Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

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Chinese Medical Journal Pulmonary and Critical Care

Medicine
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Review Article

Asthma endotypes and theratypes

Ioana Agache a,∗, Shengjie Li b, Yang Zheng b, Yadong Gao b,∗∗
a
Transylvania University of Brasov, Faculty of Medicine, Brasov 500051, Romania
b
Department of Allergy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China

a r t i c l e i n f o a b s t r a c t

Edited by: Peifang Wei The model of asthma as a single entity has now been replaced by a much more complex biological network of dis-
tinct and interrelating inflammatory and tissue driven pathways. Individual disease manifestations (phenotypes),
Keywords:
Asthma pathogenetic pathways (endotypes) and response to therapy (theratypes) are discussed here in the context of
Biomarkers current stratified management of asthma in the clinic based on biomarkers measured at the point-of-care. As the
Endotype current classification criteria result in significant overlaps among phenotypes, endotypes and theratypes, this pa-
Machine learning per further describes the advantage of combining precision immunology, imaging and the digital biomarkers in an
Precision immunology unbiased approach offered by machine learning. The new European Academy of Allergy and Clinical Immunology
Theratype (EAACI) nomenclature for hypersensitivity reaction is detailed as a basis for the stratified asthma management
with a special focus on tissue-driven mechanisms (type V asthma), metabolic/microbiome/epigenetic/neurogenic
mechanisms (type VI asthma) and direct cellular activation (type VII asthma).

Introduction: the current framework for asthma management mediators are targets for pharmaceutical intervention for patients with
uncontrolled severe asthma.
Type 2-high and type 2-low asthma T2-low asthma is traditionally defined as asthma without features of
T2 asthma and is usually connected with poor responsiveness to corti-
Asthma is a complex chronic respiratory disorder characterized costeroids (both inhaled and oral) and more severe clinical course, even
by marked heterogeneity in individual patient disease manifestations in childhood.10–12 Very little is known about its mechanisms, making it
(phenotypes, visible properties, treatable traits), pathogenetic path- a significant unmet need in asthma research.13 The definition is arbi-
ways (endotypes) and response to therapy (theratypes).1–6 Several trary and is generally based on the presence of neutrophils in sputum,
asthma phenotypes have now been identified, each defined by a unique or the absence (or normal levels) of eosinophils or other T2 markers
interaction between genetic and environmental factors, including in- in sputum (paucigranulocytic), airway biopsies or in blood. This def-
flammatory, clinical and trigger-related phenotypes. Endotypes further inition may be imprecise as we gain more knowledge from applying
describe the functional or pathophysiologic mechanisms underlying the transcriptomics and proteomics to blood and airway samples and by us-
patient’s disease. Based on the major immune-inflammatory pathway ing multiomics and imaging integration.14–16 Non-T2 inflammation is
involved, severe asthma can be classified as type-2 (T2) high, T2-low characterized by activation of T helper (Th)1 and Th17 cells and neu-
and mixed endotypes, and these categories share several common trophils, the presence of type I interferons (IFN), NOD-like receptor pro-
pathogenetic pathways such as genetic and epigenetic, metabolic, tein 3 (NLRP3) inflammasome activation, and an interleukin (IL)-1𝛽 and
neurogenic and remodeling subtypes6–8 (Fig. 1). Less is known on the IL-17 signature.12 , 17–20 IL-17 induces a predominantly neutrophilic air-
endotypes of mild asthma.7 way inflammation, mucus hypersecretion, goblet cell hyperplasia, my-
T2-high asthma is a well-established nomenclature for a common ofibroblast differentiation, and airway smooth muscle proliferation.21
subtype of asthma and is characterized by the release of signature cy- Th17 cells and its cytokines are implicated in mechanisms of steroid
tokines interleukin (IL)-4, IL-5 and IL-13 from cells of both the innate resistance in asthma via induction of glucocorticoid receptor‐𝛽 (GR‐𝛽)
and adaptive immune systems, followed by the involvement of effector expression and reduced apoptosis. Furthermore, glucocorticoid treat-
pathways mediated by specific immunoglobulin (Ig) E, mast cells and ment also enhanced IL-17 production. The NLRP3 inflammasome ac-
eosinophils.6 , 7 , 9 Several of these T2 cytokines and effectors cells and tivates caspase-1 to process pro-IL-1𝛽 into its mature, secreted form.

∗
Corresponding author at: Transylvania University of Brasov, Faculty of Medicine, Brasov 500051, Romania.
∗∗
Corresponding author at: Department of Allergy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
E-mail addresses: ibrumaru@[Link] (I. Agache), gaoyadong@[Link] (Y. Gao)

[Link]
Received 8 January 2026; Available online 13 March 2026
2097-1982/© 2026 The Authors. Published by Elsevier B.V. on behalf of Chinese Medical Association. This is an open access article under the CC BY-NC-ND license
([Link]
I. Agache, S. Li, Y. Zheng et al. Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

Fig. 1. Current framework of asthma phenotype. Major inflam-

matory pathways distinguishing T2-high and T2-low asthma en-
dotypes are shown. Left panel (without T2 biomarkers): Viral in-
fections drive Th1 responses leading to IFN-𝛾 production and GS-
DMB expression; Th17 responses produce IL-17, recruiting neu-
trophils and contributing to non-T2 asthma, often associated with
airway remodeling influenced by ORMDL3. Right panel (with T2
biomarkers): Air pollutants stimulate airway epithelium to release
IL-33, IL-25, and TSLP, activating ILC2 and promoting IL-4, IL-
13, and IL-5 production; aeroallergens engage APC to drive Th2
differentiation, resulting in elevated IgE, FeNO, and eosinophilia
characteristic of T2 asthma, allergic asthma and eosinophilic
asthma. APC, Antigen-presenting cell; Eos, Eosinophils; FeNO,
Fractional exhaled nitric oxide; GSDMB, Gasdermin B; IFN-𝛾,
Interferon-𝛾; IgE, Immunoglobulin E; IL, Interleukin; ILC2, Type
2 innate lymphoid cells; ORMDL3, Orosomucoid 1-like 3; Th, T
helper; TSLP, Thymic stromal lymphopoietin; T2, Type 2.

