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Review Article
61 (
4
); 329-341
doi:
10.25259/ANAMS_136_2025

Breaking the steroid barrier: Emerging biomarkers and targeted therapies for type 2-low asthma

1Department of Medicine, Farukh Hussain Medical College, Agra, Uttar Pradesh, India

*Corresponding author: Dr. Rahul Garg, MD Medicine, Department of Medicine, Farukh Hussain Medical College, Agra, Uttar Pradesh, India. gargrahul27@gmail.com

Received: , Accepted: ,
© 2025 Published by Scientific Scholar on behalf of Annals of the National Academy of Medical Sciences (India)
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Garg R. Breaking the steroid barrier: Emerging biomarkers and targeted therapies for type 2-low asthma. Ann Natl Acad Med Sci (India). 2025;61:329-41. doi: 10.25259/ANAMS_136_2025

Abstract

Type 2-low (T2-low) asthma represents a heterogeneous chronic respiratory condition typified by airway inflammation that is not driven by eosinophils and inferior response to conventional therapies. With India facing a burden of approximately 34.3 million asthma cases, constituting 13.09% of the global burden, understanding T2-low endotypes is crucial for effective management. This review synthesizes current knowledge on T2-low asthma, encompassing neutrophilic, mixed granulocytic, and paucigranulocytic phenotypes. The pathophysiology involves complex mechanisms including neutrophil activation, NLRP3 inflammasome signaling, epithelial dysfunction, and cytokine pathways mediated by IL-17, IL-33, IL-1β, and IL-6. T2-low asthma patients demonstrate corticosteroid resistance, frequent exacerbations, and airway remodeling. Emerging biomarkers show promise for precise endotyping, including YKL-40, S100A9, serum amyloid A1 (SAA1), and neutrophil extracellular trap (NET) components. Novel therapeutic approaches targeting specific inflammatory pathways, like IL-33/ST2 inhibitors, IL-1β modulators, and TGF-β antagonists, offer hope for personalized treatment. This comprehensive overview highlights recent developments in biomarker identification and targeted therapies that may transform T2-low asthma management, moving toward precision medicine for this challenging patient population.

Keywords

Airway inflammation
Biomarkers
Corticosteroid resistance
IL-17
NLRP3 inflammasome
NETosis
Neutrophilic asthma
Paucigranulocystic asthma
Targeted therapy
Type 2-low asthma

INTRODUCTION

Asthma affects roughly 300 million individuals globally and represents a significant healthcare burden.1 India faces a significant asthma burden according to recent research. The Global Burden of Disease study (1990-2019) found that India has approximately 34.3 million asthma cases, representing about 13.09% of the global asthma burden.1 Earlier estimates suggested an overall asthma prevalence in India of around 3%, with 2.4% in adults over 15 years and between 4-20% in children.2 The mortality rate from asthma in India stands at 13.2 deaths per thousand.1 In India, asthma accounts for approximately 27.9% of disability-adjusted life years (DALYs) among the population.1 The Indian mortality rate from asthma is triple the global average, while asthma-related DALYs in India exceed the worldwide rate by more than twice.1

Despite advances in treatment, a substantial proportion of patients experience inadequate symptom control with current therapeutic regimens.1,3 The heterogeneity of asthma has been increasingly recognized, leading to a paradigm shift from a multipurpose outlook to precision medicine built on distinct disease endotypes.4-6

Disease subtypes characterized by specific underlying physiological processes are referred to as endotypes.4-6 In asthma, the most well-established classification divides the disease into T2-high and T2-low endotypes.7,8 T2-high asthma is characterized by eosinophilic inflammation driven primarily by cytokines such as IL-4, IL-5, and IL-13. In contrast, T2-low asthma represents a more heterogeneous group with complex and often poorly understood pathophysiology.6,9-12

While considerable break-throughs have been made in understanding and treating T2-high asthma with targeted biologics such as anti-IgE, anti-IL-5, and anti-IL-4/IL-13 therapies, T2-low asthma remains a therapeutic challenge.13,14 Patients with T2-low asthma often respond poorly to conventional treatments, including corticosteroids, highlighting the demand for good comprehension of underlying mechanisms and outcomes of targeted therapies.12,15

This review focuses on the current understanding of T2-low asthma endotypes, emerging biomarkers for diagnosis and treatment stratification, and novel therapeutic approaches. Our goal is to present a thorough examination of recent developments in this area, offering insights that can both enhance clinical approaches and shape the trajectory of upcoming research endeavors.

