Gow

Brightling

Kuna

Korn

Welte

et al. SOURCE study group

Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study

Lancet Respir Med 2022 10 650 60

10.1016/S2213-2600(21)00537-3

35364018

165

Gordon

Husain

Charbeneau

Krishnan

Hogarth

Endobronchial biopsy: a guide for asthma therapy selection in the era of bronchial thermoplasty

J Asthma 2013 50 634 41

10.3109/02770903.2013.794239

23621125

166

Dunican

Watchorn

Fahy

Autopsy and Imaging Studies of Mucus in Asthma. Lessons Learned about Disease Mechanisms and the Role of Mucus in Airflow Obstruction

Ann Am Thorac Soc 2018 15 S184 91

10.1513/AnnalsATS.201807-485AW

30431352

PMC6322032

167

Thomas

Rutman

Hirst

Haldar

Wardlaw

Bankart

et al.

Ciliary dysfunction and ultrastructural abnormalities are features of severe asthma

J Allergy Clin Immunol 2010 126 722 9.e2

10.1016/j.jaci.2010.05.046

20673980

168

Savin

Zenkova

Sen’kova

Bronchial Asthma, Airway Remodeling and Lung Fibrosis as Successive Steps of One Process

Int J Mol Sci 2023 24

16042

10.3390/ijms242216042

38003234

PMC10671561