Caspase-1 also cleaves gasdermin-D (GSDMD) into fragments that as- The prevalence of T2-low asthma is difficult to estimate as most stud-
semble into a plasma membrane pore releasing mature IL-1𝛽 from cells ies are cross-sectional and influenced by concomitant treatment with
and inducing pyroptotic cell death.22 A non-canonical inflammasome corticosteroids, and by the presence of recognized or unrecognized air-
comprised of caspase-4 and caspase-5 also cleaves GSDMD, with resul- way infections or by recent exposure to outdoor or indoor pollutants.
tant activation of the NLRP3 inflammasome and caspase-1. Caspase-1 In a cohort of T2-high severe asthma patients stable on mepolizumab,
activation and GSDMD cleavage also generate neutrophil extracellu- a subgroup of patients with long duration of disease had worse clinical
lar traps (NETs). In severe asthma, sputum neutrophils correlate with parameters, increased sputum proteins with increased markers of neu-
sputum extracellular DNA levels indicative of NET formation, while trophil activity, proinflammatory cytokines and epithelial alarmins.33
increased sputum extracellular DNA is associated with increased spu- This suggests the involvement of non-T2 inflammatory pathways that
tum IL-1𝛽 and asthma severity.23 Bronchoalveolar lavage fluid from pa- are not targeted by current T2-biologics. These pathways may repre-
tients with severe asthma and high neutrophil counts had detectable sent treatable traits in severe asthma, warranting further investigation.
NETs and cytoplasts that were positively correlated with IL-17 levels.24 Another study explored the physiological changes at exacerbation in
Like other gasdermin family members, gasdermin-B (GSDMB) may pro- patients with asthma who were T2-high and T2-low and evaluated the
mote inflammasome-mediated pyroptosis in non-T2 asthma.24 Addition- stability of inflammatory phenotypes during stable disease and exac-
ally, expression levels of GSDMB correlated with genes involved in IFN erbation. At enrollment, 23.6% were T2-low. These patients had more
response in airway epithelial cells, and GSDMB contributes to child- primary care attendances and were more likely to have a previous ad-
hood asthma, possibly related to increased IL-17A response to viral mission to intensive care and to be receiving maintenance oral corticos-
infections.25 , 26 Rhinovirus infection in patients with asthma leads to teroids (OCS). At exacerbation, the T2-low events were indistinguish-
an excessive retinoic acid‑inducible gene‑I (RIG-I) inflammasome acti- able from T2-high exacerbations in terms of lung function and asthma
vation, which disrupts effective RIG-I-dependent type I/III interferon control. There was no increase in T2 biomarkers from stable to ex-
responses, leading to early functional antiviral impairment, prolonged acerbation state in the T2-low exacerbations. The inflammatory phe-
viral clearance and unresolved inflammation in vitro and in vivo. Pre- notype within individual patients was dynamic, with T2-low asthma
exposure to house dust mite augments this phenomenon by inflam- being an unstable inflammatory phenotype. The inflammatory pheno-
masome priming and auxiliary inhibition of early type I/III interferon type at study entry did not have a significant association with exacer-
responses.27 Epithelial-derived cytokines (IL-33, thymic stromal lym- bation phenotype.34 Furthermore, the inflammatory phenotype might
phopoietin [TSLP], IL-25) are similarly released by drivers of type-2 low vary according to the region or exposure—a concept coined as a regio-
pathology such as cigarette smoke, diesel exhaust particles, microbes or type.6 Using induced sputum to compare asthma inflammatory pheno-
proteases and thus can represent therapeutic targets in T2-low asthma.13 types in high income versus low- and middle-income countries (LMIC),
IL-33-activated gene signatures are elevated in neutrophilic and mixed an epidemiological survey showed that in LMIC 61% of cases were
granulocytic asthma corresponding with interleukin-1 receptor acces- non-eosinophilic, including in settings where corticosteroid use was
sory protein (IL1RAP) co-receptor expression.28 Increased expression of low.35
sphingolipid biosynthesis regulator 3 (ORMDL3) may contribute to the
development of paucigranulocytic asthma, by inducing the upregulation Defining asthma endotypes based on biomarkers
of mediators involved in airway remodeling rather than inflammation,
by promoting autophagic cell death in airway epithelial cells, by reduc- Several well-recognized biomarkers are used clinically to diagnose
ing the levels of serum sphingolipids and by increased airway hyperre- T2-high asthma, including blood eosinophils, fractional exhaled nitric
activity (AHR).29–32 oxide (FeNO), and specific immunoglobulin E (IgE)36 (Fig. 1). An ob-

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servational study comparing surrogate markers for sputum eosinophilia cell type mediating pathobiology, severity, and symptoms. Neutrophils
found blood eosinophils and FeNO to have comparable diagnostic accu- can be temporarily recruited into the airways in a number of circum-
racy, which was superior to total serum IgE in adult asthma patients.37 stances—e.g., following exposure to pollutants and pathogens or in re-
Non-T2 asthma is usually a diagnosis of exclusion based on the absence sponse to a diet rich in fat and carbohydrate. Upon activation in the
of T2 biomarkers or based on the sputum inflammatory phenotype: neu- airways, neutrophils can release their granules, DNA, and proteins, and
trophilic or paucigranulocytic. thus could contribute to airway damage. However, this increase in neu-
Evidence accumulated over 2 decades since the introduction of the trophil number driven by factors that promote neutrophilia might not
first monoclonal antibody against IL-5 showed that the pathogenetic necessarily be stable over time.
role of eosinophils is fundamentally different between asthma pheno- Based on the major biologicals clinical trials, blood eosinophils,
types.38 In the IgE-driven form of T2 asthma, blood eosinophil counts FeNO and specific and total IgE are usually used to define T2 asthma
are variable, mainly dependent on allergen exposure, and play only a endotypes: allergic asthma is defined by total serum IgE ≥30 kU/L and
minor effector role in allergen-induced asthma symptoms. By contrast, one or more positive perennial aeroallergen-specific IgE (≥0.35 kU/L)
in the eosinophilic form of T2 asthma, eosinophils are persistently ele- at baseline,58 , 59 eosinophilic asthma is defined by the blood eosinophil
vated and are crucial drivers of the disease. These considerations sug- counts ≥300 cells/μL (low cut-off ≥150 cells/μL),60 T2-high asthma is
gest that blood eosinophilia should not be considered a treatable trait defined by FeNO ≥35 parts per billion (ppb) (low cut-off ≥25 ppb)60
in people with asthma, but only a biomarker complementing an accu- (Fig. 1). Post hoc analyses from two adult populations showed that
rate endotype diagnosis. Furthermore, there is a modest correlation be- these classification criteria result in significant overlaps among these
tween eosinophil numbers in the airway and those in the blood, but this endotypes.60 Thus, in a general adult asthma population without spe-
gets weaker as asthma gets more severe and as patients are exposed to cific subtype selection, 78.0% exhibited allergic asthma; among them,
higher doses of corticosteroids.39 , 40 There are still a number of unre- 39.5% presented with eosinophilic asthma and 29.5% had T2 asthma.
solved issues related to the application of blood eosinophil counts in There were many overlapping subjects: 75.8% of those with eosinophilic
clinical practice , including: (1) the number of measurements needed asthma had allergic asthma, 41.3% of those with eosinophilic asthma
to reliably predict risk and/or clinical response, and (2) whether blood had T2 asthma, 81.1% of individuals with T2 asthma had aller-
eosinophils are helpful for both initiating therapy and monitoring its gic asthma, and 59.2% of those with T2 asthma had eosinophilic
course. asthma.60
FeNO is increased in patients with T2 asthma and is used as an ob- Consequently, more specific diagnostic criteria are needed (Fig. 1).
jective biomarker of airway inflammation. Cut-off values have been es- One example is defining allergic asthma based on the impact of aller-
tablished by the American Thoracic Society, the Global Initiative for gen exposure on asthma symptoms and control as described above us-
Asthma, and the National Institute for Health and Care Excellence, but ing a comprehensive clinical history and if needed allergen provocation
vary between guidance. FeNO levels can be predictive of blood and spu- tests.51 , 52 , 53 Another option is using combinations of biomarkers.38 , 41 A
tum eosinophil levels, but should not be used in isolation.41 High FeNO third is using biomarkers measured in the target organ (nose and lung).
can help predict response to inhaled corticosteroids (ICS) and suppres- Last, but not least, omics signatures built in an unbiased way using ma-
sion of its levels with ICS can be used to monitor adherence. FeNO levels chine learning would provide the most precise definition of asthma en-
are also a predictor of asthma risk with elevated levels associated with dotypes.6–8 , 14 , 16
increased exacerbation rates and accelerated decline in lung function; FeNO and eosinophilia, although related, represent two distinct
FeNO also has an emerging role in predicting response to dupilumab in biomarkers resulting from two different T2 cytokine pathways: IL-4
severe asthma.42–44 Persistent high FeNO can identify steroid-resistant and IL-13, which are involved in IgE synthesis and inducible nitric
inflammation in asthma.45 FeNO testing is noninvasive and easy to use, oxide synthase (iNOS) induction (leading to nitric oxide [NO] pro-
and has been shown to be cost-effective as a complement to clinical duction), and IL-5, which drives eosinophil activation, development,
assessment in improving asthma management.46 , 47 Unfortunately, its and recruitment. Consequently, they provide complementary informa-
immediate high costs preclude its wide implementation at the point- tion and should be used jointly. A risk scale for predicting asthma
of-care. Several confounders should be accounted as well: obesity can attacks based on blood eosinophil counts and FeNO has been pro-
be associated with low FeNO levels even in the presence of sputum posed. This scale was derived by extracting and pooling biomarker-
eosinophilia; and FeNO can also be increased by the presence of allergic stratified, trial-level attack rates from the control arms of several clinical
rhinitis.48 , 49 trials.61
Allergic asthma is the most common asthma phenotype, impacting Nasal secretions and sputum reflect the local inflammatory activ-
7.3% of the general population.50 It is usually diagnosed by the pres- ity and provide valuable information about the immunological reac-
ence of specific IgE to aeroallergens in conjunction with a comprehen- tion in the lung. Current techniques for nasal secretions sampling are
sive history showing the allergen exposure as the major driver of asthma mainly based on three principles: collection of spontaneous secretions,
symptoms and control. If the history is unclear, an allergen provocation nasal washings, and absorption. Collection of spontaneous secretions is
test (nasal or bronchial) done in a specialized setting is recommended to appropriate in subjects with nasal hypersecretion. Nasal washings are
ensure a correct diagnosis.51–53 The correct diagnosis of allergic asthma associated with an unpredictable, high dilution and concentrations of
is essential for recommending allergen avoidance measures and allergen markers often fall below detection limits of immunological assays.62
immunotherapy (AIT), as add-on to the regular controller asthma treat- Absorption seems to provide the best compromise between sufficient
ment.54 The addition of AIT was proven to be able to decrease the ICS sample amounts and detectability of inflammatory mediators and IgE.62
dose while maintaining asthma control.53 , 54 It is also cost-effective.55 Nasal swabs for eosinophil granule proteins or activation products hold
Measuring cumulative levels of IgE specific for respiratory allergens promise.63 Using formalin-fixed paraffin-embedded sputum plugs for
could be a useful screening method for detecting an allergic phenotype easy assessment of sputum eosinophils numbers will soon become avail-
of severe asthma and may serve as a biomarker to enhance the success able at the point of care.64 , 65 Streamlining the sputum processing to
of IgE-targeted therapy.56 make dispersed fluid an easy biospecimen suitable for rapid assessment
Increased sputum neutrophils are usually used to diagnose T2-low tests to identify key markers of inflammation such as eosinophilic perox-
asthma. However, it is unresolved whether this is indeed the case.13 , 57 idase (EPX), myeloperoxidase, elastase, tryptase, and IgG autoantibodies
The association between asthma severity and neutrophil number has (antinuclear antibodies, anti EPX, anti-MARCO [macrophage receptor
led to the use of the term neutrophilic asthma, which implies the exis- with collagenous structure]) will also be soon within reach in asthma
tence of a specific asthma endotype in which neutrophils are the major centers.66–70