DEFINING T2-LOW ASTHMA

Historical context and evolution of asthma classification

The comprehension of asthma has evolved significantly over the past decades. Initially viewed as a single disease typified by reversible airflow limitation, asthma is now recognized as a heterogeneous syndrome encompassing multiple endotypes with distinct pathophysiological mechanisms.4-6 The concept of asthma phenotypes emerged with studies identifying clusters of clinical and inflammatory characteristics.16,17

The pioneering work by Woodruff et al. (2009) provided the foundation for the division of asthma into T2-high and T2-low endotypes based on gene expression patterns, identifying a T2-high gene signature characterized by elevated expression of IL-5, IL-13, and periostin in bronchial biopsies, which correlated with eosinophilic inflammation and response to corticosteroids.7

Current definition and clinical characteristics of T2-low asthma

T2-low asthma is defined by the absence or minimal presence of T2 inflammatory biomarkers such as blood or sputum eosinophils, exhaled nitric oxide (FeNO), and serum periostin, as shown in Table 1.4,9,18 T2-low asthma can be classified into three distinct inflammatory patterns based on sputum cell profiles: neutrophilic asthma (NA), mixed granulocytic asthma (MGA), and paucigranulocytic asthma (PGA).6,12,19

Table 1: Comparison of T2-High and T2-Low asthma.
Characteristic T2-High T2-Low
Inflammatory pattern Predominantly eosinophilic inflammation Neutrophilic, mixed granulocytic or paucigranulocytic
Key biomarkers

  • ↑Blood eosinophils

  • ↑FeNO

  • ↑Serum IgE and periostin

  • ↑IL-4, IL-5, IL-13

  • ↑YKL-40, S100A9 (NA)

  • ↑SAA1 (NA)

  • ↑IL-17, 1L-18, 1L-1β (NA)

  • ↑Glutaredoxin-1 (PGA)
Response to corticosteroid Generally good response Poor response (NA, MGA) Variable response (PGA) Higher steroid doses required
Response to corticosteroid Generally good response

Poor response (NA, MGA)

Variable response (PGA) Higher steroid doses required
Disease progression Associated with a higher risk of reduced lung function and more frequent exacerbations Progress at a slower rate compared to T2-high but still there is high propensity for exacerbations
Age of onset Typically develops earlier in life, often during childhood. Can have a later onset, sometimes in adulthood,
Common comorbidities

  • Allergic rhinitis

  • Chronic rhinosinusitis with and without nasal polyps

  • Eczema/atopic dermatitis

  • Obesity

  • Obstructive sleep apnea (OSA)

  • Gastroesophageal reflux disease (GERD)

  • Diabetes mellitus
Prevalence 83-89% 11.2-16.9%
Targeted therapies

  • Anti-IgE (Omalizumab)

  • Anti-IL-5 (Mepolizumab, benralizumab, reslizumab)

  • Anti-IL-4R (Dupilumab)

 For NA:

  • IL-33 blockers: Astegoilmab, Itepekimab

  • IL-1 pathway inhibitors: anakinra, canakinumab

For MGA:

  • TSLP inhibitors: Tezepelumab

  • For PGA:

  • TGF-β inhibitors: Galunisertib

  • Antifibrotic agents: Pirfenidone
Airway function

  • Variable airflow obstruction

  • Lower RV/TLC

  • Good bronchodilator response

  • More fixed airflow obstruction

  • Higher RV/TLC (air trapping)

  • Reduced bronchodilator response

FeNO: Fractional exhaled Nitric Oxide, IgE: Immunoglobulin E, IL: Interleukin, NA: Neutrophilic asthma, MGA: Mixed granulocytic asthma, PGA: Paucigranulocytic asthma, SAA1: Serum amyloid A1, TSLP: Thymic stromal lymphopoietin, TGF-β: Transforming growth factor beta, RV/TLC: Residual volume/total lung capacity.