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Opportunities for asthma management in the era of precision ical approach. However, a recent study reported the lack of any signif-
medicine icant correlations between VOCs and inflammatory markers in a well-
characterized cohort of adult patients with asthma with a broad spec-
Precision immunology, deep phenotyping and novel imaging techniques trum of clinical phenotypes.83
In more recent years, single-cell analysis provided the profiles of
Molecular phenotyping based on a transcriptomic analysis of major immune and mesenchymal clusters in the human respiratory
bronchial epithelial and sputum cells has revolutionized the understand- tract,84 , 85 offering novel insights into the differentiation of pathogenic
ing of asthma pathogenesis. More than a decade ago, a T2 high inflam- Th2 cells in the airways, which are enriched for genes and pathways
mation cluster characterized by eosinophilia and recurrent exacerba- associated with lipid and glucose metabolism.86 Meanwhile, a frame-
tions was initially described.71 This discovery was followed by the char- work for efficient capture of granulocytes in tissue compartments, over-
acterization of several T2-low clusters linked with IL-6 trans-signaling, coming traditional limitations of single-cell RNA sequencing, was re-
IFN pathways, inflammasome activation and mitochondrial oxidative cently published. The resulting dataset serves as a valuable resource for
phosphorylation pathways.72 , 73 understanding airway granulocyte biology and inflammation, enabling
Currently, the multi-omics unbiased approach for asthma endotyp- detailed exploration of asthma pathogenesis.87 Based on these method-
ing led to major novel discoveries related to alterations of the arginine ological innovations, recent studies have examined the effects of IL-13
metabolome, mechanisms of ferroptotic death in airway epithelial cells on human airway epithelial cells. IL-13 was shown to induce a mucus
in asthma, abnormal lipid metabolism or dose-dependent metabolomic secretory program across all epithelial cell types, converting both mu-
changes induced by ICS in high doses.74–77 The severe asthmatic and cus and defense secretory cells into a metaplastic state characterized by
high FeNO asthmatic patients were shown to have unique endotypes increased mucin production and secretion. In ciliated cells, IL-13 expo-
that suggest changes in NO-associated taurine transport and bile acid sure led to endoplasmic reticulum (ER) stress and cell death.88 The re-
metabolism.78 Shotgun lipidomics of induced sputum supernatant in the sulting remodeled epithelium secretes a pathologic proteome marked by
U-BIOPRED patients revealed a spectrum of 9 molecular phenotypes, mucin imbalance and depletion of innate immunity factors, ultimately
highlighting significant differences between the sputum lipidomes of impairing mucociliary clearance.88 These insights into pathogenic type
asthma patients and healthy controls, and also within the asthma patient 2 immunity have paved the way for targeted biologic therapies. High-
population.79 Sputum lipid phenotypes with higher levels of nonen- parameter flow cytometry analysis of peripheral blood mononuclear
dogenous, cell-derived lipids were associated with significantly worse cells recently reported a new mechanism for how mepolizumab reduces
asthma severity, worse lung function, and elevated granulocyte counts. airway inflammation by re-directing trafficking of inflammatory T2 lym-
These findings suggest a novel mechanism of increased lipid loading in phocytes away from airway-homing.89 Collectively, these findings un-
the epithelial lining fluid of asthma patients resulting from the secre- derscore the complexity of asthma pathogenesis, which involves epithe-
tion of extracellular vesicles by granulocytic inflammatory cells, which lial remodeling, immune cell trafficking, and microenvironmental fac-
could reduce the ability of pulmonary surfactants to lower surface ten- tors. Recent advances in next-generation sequencing and imaging tech-
sion in asthmatic small airways, as well as compromising its role as nologies have enabled the application of spatial transcriptomics to study
an immune regulator. In the same cohort, unbiased label-free quanti- lung remodeling, shedding light on the importance of specialized niches
tative mass spectrometry of sputum supernatants described 10 asthma in the context of chronic inflammation and gene–environment interac-
proteotypes, with 3 highly eosinophilic, 3 highly neutrophilic, and 2 tions.90 Activation of immune cells in specialized regions of the lungs,
highly atopic with relatively low granulocytic inflammation.80 Integrat- such as the adventitial cuffs, involves specific immune regulatory mech-
ing biobank-scale genetics and plasma proteomics identified 70 proteins anisms, including the production of IL‐33 and chemokines, and extra-
with putative causal roles in asthma risk, including known drug targets cellular matrix (ECM) deposition.91 , 92 Dysregulation of this niche can
and proteins without prior genetic evidence in asthma (e.g., GTP cy- initiate airway remodeling via hyperactivation of mast cells (MCs) and
clohydrolase 1 feedback regulatory protein [GCHFR], tudor and KH do- induce vascular damage.93
main containing [TDRKH], and C-type lectin domain family 7 member Sophisticated three-dimensional lung imaging using high resolu-
A [CLEC7A]).81 The genetic architecture of causally associated proteins tion computed tomography (HRCT), ventilation imaging (single pho-
provided evidence for a TLR-1–IL-27 asthma axis. An integrated species- ton emission computed tomography [SPECT] and positron emission to-
level metagenomic data with inflammatory mediators characterized the mography [PET]), magnetic resonance imaging (MRI) and ultrahigh
prevalence of dominant potentially pathogenic organisms in relation resolution techniques such as micro-computed tomography and syn-
to the host immune responses.82 Neutrophilic asthma was associated chrotron imaging is now highly developed. Optical coherence tomogra-
with Haemophilus influenzae (H. influenzae), Moraxella catarrhalis (M. phy (OCT) and endobronchial ultrasound enable high-resolution imag-
catarrhalis), Streptococcus pneumoniae (S. pneumoniae) and Tropheryma ing of the large airways accessible to bronchoscopy. HRCT scanning pre-
whipplei (T. whipplei) with elevated type-1 cytokines and proteases; dominantly provides measurements of airways and lung structure, as
eosinophilic asthma was associated with higher M. catarrhalis, but lower well as small airway function from the difference between inspiratory
H. influenzae, and S. pneumoniae abundance. H. influenzae load was cor- and expiratory images. Imaging-based biomarkers, including airway di-
related with eosinophil cationic protein, elastase and IL-10. Rothia mu- mensions, blood vessel volumes, mucus scores, extent of ventilation de-
cilaginosa was positively associated with IL-6 and negatively with fibrob- fect, and extent of air trapping, often have increased sensitivity com-
lastic growth factor (FGF). Bayesian network analysis also revealed close pared with that of traditional lung function measurements and are in-
and distinct relationships of H. influenzae and M. catarrhalis with type-1 creasingly being used as end points in clinical trials. High mucus burden
airway inflammation. The study also showed that the microbiomes and represents a distinct T2-high asthma phenotype that can contribute to
cytokine milieu were distinct between upper and lower airways.82 chronic symptoms and acute exacerbations, potentially leading to fatal
“Breathomics” in asthma is a rapidly growing area of significant sci- respiratory failure.94 The mucus plug scoring system based on the spatial
entific interest. The repeatedly observed associations between breath extent of plugging by determining the number of occluded pulmonary
volatile organic compounds (VOCs) and sputum or blood inflammatory segments has shown a compelling relationship between mucus burden,
cells suggest that breathomics are on the brink of introduction as a airway obstruction, asthma control and exacerbation risk.94 , 95 Differ-
valuable clinically tool. However, there are major concerns about un- ences in mucus appearance on OCT correlate with mucin content, sug-
resolved methodological issues and a general paucity of high-quality gesting that OCT is sensitive to differences in mucus composition as well
data. Numerous breath VOC studies yielded many valuable insights, as in volume.96 Asthma patients with high mucus burdens respond well
which increase our awareness of interfering environmental, lifestyle and to biologic therapy, which clears plugs and normalizes ventilation.97–99
metabolic factors and of the need of a more standardized methodolog- Ventilation heterogeneity, a classic feature of asthma, has been known

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Fig. 2. Asthma management in the era of precision medicine. Data from multiomics, single-cell/spatial transcriptomics, biomarkers, symptoms/comorbidities, and
sophisticated 3D lung imaging are processed through machine learning to characterize individual molecular signatures. These signatures are combined with real-time,
theratype-based personalized interventions, ultimately supporting precision medicine. BALF, Bronchoalveolar lavage fluid.

to predict AHR. SPECT ventilation imaging adds spatial characterization patient care and management. Digital health technology uses computing
information on the impact of peripheral airways on AHR.100 Combined platforms, connectivity, software, artificial intelligence, machine learn-
with quantitative computed tomography imaging, it can delineate clus- ing, and sensors to manage illnesses and health risks and promote well-
ters within patients with severe asthma based on differences in venti- ness with a strong emphasis on personalized health care. This includes
lation heterogeneity and airways resistance, thus guiding the strategies wearable devices, mobile health, telehealth, health information technol-
for the inhalational treatment.101 PET and MRI also provide informa- ogy, remote monitoring, and telemedicine.
tion on the distribution of ventilation. The severity of airway closure Digital technologies can play a central role in achieving precision
measured using MRI was associated with the clinical risk of asthma medicine across the patient journey, from diagnosis to remission. For di-
exacerbations.102 , 103 The response of ventilation defects to the acute agnosis, smartphones and artificial-intelligence-enabled devices can ob-
bronchodilator inhalation was associated with sputum eosinophilia.104 jectively capture respiratory symptoms, while digital peak flow meters
Airway closure can be widespread, distributed in a patchy, “clustered” enable home assessment of airflow variability. For routine monitoring
manner. It can be the consequence of airway remodeling, parenchymal and self-management, technologies can monitor biomarkers more fre-
remodeling, mucus plugs or local inflammation.104 Consequently, the quently, digital inhalers can improve medication adherence and asthma
distribution of airway closure and its response to a bronchodilator or an control whilst serious games can improve patient knowledge. Symptom
anti-inflammatory agent represent a reliable phenotyping and theratyp- tracking, lung function monitoring and environmental parameters can
ing tool. help identify exacerbation triggers. For assessing remission, digital tech-
nologies can capture most of the components of remission definitions,
Machine-learning approaches from exacerbations to reliever use, enabling a more objective assess-
ment of this emerging endpoint.117 Digital technologies also allow for
The application of mathematical and computational analysis, to- remote, objective, granular, and non-invasive data collection, offering
gether with the modeling of biological and physiological processes, is the opportunity to move towards decentralized asthma clinical trials.
transforming our understanding of asthma pathophysiology. A system- This approach could facilitate recruitment of inclusive and generaliz-
atic biology approach to define asthma endotypes and theratypes in- able study populations, enhance personalization and sustainability, re-
tegrates multi-omic data derived from genomic, transcriptomic, pro- duce research costs, and accelerate market access for novel asthma treat-
teomic, metabolomic, lipidomic, breathomic, and metagenomic from ments.118 Inhaler-based digital biomarkers can also be objectively eval-
disease-relevant tissues (lung biopsies, bronchoalveolar lavage [BAL], uated to indicate changes in response to therapeutic interventions119
sputum, nasal secretions, skin, blood), together with imaging data, deep (Fig. 2).
clinical phenotyping, and patient-reported outcomes.14 , 16 , 105–116 Inte-
gration of these datasets will provide a greater understanding of the The new European Academy of Allergy and Clinical Immunology
molecular pathways associated with asthma in each individual patient (EAACI) nomenclature as a basis for stratified asthma
and thus guide their personalized management (Fig. 2). management

Digitally empowered asthma care The new nomenclature for hypersensitivity reactions developed by
the EAACI provides a modern approach for asthma and allergic dis-
The landscape of health care is transforming rapidly as technology eases, based on disease endotypes and theratypes.120 Hypersensitivity
advancements accelerate integration of digital health technology into reactions originally described by Gell and Coombs have been extended

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Fig. 3. Type V hypersensitivity asthma driven by epithelial barrier dysfunction and tissue remodeling. Key pathways involved in Type V asthma according to the
new EAACI nomenclature are shown. Environmental insults (allergens, viruses, bacteria, pollutants, and other inhaled hazardous materials) initiate epithelial barrier
dysfunction via recognition of PAMPs and DAMPs/proteases, leading to IFN responses, enhanced viral replication, and release of cytokines, chemokines and alarmins,
T2 inflammation, and airway remodeling. These mediators drive angiogenesis, abnormal ECM deposition, ASM phenotypic changes, goblet cell hyperplasia with
mucus plugging, and eosinophilic infiltration with IgE production, ultimately resulting in airway hyperreactivity. ASM, Airway smooth muscle; DAMPs, Damage-
associated molecular patterns; EAACI, European Academy of Allergy and Clinical Immunology; ECM, Extracellular matrix; IFN, Interferon; IgE, Immunoglobulin E;
PAMPs, Pathogen-associated molecular patterns; T2, Type 2.