Key clinical characteristics of T2-low asthma include:

  • Increased frequency among elderly patients who develop asthma later in life16,20

  • Resistance to standard medications, particularly corticosteroids12,15,21

  • A tendency toward asthma flare-ups and more serious disease manifestations13,22

  • Diminished effectiveness of bronchodilators, as shown by lower forced expiratory volume measurements (FEV1%)12

  • Airway obstruction and air confinement, measured by forced vital capacity (FVC%)12

  • Increased functional residual capacity (FRC)12

  • Greater need for steroids delivered through inhalers and orally to manage symptoms effectively.12,15,21

The prevalence of these T2-low phenotypes varies, with NA and MGA comprising approximately 4.3-5.4% and 5.2-6.7% of all asthma patients, respectively.19,23 PGA represents approximately 17-48% of asthma cases.13,17,23,24 These estimates vary depending on the cutoff values used for defining the inflammatory patterns.

INFLAMMATORY PHENOTYPES OF T2-LOW ASTHMA

Neutrophilic asthma

NA is a distinct asthma phenotype characterized by increased neutrophil presence in the airways. The definition of NA varies in medical literature, with proposed thresholds ranging from 40% to 76% of neutrophils in sputum samples. These varying cutoffs reflect differences in patient age, sputum collection methods, population demographics, and environmental exposures, including microbiota and air pollutants.24-28

Clinical features of NA include:

  • Decreased nitric oxide levels23

  • Lower blood eosinophil and basophil counts23

  • Compromised lung function23

  • Chronic neutrophilia23

  • Increased need for high-dose inhaled corticosteroids23

  • Higher risks of asthma exacerbations29

  • Oral corticosteroid dependence in some cases29

For definitive diagnosis of NA, the gold standard approach combines bronchial biopsy with sputum inflammatory cell analysis. Research has established a diagnostic threshold of 47.17 neutrophils per square millimeter in the bronchial lamina propria for patients with mild to severe asthma.30

Mixed granulocytic asthma

MGA is identified by both eosinophilia and neutrophilia in the sputum.17,23 This phenotype represents approximately 5.2-6.7% of all asthma patients.19,23 Patients diagnosed with MGA demonstrate elevated levels of both eosinophils and neutrophils in their airways. This dual inflammatory pattern correlates strongly with higher frequencies of asthma flare-ups and diminished effectiveness of steroid therapies.13,17

Paucigranulocytic asthma

PGA presents with typical eosinophil counts in the bloodstream and standard concentrations of eosinophils and neutrophils in airway secretions, while displaying the lowest nitric oxide measurements compared to other asthma types.13,19,23,24 This form of asthma tends to show modest severity and responds well to standard anti-inflammatory treatments.19,23,24 The absence of clearly defined diagnostic criteria for PGA has complicated efforts to comprehend its biological mechanisms and create specific therapeutic approaches for this subtype. Emerging research indicates that compromised respiratory function in PGA patients correlates with disrupted oxidative stress balance in the airways. Measurements of glutaredoxin-1 and protein-glutathione mixed disulfide concentrations in airway samples have proven useful for differentiating PGA patients from individuals with alternative asthma phenotypes.31

PATHOPHYSIOLOGICAL MECHANISMS IN T2-LOW ASTHMA

T2-low asthma involves multiple, often overlapping pathways that cause airway inflammation and remodeling [Figure 1], distinct from T2-high asthma, where IL-4, IL-5, and IL-13 play well-established roles. Understanding these mechanisms is crucial for identifying potential biomarkers and therapeutic targets.

Pathophysiological Mechanisms of T2-Low Asthma. The central blue circle represents T2-low asthma, with solid lines indicating direct mechanistic pathways and dotted lines showing cross-pathway interactions.
Figure 1:
Pathophysiological Mechanisms of T2-Low Asthma. The central blue circle represents T2-low asthma, with solid lines indicating direct mechanistic pathways and dotted lines showing cross-pathway interactions.