into nine different types comprising antibody-(I–III), cell-mediated (IV by secreting, for example antimicrobial peptides, anti‐proteases and an-
a–c), tissue-driven mechanisms (V–VI) and direct response to chemicals tioxidants, and is part of the innate immune system. Airway epithelial
(VII). Types I–III are linked to classical and newly described clinical cells express pattern recognition receptors (PRRs) like toll‐like receptors
conditions. Type IVa–c is specified and detailed according to the cur- (TLRs), retinoic acid‐inducible gene (RIG)‐I‐like receptors (RLRs), nu-
rent understanding of T1, T2 and T3 responses. Type V involves epithe- cleotide‐binding oligomerization domain (NOD)‐like receptors (NLRs),
lial barrier defects and tissue remodeling, and is clinically associated C‐type lectin receptors, protease activated receptor (PAR)‐2 and puriner-
with severe, persistent asthma characterized by fixed airflow obstruc- gic receptors.121 These recognize pathogen‐associated molecular pat-
tion, frequent exacerbations, and progressive decline in lung function. terns (PAMPs) from inhaled microbes, parasites and allergens as well
Type VI involves metabolic/microbiome/neurogenic-induced immune as alarmins/damage‐associated molecular patterns (DAMPs) released
dysregulation and underlies heterogeneous clinical presentations linked from dying or damaged cells. Upon recognition of PAMPs or DAMPs,
to obesity, sex differences, and other triggers. Type VII involves direct PRRs activate the inflammasome, leading to caspase‐1 activity and sub-
cell activation via ion channels, receptors, or inflammatory responses to sequent cleavage of IL‐1𝛽 and IL‐18 into active forms, and provide
pollutants, irritants, or mechanical stress, and is clinically significant for downstream signaling that promotes the release of pro‐inflammatory cy-
trigger-specific exacerbations and marked airway hyperresponsiveness. tokines/chemokines, including IL‐6, IL‐8, C-C motif chemokine ligand
It is notable that several combinations of mixed types may appear in the (CCL) 20, CCL17, thymic stromal lymphopoietin (TSLP), IL‐25, IL‐33
clinical setting.120 and granulocyte macrophage colony stimulating factor (GM‐CSF) that
attract and/or activate cells from the innate and adaptive immune sys-
Type V asthma tem.121 , 122 , 127–134 The epithelial derived cytokines TSLP, IL‐25, and
IL‐33 activate T2 innate lymphoid cells (ILC2), which secrete T2 cy-
Type V hypersensitivity reaction includes the contribution of the tokines.135 Dendritic cells (DCs) educated by the T2 cytokines induce
tissue as initiator and further modulator of the immune-inflammatory the differentiation of Th2 cells, which further secrete T2 cytokines and
reactions (Fig. 3). The epithelial barrier dysfunction, the airway induce specific IgE production, eosinophilic infiltration into the airways
smooth muscle (ASM) phenotype switch, the abnormal mucus pro- and goblet cell hyperplasia with excessive mucus production.136 T2 cy-
duction, the activation of the epithelial–mesenchymal trophic unit tokines further promote the epithelial barrier dysfunction.137 , 138 Smok-
and the profound changes in the ECM and pulmonary blood vessels ing‐induced Th17‐mediated inflammation can further reduce epithelial
have been documented for decades as central to the pathogenesis of barrier function through Th17 cytokine IL‐17.139 The impaired epithe-
asthma, frequently dissociated from the immune-inflammatory path- lial barrier function is accompanied by compromised IFN responses in
ways.5–7 , 121–124 asthma, resulting in increased viral replication.140 Upon damage, the
Epithelial damage is a pathological feature observed in all phe- epithelial barrier is disrupted and releases growth factors such as epi-
notypes of asthma, occurring early, before the onset of inflammation dermal growth factor (EGF) and transforming growth factor (TGF)‐𝛽,
and the clinical diagnosis of asthma.125 , 126 Allergens, viruses, bacte- which activate fibroblasts and myofibroblasts.141 Allergens, irritants
ria, pollutants and other inhaled environmental insults are in first con- and microbes (including the normal flora) enter the tissue through
tact with the airway epithelial barrier, which forms a continuous lin- the disrupted barrier and induce a chronic immune-inflammatory re-
ing of the respiratory system from the nose to the trachea, bronchi, sponse.122 , 136 EGF and TGF‐𝛽 promote excessive deposition of ECM
bronchioles and finally the alveoli.127–134 In addition to the physical components, resulting in subepithelial fibrosis, airway wall thickening
barrier function and mucociliary clearance of foreign particles, the air- and increased ASM mass. In addition, release of vascular endothelial
way epithelium acts as chemical barrier against environmental insults growth factor (VEGF) by airway epithelial cells increases the size of air-

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I. Agache, S. Li, Y. Zheng et al. Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

way wall vessels and promotes angiogenesis. Last but not least, there creased reticular basement membrane formed by collagens and laminins
might be a genetic predisposition to irritant-induced epithelial barrier is one of the earliest events present in childhood asthma and correlates
dysfunction: lower expression of the susceptibility gene hedgehog in- with the severity of the disease.161
teracting protein (HHIP) in airway epithelial cells from patients may Angiogenesis and associated vascular remodeling are one of the
contribute to abnormal epithelial repair.142 pathological hallmarks of asthma. The mechanisms underlying angio-
Goblet cell hyperplasia and mucous plugging are a classical feature genesis in asthmatic airways and its clinical relevance represent a rela-
of asthma, and the functions of this mucus during a lung immune re- tively nascent field in asthma when compared to other airway remod-
sponse remain elusive, despite widespread evidence of its involvement eling features. Angiogenesis involves the destruction of the vascular
in cases of fatal asthma.94 , 143 Alterations in the quality, rather than basement membrane and remodeling of the ECM, which paves way for
merely the quantity, of mucus are a more relevant parameter of asthma. the migration and proliferation of endothelial cells as well as the syn-
Pathogenic mucus from asthma has a significantly higher elastic modu- thesis of new matrix components. Matrix metalloproteinases (MMPs)
lus, making it much stickier and harder to expectorate by coughing.144 play an important role in this disruption and neovascularization pro-
A high elastic modulus indicates extensive cross-linking of the mucus, cess, together with various angiogenic factors (hypoxia inducible fac-
which results in an incredibly tenacious substance that cannot be moved tor, VEGF, FGF-2 and angiopoietins) that are secreted by the infiltrating
by the muco-ciliary escalator, is hard to expectorate, and remains lodged eosinophils, basophils, and mast cells as well as by the resident epithe-
in the airways. The two primary mucins (MUC) found in the human lung lial, endothelial, and ASM cells.162 , 163 Several of these angiogenic fac-
are MUC5B and MUC5AC. MUC5B is secreted at high levels in submu- tors have been tested as prognostic biomarkers: VEGF mRNA-expressing
cosal glands and secretory cells in the distal airways, whereas MUC5AC cells in the airway mucosa correlate with AHR; while angiomotin and
is secreted by goblet cells. Healthy lungs contain mostly MUC5B, but a angiostatin, when analyzed together, can distinguish between stable and
common feature of asthmatic mucus is dysregulation of this ratio, with exacerbated states in asthma patients.164 , 165
MUC5AC being dramatically upregulated, particularly in patients with A study exploring the airway pathology in T2-high versus T2-low
an eosinophilic asthmatic phenotype.145 Serum galectin-10 is one poten- severe asthma showed that the remodeling features of ASM mass and
tially valuable marker that could point to the presence of a crystal-rich MUC5AC expression were increased in both asthma groups compared
plug.146 More is needed to develop clinically applicable scoring systems with healthy controls and were similar across T2-high and T2-low sub-
for mucus load in asthma on the basis of dynamic HRCT scans and other groups. Submucosal glands were increased in T2-intermediate and T2-
advanced imaging modalities that can pinpoint ventilation heterogene- low asthma. In spite of similar tissue cellular inflammation, sputum IL-
ity, perhaps supplemented with invasive bronchoscopic procedures al- 4, IL-5 and CCL26 were higher in T2-high than in T2-low asthma.166
lowing us to access mucus plugs. Taken together, while T2 cytokine profiles differed between subgroups,
ASM cells participate in the AHR as well as the inflammatory and re- airway remodeling was similarly evident in both, suggesting that remod-
modeling processes observed in asthmatic subjects. The increased ASM eling might operate through a distinct pathogenetic pathway indepen-
mass may be collectively due to airway infiltration of myofibroblasts, dent of T2 inflammation. This may contribute to residual disease beyond
neighboring airway smooth muscle cells in the bundle, or circulating eosinophilic exacerbations.
hemopoietic progenitor cells. However, the relative contribution of each
cell type is not well understood.147 ASM has a vast repertoire of inflam- Type VI asthma
matory receptors that, upon activation, contribute to prominent fea-
tures in asthma, notably immune cell recruitment and activation, hy- Type VI hypersensitivity reactions include mechanisms driven by
percontractility, proliferation, migration, and extracellular matrix pro- metabolic, hormonal, epigenetic, neuro-immune interactions and the in-
tein deposition.148 These phenotypic changes in ASM can be mediated teractions with the microbiome (Fig. 4). Thus, this hypersensitivity type
by epithelial derived cytokines (TSLP), T2 (e.g., IL-4, IL-13,) and type 1 provides an integrative framework for understanding the disease.
(T1) (tumor necrosis factor [TNF]-𝛼, IFN-𝛾) and type 3 (T3) (IL-17A) cy-
tokines, and by TGF-𝛽, a key driver in paucigranulocytic asthma, high- Metabolic pathways driving asthma pathogenesis
lighting roles for ASM modulating both T2 and non-T2 asthma endo- Obesity is associated with more severe asthma, however, the mecha-
types.149–156 CD4 T cell infiltration of ASMs bundles was correlated with nisms responsible are poorly understood. Obesity is associated with low-
asthma severity.157 The increased expression of ECM proteins further in- grade systemic inflammation, and it is possible that this inflammation
fluences the ASM phenotypic switch.158 Both IL‐13 and IL‐17A enhance extends to the airways, contributing to worse asthma outcomes. A recent
ASM adhesion to the ECM by activating 𝛽1 integrin.159 meta-analysis that included 40 studies showed that sputum neutrophils
Abnormal deposition of ECM proteins is a key factor in the develop- were 5% higher in obese versus non-obese asthmatics; blood neutrophil
ment of tissue remodeling that results in symptoms and impaired lung count was also higher, as were bronchial submucosal eosinophil counts
function in these diseases. Tissue remodeling in the lungs is complex and sputum IL-5 levels. Conversely, FeNO was 4.5 ppb lower in obesity.
and differs between compartments. Some pathways are common but Blood C reactive protein, IL-6 and leptin were also higher in obesity.167
tissue remodeling around the airways and in the parenchyma has differ- IL‐6 expression is increased in the context of metabolic syndrome and
ent morphologies. Hence it is critical to evaluate both common fibrotic obesity in severe asthma and has been associated with diminished air-
pathways and those that are specific to different lung compartments. way function.168 Consequently, the different pattern of inflammation in
Immune cells use the ECM scaffold to migrate through the lungs. Using obese asthmatics should be further explored in order to develop proper
an IL‐33 mediated lung inflammation model, it demonstrated that ILC2 targeted interventions.
are actively recruited to specific locations of the airway wall, such as the Biomarkers related to the tricarboxylic acid cycle, hypoxia response,
adventitial cuff, at the intersection between the large blood vessels and amino acid metabolism (glutamine, L-arginine) and oxidative stress are
the large airways.92 ILC2s were most prominent in areas with high levels all associated with asthma diagnosis or with increased asthma morbid-
of ECM. Collagen‐I fibers may induce a more polarized ILC2 morphol- ity.168–170 Individuals with asthma and control subjects differ in air-
ogy, resulting in increased traction, decreased velocity, and prolonged way epithelial cell rates of glycolysis and oxidative phosphorylation and
dwell time at specific lung sites, ultimately enhancing inflammation. in mitochondrial function and structure.171 , 172 Obese individuals with
Chemokines bind to ECM components, including glycosaminoglycans. asthma have lower L-arginine concentrations, and their airway epithe-
Changes in the amount and geometry of the ECM may greatly influ- lial cells produce less nitric oxide (NO) because of NO synthase (NOS)
ence the availability of these mediators to immune cells, and therefore uncoupling. When this occurs, NOS preferentially makes anion super-
could alter the regulation of immune cell functions locally.160 Last but oxide instead of NO. Reduced NO bioavailability can impair bronchodi-
not least, the dynamics of ECM change with age and development: an in- lation while also affecting mitochondrial function. Loss of this NO in-