A. Neutrophilic and mixed granulocytic inflammation pathways

1. Airway epithelial cell-mediated mechanisms

Airway epithelial cells (AECs) serve as mediators between the internal and external environments through cytokine signaling. When damaged or exposed to pathogens and irritants, AECs release alarm molecules, including IL-33 and thymic stromal lymphopoietin (TSLP).32-34 These alarm signals activate specific receptors, triggering downstream pathways that stimulate immune responses.35 TSLP can prompt dendritic cells to secrete IL-6 and IL-23, which drive CD4+ T-cell differentiation into Th17 lymphocytes. Additionally, AECs produce CXCL8 (IL-8), which attracts and activates neutrophils in severe asthma cases. IL-8-induced NETs correlate negatively with FEV1/FVC ratios, suggesting a possible connection between these structures and airflow restrictions.36

2. Neutrophil extracellular traps (NETs)

Neutrophil activation involves NETosis, where neutrophils release extracellular chromatin structures containing proteins and enzymes in response to various pathogens and inflammatory stimuli.32-34,36 These NETs capture and neutralize pathogens, but their dysregulation can contribute to autoimmune diseases, thrombosis, and tissue damage, including NA or MGA.37 NETs can damage AECs and activate eosinophils. The alarmin IL-33, released by damaged epithelial cells, can trigger neutrophil activation through specific receptor interactions, with increased IL-33 receptor expression observed in severe NA/MGA patients.34,38

3. Leukocyte-mediated mechanisms

The transformation process wherein undifferentiated CD4+ T-cells develop into specific T helper cell lineages, including Th1, Th2, and Th17 populations, represents a fundamental immunological mechanism underlying the diverse endotypes observed in asthma pathophysiology. In T2-low asthma, neutrophil and macrophage activation may result from Th1-produced IFN-γ and Th17-produced cytokines including IL-17A, IL-17E, IL-17F, and IL-22.39 IL-17, primarily secreted by Th17 and ILC3 cells under ROR-γt/ROR-c transcription factor regulation, is elevated in severe NA patients, correlating with bacterial infections, neutrophilia, smoking, frequent exacerbations, and steroid resistance.29,40-42 IL-17 also contributes to steroid resistance by reducing histone deacetylase 2 (HDAC2) activity.15 IL-17 promotes airway remodeling through goblet cell hyperplasia and smooth muscle proliferation, while stimulating structural cells to release neutrophil-activating factors like CXCL8/IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and TNF-α.40

4. NLRP3 inflammasome activation

The NLRP3 inflammasome functions as a multiprotein cytoplasmic complex that, upon activation, triggers the release of inflammatory mediators including interleukin-1β and interleukin-18. Research has demonstrated enhanced activity of the NLRP3 inflammasome pathway specifically in NA cases, which may explain the reduced responsiveness to steroid therapy observed in these patients.43,44

5. Otulin dysregulation

Recent research has identified downregulation of otulin, a deubiquitinase enzyme, as a potential mechanism for inflammasome activation in NA, suggesting a novel therapeutic target.45

6. Macrophage-mediated mechanisms

Macrophages are essential for immune homeostasis, but transcriptomic analyses suggest their function may be impaired in asthma patients.46 When stimulated by lipopolysaccharide or IFN-γ, they polarize to a proinflammatory M1 phenotype, releasing cytokines like IL-1β, TNF-α, and IL-6 that recruit airway neutrophils and reduce responsiveness to anti-inflammatory treatments.47 IL-1β release from macrophages is modulated by inflammasomes, which activate this cytokine to sustain inflammation in NA.47 Elevated IL-6 levels in serum, sputum, and plasma correlate with asthma severity, decreased lung function, obesity, and neutrophilia.48-50 TNF-α contributes to NA pathophysiology, with its inhalation shown to increase airway hyperresponsiveness and sputum neutrophilia.51

Non-inflammatory mechanisms

Beyond inflammation, several non-inflammatory mechanisms contribute to T2-low asthma pathophysiology:

  • 1.

    Neurogenic inflammation: Neurogenic mechanisms, including sensory nerve activation and neuropeptide release, contribute to bronchospasm and airway hyperresponsiveness in T2-low asthma.14,20

  • 2.

    Metabolic pathways: Emerging evidence suggests that metabolic dysfunction, particularly in obesity-associated asthma, contributes to T2-low inflammation through altered lipid metabolism, including ceramide accumulation.52,53

  • 3.

    Airway remodeling: The T2-low asthma phenotype frequently exhibits more extensive structural alterations in the airways, including hypertrophy of bronchial smooth muscle tissue, fibrotic changes beneath the epithelial layer, and accumulation of extracellular matrix components.14,22 These structural changes contribute to fixed airflow limitation and poor response to conventional therapies.

B. Mechanisms in paucigranulocytic asthma

The mechanisms underlying PGA remain incompletely understood. Unlike neutrophilic or eosinophilic asthma, PGA airways lack significant granulocyte infiltration, suggesting a distinct pathophysiology. The architectural restructuring of airways emerges as a critical component in disease progression, possibly mediated through TGF-β signaling cascades that enhance collagen production and foster fibrotic tissue development. Epithelial-mesenchymal transitions may also contribute to airway remodeling in PGA patients.54,55

EMERGING BIOMARKERS FOR T2-LOW ASTHMA

The recognition of reliable biomarkers for T2-low asthma presents a significant problem due to the heterogeneity of this endotype and the lack of a dominant inflammatory pathway. Unlike T2-high asthma, which has well-accepted biomarkers such as blood eosinophils, FeNO, and serum IgE, T2-low asthma biomarkers are still emerging. The identification of reliable biomarkers for T2-low asthma is essential for accurate diagnosis, endotyping, and personalized treatment approaches. Several potential biomarkers have been identified for different T2-low phenotypes.

A. Biomarkers for neutrophilic asthma

YKL-40 (Chitinase-like protein)

YKL-40 (human cartilage glycoprotein 39) has emerged as a potential NA biomarker.30 Elevated serum levels correlate with lung YKL-40 concentrations, reduced FEV1%, and severe asthma risk. YKL-40 levels significantly associate with neutrophil activation markers, including myeloperoxidase, IL-8, IL-6, and soluble IL-6 receptor.30,56

S100A9

Research has highlighted S100 calcium-binding protein A9 (S100A9) as a promising diagnostic indicator for NA.57 This protein functions as a damage-associated molecular pattern (DAMP) molecule and shows elevated concentrations in both blood serum and sputum samples from NA patients. The measured levels of S100A9 show significant correlation with neutrophil abundance and asthma severity, suggesting this protein could serve as a valuable clinical marker for both diagnosis and prognosis assessment.57

Serum amyloid A1 (SAA1)

Serum amyloid A1 (SAA1) is an acute-phase protein that is elevated in patients with NA.58 SAA1 may serve as a substitute marker for neutrophilic inflammation and help identify patients who might benefit from targeted therapies.

NET components

Components of NETs have emerged as potential biomarkers for NA:

  • 1.

    Cell-free DNA in sputum and plasma has been associated with neutrophilic inflammation and disease severity in asthma36

  • 2.

    Myeloperoxidase-DNA complexes, specific markers of NETs, have been found in higher concentrations in the airways of patients with NA and correlate with disease severity36

Cytokines and chemokines

Several inflammatory mediators have been suggested as budding biomarkers for T2-low asthma:

  • 1.

    IL-17: Elevated in both sputum and serum of patients with NA, IL-17 correlates with disease severity and steroid resistance.10,34 However, significant overlap exists between IL-17 levels in different asthma endotypes, limiting its specificity.29,59,60

  • 2.

    IL-8 (CXCL8): IL-8 effectively attracts neutrophils to inflammatory sites, with concentrations found in sputum and blood showing a correlation with neutrophilic inflammation. This relationship makes IL-8 a potential biomarker for identifying the T2-low endotype of asthma.61 Studies have found that patients with higher IL-8 levels tend to experience more severe disease manifestations and typically respond less favorably to corticosteroid treatment.12

  • 3.

    IL-1β: Associated with NLRP3 inflammasome activation, IL-1β levels in sputum may identify patients with inflammasome-driven neutrophilic inflammation.43,44

Metabolic biomarkers

Metabolomic approaches have identified several potential biomarkers in T2-low asthma:

  • 1.