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I. Agache, S. Li, Y. Zheng et al. Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

Fig. 4. Type VI hypersensitivity asthma driven by metabolic, hormonal, microbiome, trained immunity, and neuro–immune interactions. Multifaceted drivers of
Type VI hypersensitivity reactions in asthma according to the new EAACI nomenclature. The central circle represents the convergence of metabolic pathways (e.g.,
obesity-related inflammation, oxidative stress, lipid mediators), microbiome dysbiosis (e.g., gut, lung), hormonal influences (e.g., sex steroids, incretins), trained
immunity (epigenetic and metabolic reprogramming of innate cells), and neurogenic inflammation (neuropeptides, neurotrophins, and neural–immune crosstalk).
These interconnected mechanisms contribute to immune dysregulation, airway inflammation, remodeling, and hyperreactivity, highlighting their relevance in asthma
pathogenesis and potential for stratified management. AA, Arachidonic acid; Ach, Acetylcholine; AEC, Airway epithelial cell; AERD, Aspirin-exacerbated respiratory
disease; AHR, Airway hyperreactivity; ASM, Airway smooth muscle; CGRP, Calcitonin gene-related peptide; CysLTs, Cysteinyl leukotrienes; EAACI, European Academy
of Allergy and Clinical Immunology; ECM, Extracellular matrix; Eos, Eosinophils; ER, Endoplasmic reticulum; GABA, 𝛾-aminobutyric acid; GC, Glucocorticoid;
GLP1RA, Glucagon-like peptide-1 receptor agonist; HDM, House dust mite; HDAC9, Histone deacetylase 9; IL, Interleukin; LAMA, Long-acting muscarinic antagonist;
NANC, Non-adrenergic non-cholinergic; Neu, Neutrophils; NKA, Neurokinin A; NO, Nitric oxide; NOS, Nitric oxide synthase; ORMDL3, Orosomucoid 1-like 3; PGE,
Prostaglandin E; PGD, Prostaglandin D; PNEC, Pulmonary neuroendocrine cell; RAS, Renin-angiotensin system; RAMP, Receptor activity-modifying protein; ROS,
Reactive oxygen species; SCFA, Short chain fatty acids; SERCA: Sarco/endoplasmic reticulum Ca2 + -ATPase; SP, Substance P; Th, T helper; TNF-𝛼, Tumor necrosis
factor-𝛼.

hibitory mechanism in obesity, in addition to increased glycolytic rates, a concomitant impairment of antioxidant responses lead to oxida-
is associated with increased maximal mitochondrial respiration, which tive stress in asthma. Oxidative stress is augmented in severe asthma
in turn increases the production of reactive oxygen species (ROS). Un- and during exacerbations, as well as by air pollution and obe-
stimulated airway epithelial cells from obese subjects with asthma dis- sity, both linked to T2 low asthma. Several common causes of ox-
play increased degrees of oxidative and nitrative stress.173 idative stress were linked to acquired glucocorticoid resistance in
ROS play a central role in airway epithelium-mediated sensing, asthma.175 Antioxidant treatment may be beneficial to glucocorti-
development of innate and adaptive immune responses, and airway coid resistant and T2-low asthma. Unfortunately, antioxidant com-
remodeling and AHR.174 Over-production of ROS resulting from in- pounds have proven clinically ineffective, partly due to poor stabil-
filtrating immune cells, particularly eosinophils and neutrophils, and ity and rapid in vivo metabolism.176 The compartmentalized nature of

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I. Agache, S. Li, Y. Zheng et al. Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