    Ceramides: Altered ceramide metabolism, particularly increased C18:0 ceramide, has been observed in obesity-associated T2-low asthma.52 Serum ceramide levels may serve as biomarkers for this specific endotype.

  • 2.

    Amino acid metabolites: Changes in tryptophan, arginine, and glutamine metabolism have been identified in T2-low asthma and may serve as potential biomarkers.53 However, further validation in larger cohorts is needed.

Sputum and blood neutrophils

Sputum neutrophilia (>61-76% of total cells) is a characteristic feature of neutrophilic T2-low asthma.17,24 However, several limitations restrict its use in clinical practice, including technical challenges in sputum collection and processing, poor correlation between blood and sputum neutrophil counts, variability in neutrophil counts due to infections, corticosteroid use, and environmental exposures, and lack of standardized cutoff values.

Blood neutrophil-to-lymphocyte ratio (NLR) has been proposed as a more accessible substitute marker for airway neutrophilia, with preliminary studies showing correlations with asthma severity in T2-low patients.62,63 However, further validation is needed before implementation in clinical practice.

Sputum and blood eosinophils

In T2-low asthma, sputum eosinophil counts are generally below 2% or 3%, depending on the definition used. Sputum eosinophilia >3% is often associated with a better response to corticosteroid therapy, which is less effective in T2-low asthma.24,64 Similarly, blood eosinophil counts are typically within the normal range (e.g., 30-350 cells/µL) or lower in T2-low asthma. A significant portion of patients with T2-low asthma may have had elevated blood eosinophils in the past, suggesting that the phenotype may be a shift from T2-high asthma.24,64

Mixed-granulocytic asthma is considered when sputum eosinophils ≥2% and neutrophils ≥40%.64

B. Biomarkers for paucigranulocytic asthma

Identifying biomarkers for PGA is particularly challenging due to the lack of prominent inflammatory cells in the airways. However, some potential biomarkers have been identified:

  • 1.

    The presence of glutaredoxin-1 and protein-glutathione mixed disulfides in sputum samples has been identified as a potential distinguishing marker between patients who have PGA and individuals with other asthma phenotype classifications.31

  • 2.

    Analysis of gene expression patterns through transcriptomic examination of sputum specimens has revealed distinctive molecular signatures associated with PGA.54,64

C. Composite biomarker approaches

Given the limitations of individual biomarkers, composite approaches combining multiple markers may provide better classification of T2-low asthma endotypes:

  • 1.

    Cluster analysis of inflammatory biomarkers: Studies such as the International Severe Asthma Registry have used cluster analysis of multiple inflammatory markers to identify distinct T2-low endotypes with different clinical characteristics and outcomes.65

  • 2.

    Transcriptomic profiling: Gene expression profiles in AECs or peripheral blood may help identify T2-low endotypes with distinct underlying mechanisms.66

  • 3.

    Systems biology approaches: Integration of multiple data types (genomics, transcriptomics, proteomics, metabolomics) may provide a more comprehensive characterization of T2-low endotypes.67

Recent work by Heaney et al. (2021) demonstrated that a composite type-2 biomarker strategy could detect patients with T2-low asthma who might get relief from alternative treatment approaches.68 Similarly, the BREATHE study showed that combining multiple biomarkers improved the identification of T2-low patients compared to individual markers.69

CURRENT AND EMERGING TREATMENT APPROACHES

Management of T2-low asthma presents significant challenges due to the heterogeneity of underlying mechanisms and relative resistance to conventional therapies, including corticosteroids. This section reviews current treatment strategies and emerging targeted approaches for T2-low asthma.

A. Limitations of conventional therapies

Corticosteroid Resistance

Steroid resistance is a hallmark of T2-low asthma, particularly in patients with NA. Several mechanisms contribute to this steroid resistance:

  • 1.

    Neutrophil cell death through apoptosis may be inhibited by steroids, potentially extending their lifespan.70

  • 2.

    Neutrophil activation involves the process of NETosis, which may not be effectively targeted by steroids.12

  • 3.

    IL-17, a key cytokine in NA, can reduce the expression and activity of HDAC2, a crucial enzyme for the anti-inflammatory actions of steroids.15

  • 4.

    Activation of pro-inflammatory transcription factors resistant to corticosteroid inhibition, such as NF-κB and AP-1.12,15

As a result, patients with NA or MGA typically require higher doses of inhaled and oral corticosteroids to control their symptoms yet may still experience suboptimal disease control.29

Other conventional therapies

Other components of standard asthma treatment, including long-acting β2-agonists (LABAs), long-acting muscarinic antagonists (LAMAs), and leukotriene modifiers, show variable efficacy in T2-low asthma:

  • 1.

    LAMAs, such as tiotropium, may provide benefit in some T2-low patients by targeting bronchoconstriction independent of inflammatory pathways.20,71

  • 2.

    Macrolide antibiotics have shown efficacy in some patients with NA, likely due to their anti-inflammatory properties rather than antimicrobial effects.12,71

  • 3.

    Leukotriene modifiers typically show reduced response in T2-low compared to T2-high asthma.20

B. Targeted therapies for T2-low endotypes

Therapies targeting the epithelium

Several biologics targeting epithelial-derived cytokines show promise in treating T2-low asthma:

  • 1.

    Tezepelumab: This monoclonal antibody blocks TSLP signaling. Although it did not significantly change neutrophil counts in bronchial biopsies in a study of moderate-to-severe asthma, it manifested good safety and tolerability.32

  • 2.

    Itepekimab: Targeting IL-33 signaling, itepekimab improved pre-bronchodilator lung function in patients with moderate-to-severe asthma and manifested good safety.33

  • 3.

    Astegolimab: This monoclonal antibody blocks the IL-33 receptor (ST2). It reduced asthma exacerbation rates, with particularly promising results in patients with low eosinophil counts (<150 cells/μL), suggesting potential efficacy in T2-low asthma.72

  • 4.

    GSK3772847: Another IL-33 receptor blocker, it decreased asthma exacerbations by 18% compared to placebo in patients who had uncontrolled asthma.73

  • 5.

    AZD5069: This CXCR2 receptor antagonist decreased sputum neutrophil counts by 90% in patients with moderate persistent NA but did not show significant improvements in clinical outcomes.74

Therapies targeting leukocytes

Several biologics targeting leukocyte-derived cytokines have been investigated:

  • 1.

    Brodalumab and CJM112: These IL-17 pathway inhibitors targeting the IL-17 receptor and IL-17A, respectively, did not demonstrate significant clinical benefits in patients with moderate-to-severe asthma.59,75

  • 2.

    Risankizumab: This IL-23 inhibitor failed to demonstrate meaningful clinical benefits in individuals with severe asthma. It neither substantially improved patient outcomes nor altered the neutrophil levels measured in sputum samples.76

  • 3.

    IFN-β supplementation: Despite the rationale for using IFN-β to enhance antiviral immunity in asthma, clinical trials with SNG001 and AZD9412 (inhaled IFN-β) have shown disappointing results.77,78

Therapies targeting macrophages

Several biologics targeting macrophage-derived cytokines are under investigation:

  • 1.

    Anakinra and canakinumab: These IL-1 pathway inhibitors (IL-1 receptor antagonist and anti-IL-1β antibody, respectively) have shown promising results in small studies, reducing airway neutrophilia and decreasing IL-1β levels.79,80

  • 2.

    Sirukumab and clazakizumab: These IL-6 inhibitors are being studied for their potential in treating severe asthma, but safety concerns have led to the withdrawal of sirukumab due to increased mortality and malignancy risks.81,82

  • 3.

    Etanercept: This TNF-α receptor blocker improved post-bronchodilator lung function in a small study of patients with refractory severe asthma but did not alter sputum IL-8 levels.83

  • 4.

    Golimumab: Another TNF-α antagonist, failed to demonstrate meaningful improvements in respiratory function or reductions in asthma attacks when compared to placebo. Additionally, patients receiving this therapy experienced adverse events, including heightened risk of infections and cancer development.84

Therapies for airway remodeling in paucigranulocytic asthma

For patients with PGA, therapies targeting airway remodeling show promise:

  • 1.