ROS production and sensing, and the role of ROS in homeostatic re- nity. Patients with aspirin exacerbated respiratory disease (AERD) have
sponses and in the action of corticosteroids and 𝛽2-adrenergic receptor overproduction of cysteinyl leukotrienes (cysLTs) and inflammatory
(𝛽2AR) agonists, add another layer of complexity to antioxidant therapy prostaglandins (PGs) such as prostaglandin D2 (PGD2 ), as well as un-
development. derproduction of the anti-inflammatory prostaglandin E2 (PGE2 ), high
Lipid metabolism, especially in distinct cells such as T cells, levels of mast cell activation, platelet activation, and severe T2 respira-
macrophages, granulocytes, and non-immune cells, plays an essen- tory inflammation.186 , 187 PGE2 stabilizes and prevents the activation of
tial role in the pathogenesis of asthma, as lipids are potent signaling MCs and ILC2s, and prevents the formation of cysLTs by inhibiting the
molecules that regulate a multitude of cellular response. Tissue-resident translocation of 5-lipoxygenase.188 , 189 Both cysLTs and inflammatory
alveolar macrophages display a unique metabolic profile, influenced by prostaglandins likely play a role in amplifying respiratory tract inflam-
the concentrations of glucose and lipids in the microenvironment.177 mation and eosinophilia.190 Several studies link AERD to diminished
An unsupervised, group-agnostic integrative multi-omic factor analysis production (or increased catabolism) of PGE2 in the respiratory tract,
performed using host/bacterial (meta)transcriptomic and bacterial shot- associated with diminished expression and function of cyclooxygenase-
gun metagenomic datasets from bronchial brush samples paired with 2 (COX-2) and/or microsomal (m) prostaglandin E synthase (PGES)-1,
metabolomic/lipidomic data from bronchoalveolar lavage (BAL) sam- the dominant PGES isoform upregulated during inflammation.190 , 191
ples acquired from children of 1 to 17 years old showed one signa- Since COX-1 is exquisitely sensitive to inhibition by aspirin, a chronic
ture characterizing preschool-aged recurrent wheeze and another cap- reduction in COX-2/mPGES-1-derived PGE2 could account for aspirin-
turing an inferred trajectory from health to wheeze and school-aged induced reactions in AERD, by removing a critical COX-1-dependent
asthma. Recurrent wheeze was driven by T1-immune signatures, cou- “braking” function. Urinary levels of leukotriene E4 (LTE4 ), a marker
pled with upregulation of immune-related lipids and metabolites, par- of systemic cysLT production, are characteristically elevated in patients
ticularly those associated with neutrophils. Comparatively, progression with AERD and increase further during non-steroidal anti-inflammatory
toward asthma from ages 1 to 18 was dominated by changes related drugs-induced reactions.190 The overproduction of these lipid mediators
to airway epithelial cell gene expression, T2-immune responses, and may be driven by epithelial–immune crosstalk: Epithelial cell-derived
constituents of the airway microbiome, such as increased Haemophilus TSLP stimulates human MCs to generate PGD2 , which activates platelets
influenzae.178 A clear association was demonstrated between nonaller- to release high amounts of epithelial alarmin IL-33.192 , 193 However,
gic childhood asthma, lower whole-blood sphingolipids, and asthma- there are no specific clinical trials targeting the epithelial derived cy-
risk 17q21 genotypes encoding ORMDL3.179 ORMDL3 encodes an ER- tokines in AERD. As severe T2 inflammation is a hallmark of the dis-
resident transmembrane protein that regulates the activity of serine ease, targeting its key cytokines IL-4 and IL-13 with dupilumab proved
palmitoyltransferase (SPT), the first and rate-limiting enzyme for sph- very successful within the 1st month after initiating treatment.194 Oma-
ingolipid biosynthesis in cells. Sphingolipids are essential for formation lizumab dramatically decreased urinary levels of both LTE4 and PGD2
and integrity of cellular membranes; they also serve as precursors for metabolites and induced improvement in baseline symptoms.195 These
bioactive molecules that regulate key cellular processes and can be syn- findings, along with the efficacy of dupilumab, point to a central role for
thesized both de novo and through recycling pathways. In addition to its both IgE- and IL-4/13-driven pathways in AERD. The marked response
role in sphingolipid biosynthesis, ORMDL3 has been implicated in other to omalizumab specifically supports the involvement of local IgE in driv-
cellular processes relevant to asthma, such as ER stress and the unfolded ing eicosanoid production and mast cell activation, though the antigen
protein response (UPR), which are involved in asthma exacerbation.180 specificity of this local IgE remains to be determined.196
Aside from SPT regulation, ORMDL3 is also reported to regulate the sar- Overall, diets emphasizing the consumption of plant-based foods
coendoplasmic reticulum (SR) calcium transport ATPase (SERCA) pump, might protect against asthma development and improve asthma symp-
which transports calcium ions from the cytoplasm into the SR. This pro- toms through their effects on systemic inflammation, oxidation, and mi-
cess is vital for maintaining homeostatic levels of calcium ions inside the crobial composition. Additionally, increased fruit and vegetable intake,
ER, and any dysregulation of ER calcium levels can result in increased reduced animal product consumption, and weight management might
ER stress, UPR, and exacerbation of asthma pathogenesis. Changes in mediate cytokine release, free radical damage, and immune responses
ORMDL3-dependent regulation of the SERCA pump could elicit ER stress involved in the development and course of asthma.197 , 198
and UPR in multiple cell types, including CD4+ T cells, contributing to
increased incidence and/or severity of asthma in patients carrying OR- Hormonal impact on asthma
MDL3 risk single nucleotide polymorphisms (SNPs). The CD4+ T cells There are marked sex differences in asthma prevalence and severity.
from humans harboring 17q12–21 asthma risk SNPs display ∼3-fold Estrogen, progesterone, and testosterone directly interact with airway
overexpression of ORMDL3.181 In these patients, dynamic changes in epithelial cells, ASM cells, the mononuclear phagocyte system, innate
the expression and activity of key SERCA pumps in response to T cell lymphoid cells, eosinophils, mast cells, T cells, and B cells.199–201 An-
receptor activation would be hindered by higher ORMDL3 expression imal studies have shown that estrogen increases T2-mediated airway
in CD4+ T cells. This would result in reduced calcium uptake into the inflammation and AHR, while testosterone decreases T2-mediated in-
ER through SERCA pumps and increased cytosolic calcium concentra- flammation and protects against remodeling.201 , 202 Females have in-
tions in resting T cells, altering the key rheostat of early T cell sig- creased IL-17A-mediated airway inflammation compared to males.203 In
naling.182 This dysregulation might also induce ER stress, activate the line with the protective effects of testosterone against airway inflamma-
UPR, and alter T cell differentiation and function. ORMDL3 overexpres- tion and remodeling, nebulized dehydroepiandrosterone-3-sulfate—an
sion was reported to skew CD4+ T cell differentiation toward a Th2 and androgen precursor—was shown to improve asthma control, while the
Th17 imbalance.183 , 184 Altered sphingolipid synthesis via SPT regula- use of oral contraceptives may worsen asthma symptoms.204 , 205 The
tion is the major driver of these changes in T cell differentiation and complex sex steroid signaling in the lung, its interaction with inflamma-
function, which may also indirectly influence calcium homeostasis and tory mediators and other hormones (for example in obesity) and with
ER stress via sarco/endoplasmic reticulum Ca2+ –ATPase 2B (SERCA2B). the local steroid metabolism, and its age-specificity, deserve further ex-
Furthermore, increased ORMDL3 expression induces autophagy, possi- ploration for developing targeted interventions based on sex in asthma
bly through interacting with SERCA2, thereby inhibiting calcium uptake patients. Furthermore, genetic and epigenetic factors further shape sex-
into the ER/SR, and induces cell death, impairing bronchial epithelial related differences in asthma. The X chromosome harbors immune-
function in asthma.185 regulatory genes, including TLR7 and TLR8, which amplify inflamma-
Once regarded principally as regulators of smooth muscle tone tory responses in females.206 , 207 The sex-dependent expression of IL-13
and vascular permeability, arachidonic acid-derived lipid mediators are and ORMDL3 influences eosinophilic inflammation and airway remod-
now well known to regulate features of innate and adaptive immu- eling.208 Epigenetic modifications, such as DNA methylation and mi-

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I. Agache, S. Li, Y. Zheng et al. Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