    Galunisertib: This TGF-β1 receptor blocker effectively limits scarring processes. Both laboratory studies and human clinical investigations across multiple disorders characterized by tissue fibrosis have demonstrated its potential benefits.85

  • 2.

    Pirfenidone: An antifibrotic agent, which has demonstrated capabilities in decreasing the accumulation of collagen and limiting fibrotic processes across various respiratory conditions.86

  • 3.

    PPAR-γ agonists: Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, such as rosiglitazone, have shown potential in restoring epithelial integrity and reducing airway hyperresponsiveness in preclinical models.12,87

  • 4.

    Bronchial thermoplasty (BT): BT substantially decreases nervous tissue density within both the epithelial layer and muscle tissues surrounding the airways. This reduction in nerve fibers appears to diminish neural response pathways, which may explain how the treatment produces its positive clinical outcomes.88

Metabolic modulators

For obesity-associated T2-low asthma, therapies targeting metabolic dysfunction show promise:

  • 1.

    Statins: Beyond their primary function of decreasing lipid levels, statins have anti-inflammatory properties that may benefit patients with metabolic asthma.12,14,88

  • 2.

    Weight loss interventions: Dietary changes and bariatric surgery have demonstrated benefits in asthma control and lung function in obese patients with T2-low asthma.14,88

Figure 2 presents a comprehensive clinical algorithm that integrates biomarker assessment with phenotype-specific treatment approaches, providing a framework for precision medicine in T2-low asthma management.

Diagnostic and treatment algorithm for T2-low asthma phenotypes. FeNO: Fractional exhaled nitric oxide, ICS: Inhaled corticosteroids, LABA: Long-acting β2-agonists, LAMA: Long-acting muscarinic antagonists, IL: Interleukin, TSLP: Thymic stromal lymphopoietin, TGF-β: Transforming growth factor-beta, SAA1: Serum amyloid A1. NLR: Neutrophil-to-lymphocyte ratio.
Figure 2:
Diagnostic and treatment algorithm for T2-low asthma phenotypes. FeNO: Fractional exhaled nitric oxide, ICS: Inhaled corticosteroids, LABA: Long-acting β2-agonists, LAMA: Long-acting muscarinic antagonists, IL: Interleukin, TSLP: Thymic stromal lymphopoietin, TGF-β: Transforming growth factor-beta, SAA1: Serum amyloid A1. NLR: Neutrophil-to-lymphocyte ratio.

FUTURE DIRECTIONS AND CHALLENGES

Despite advances in understanding T2-low asthma, several challenges and opportunities remain for future research and clinical practice:

  • 1.

    Standardization of biomarkers: Establishing consensus on cutoff values for defining different T2-low phenotypes is essential for accurate diagnosis and treatment selection.

  • 2.

    Personalized treatment approaches: Developing treatment algorithms based on specific endotypes and biomarker profiles may improve outcomes in T2-low asthma.

  • 3.

    Novel therapeutic targets: Further research is needed to identify and validate new therapeutic targets for T2-low asthma, particularly for PGA.

  • 4.

    Combination therapies: Given the complex pathophysiology of T2-low asthma, combination approaches targeting multiple pathways simultaneously may be more effective than monotherapies.

  • 5.

    Implementation in clinical practice: Translating research findings into clinical practice requires robust biomarkers that are accessible, reliable, and cost-effective.

CONCLUSION

T2-low asthma presents a critical therapeutic challenge, with corticosteroid resistance affecting millions globally. Our evolving understanding of its diverse endotypes—neutrophilic, mixed granulocytic, and paucigranulocytic, has revealed distinct pathophysiological mechanisms and promising biomarkers, including YKL-40, S100A9, and NET components. Novel therapeutic approaches targeting IL-33/ST2, IL-1β, and TGF-β pathways offer unprecedented hope for this underserved patient population. As we advance toward personalized medicine, standardizing biomarkers and implementing targeted therapies will transform T2-low asthma management, ultimately improving outcomes for patients who have long struggled with conventional treatments.

Ethical approval

Institutional Review Board approval is not required.

Declaration of patient consent

Patient’s consent not required as there are no patients in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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