croRNA regulation, further impact immune activation and corticosteroid as histamine or short chain fatty acids (SCFAs), which may influence
responsiveness.208 immune responses in distal parts of the body. For instance, the abun-
Incretins may have anti-inflammatory effect in asthma, whereas hy- dance of histamine-secreting bacteria is significantly higher in fecal sam-
perthyroidism can exacerbate asthma and hypothyroidism is associated ples of asthma patients compared with non-asthmatic volunteers.228 In
with milder asthma symptom.209 Glucagon-like peptide-1 receptor ag- parallel, SCFAs have been shown to activate olfactory receptors in the
onists (GLP-1 RAs), originally developed for the treatment of type 2 di- lung,229 particularly OR51E2 expressed on ASM cells, where they slow
abetes, have attracted attention for their potential therapeutic benefits cytoskeletal remodeling and reduce ASM proliferation.229 Soluble fiber
in asthma due to their anti-inflammatory properties and effects on ASM supplementation, essential for the generation of SCFA, has been found
function.210 , 211 However, concerns have been raised about the possibil- to decrease sputum eosinophilia and sputum histone deacetylase 9 gene
ity of GLP-1RAs inducing or exacerbating asthma symptoms.212 Reassur- (HDAC9) expression in asthma patients.230 These observations estab-
ing data from a large adult asthma cohort suggest that metformin was lish a non-immune gut–lung mechanism that ties gut microbial com-
associated with a lower rate of asthma attacks, with further reductions munities to asthma endotypes through both metabolic and epigenetic
when GLP-1 RA was added.213 Furthermore, liraglutide attenuated in regulation.
vivo platelet activation in an AERD murine model and in vitro activation
in human platelets from patients with and without AERD.214
Trained immunity in asthma pathogenesis
Dysregulation of renin-angiotensin system contributes to the pro-
Trained immunity refers to the enhanced response of innate im-
inflammatory, pro-oxidative, and pro-fibrotic processes that occur in
mune cells to subsequent encounters with antigens, facilitated by epi-
pulmonary diseases like asthma, chronic obstructive pulmonary dis-
genetic and metabolic modifications.231 While having beneficial effects
ease, idiopathic pulmonary fibrosis, and acute lung injury. Inhibi-
against pathogens, it may worsen inflammatory diseases by promoting
tion of the pro-inflammatory angiotensin-converting enzyme (ACE)–
disease progression through mechanisms such as inflammasome activa-
angiotensin (Ang) II axis and activation of the protective ACE2–Ang-
tion and epigenetic reprogramming.232 Early-life viral infections have
(1-7)–Mas receptor axis have each demonstrated varying degrees of ef-
been shown to promote sustained innate immune memory (trained im-
ficacy in experimental respiratory disease models and human trials.215
munity) in macrophages, which drives the differentiation of naive Th
cells toward Th2 and Th17 cells.233 Combined with allergen exposure,
Impact of the microbiome on asthma
they induce metabolic reprogramming in lung macrophages leading to
The effect of microbiota dysbiosis on asthma heterogeneity and nat-
allergic asthma in childhood.233 Even a short exposure to allergens
ural evolution seems intuitive, notwithstanding that until recently the
leads to a fundamental reprogramming of lipid mediator metabolism,
lung and gut microbiome composition have been addressed in studies
with macrophages representing particularly plastic responder cells.234
on phenotypes and endotypes of asthma.216 , 217
Pollution-induced trained immunity accounts for an enhanced inflam-
Proteobacteria appear repeatedly to be the most dominant phylum
matory response (TNF, IL-6, and IL-8) and defines a special pediatric
overrepresented in the airways of patients with asthma compared with
asthma endotype that can be depicted by enhanced H3K27ac marks in
non-asthmatic volunteers across several human studies.218 , 219 The Pro-
circulating monocytes.235 Trained immunity was also linked to the dif-
teobacteria phylum is represented by potentially pathogenic bacteria,
ferential antiviral cytokine production between asthmatic patients and
including those that belong to the genera Haemophilus, Moraxella, and
healthy subjects.236
Neisseria.220 Patients with neutrophilic asthma, usually receiving high
Distinct neonatal DNA methylation modules are associated with the
ICS doses, demonstrate a less diverse bacterial load with relative en-
capacity to mount innate immune responses, underscoring a link be-
richment in Haemophilus and Moraxella species, and a reduction in the
tween neonatal epigenetics and childhood asthma risk. The fetal in-
relative abundance of Streptococcus, Gemella, and Porphyromonas taxa
nate immune system can be trained by microbial exposures during preg-
compared with patients with eosinophilic asthma.221 , 222 In contrast to
nancy, thus shedding new light on the mechanisms explaining asthma-
reproducible findings in neutrophilic asthma, the status of the micro-
protected farm children.237–239
biota in eosinophilic and T2 high asthma is less clear and more hetero-
Bacterial lysates can promote trained immunity against pathogens.
geneous, potentially reflecting again the differences in underlying endo-
In a randomized controlled trial, mucosal bacterial immunotherapy
types or mixed responses caused by ICS treatment. Subjects with atopic
based on whole inactivated bacteria shows safety and clinical efficacy
asthma demonstrate enrichments in bacteria from the genera Fusobac-
against recurrent wheezing attacks in children.240 Innate immune cells
terium and Porphyromonas and the Sphingomonodaceae family, and de-
trained with specific stimuli might also acquire anti-inflammatory fea-
creased relative abundance of members of Mogibacteriaceae family and
tures and promote tolerance, which may have important implications for
Lactobacillales order.223 Increased numbers of sputum eosinophils have
chronic inflammatory diseases such as asthma. Recent findings showed
been connected with the presence of T. whipplei.222 Streptococcus abun-
that allergoid–mannan conjugates, which are next generation vaccines
dance was also reported to be increased in patients with severe asthma
for AIT, can reprogram monocytes into tolerogenic DCs by mechanisms
compared with healthy control,224 while Actinobacteria abundance was
depending on metabolic and epigenetic rewiring.241
associated with molecular indicators of steroid responsiveness (FK506
binding protein, FKBP5).218
The concept of the gut–lung connection was born out of the obser- Neurogenic inflammation in asthma
vation that different lung diseases can be influenced by intestinal mi- In addition to the classical cholinergic and adrenergic systems, hu-
croenvironment changes and vice versa. The microbiota is an important man airways are also innervated by non-adrenergic, non-cholinergic
factor responsible for interactions between these two sites in asthma.225 (NANC) pathways comprising an excitatory branch that mediates bron-
Many studies show that early life is the most important period during choconstriction via tachykinins, substance P (SP) and neurokinin (NK)
which microbiota dysbiosis in the gut may lead to the development A, and an inhibitory branch that induces bronchodilation via vasoac-
of many respiratory diseases, as the gut microbiota has a significant tive intestinal peptide (VIP) and NO. Imbalances between excitatory and
influence on immune cell maturation and resistance to pathogens.226 inhibitory NANC signaling also contribute to AHR. The airway epithe-
In adults, both obese and non-obese asthma patients with severe dis- lium contains pulmonary neuroendocrine cells (PNEC) filled with neu-
ease have reduced fecal levels of Akkermansia muciniphila. This deple- rotransmitters (serotonin and gamma-aminobutyric acid [GABA]) and
tion may have a causal role in disease pathogenesis, as supported by neuropeptides (SP, NKA, VIP, calcitonin-gene related peptide [CGRP],
murine models showing that a loss of this bacterium exacerbates acute and nociception/orphanin FQ(N/OFQ)), which are released upon vari-
and chronic airway inflammation.227 The effects of the gut microbiota ous environmental exposures. Together with classical neurotransmitters
on asthma are at least partially mediated by bacterial metabolites, such such as acetylcholine (ACh) and neuropeptide Y (NPY) from autonomic

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nerve fibers, these mediators create a complex neurochemical environ- mune cells. Specifically, SP-mediated Mas-related G protein-coupled re-
ment within the airway wall. This environment is further modified by ceptors (MRGPR) B2 activation on MCs contributes to airway inflamma-
neurotrophins (e.g., nerve growth factor and brain-derived neurotrophic tion and goblet cell hyperplasia.260 These responses are modulated by 𝛽-
factor) secreted by structural and inflammatory cells, including epithe- arrestin 2, which promotes MCs recruitment to facilitate their activation
lial cells, lymphocytes, and eosinophils.242 , 243 Under pathological con- through Fc𝜀RI.260 In addition to these neuronal pathways, PNECs rep-
ditions, this finely tuned neurochemical network can be disrupted. For resent another key sensory population in the airway epithelium. Their
instance, allergens such as house dust mites have been shown to in- functional importance is underscored by studies showing that bronchial
duce PNECs hyperplasia, which may contribute to exacerbated asthma thermoplasty attenuates airway disease by interfering with PNEC secre-
response.244 tion and synapse formation.261
The release of SP, NKA, and serotonin may exacerbate the inflamma-
tory response, while VIP, N/OFQ, and GABA show anti-inflammatory Type VII asthma
activity. The GABA-ergic system was however linked to mucus over-
production.245 Tachykinins may cause vasodilatation, plasma exuda- Type VII hypersensitivity covers direct cell activation leading to tis-
tion, and mucus secretion, whereas CGRP may contribute to hyper- sue damage. This activation can occur through mechano- or chemical-
emia of inflammation. Their effect may be amplified further by loss sensitive ion channels, through transmembrane G protein-coupled re-
of the major degrading enzyme, neutral endopeptidase, from epithelial ceptors (GPCRs) or through direct activation of intracellular pathways
cells. The CGRP–receptor activity‑modifying protein 1 (RAMP1) axis en- (Fig. 5). These pathogenic mechanisms are central to asthma following
hances Th2 and Th9 responses; and the SP–NK1 receptor (NK1R) axis exposure to pollutants, cold temperature, microbes, allergens, various
promotes the synthesis of chemokines in eosinophils, mast cells, and metabolites or drugs or as a consequence of extensive airway remodel-
neutrophils.246 In contrast, VIP–VIP receptor 1 (VPAC1) and N/OFQ– ing. They also define asthma theratypes such as those with primary or
N/OFQ peptide receptor (NOP) axes cause bronchodilation and anti- acquired resistance to corticosteroids.
inflammatory and anti-remodeling effects.247–249 Sputum SP concentra- More than 300,000 new substances have been introduced into hu-
tion was significantly higher in adults with asthma and significantly man lives after 1960s without adequate assessment on their health
corelated with the eosinophil cell count in induced sputum and with the and environmental impact. Many of them have ended up as pollutants.
forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) ra- Perfluoroalkyl substances (PFAS) are widely used in various manufac-
tio.250 Asthmatic children also exhibited an increased level of SP, along turing processes. Accumulation of these chemicals has adverse effects
with a higher proportion of M2 macrophages in their bronchoalveolar on human health, including inflammation in multiple organs. Double-
lavage fluid.251 Mechanically, SP interaction with its NK1R activates stranded DNA receptor absent in melanoma 2 (AIM2) can recognize per-
the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear fluorooctane sulfonate, a common form of PFAS, to trigger IL-1𝛽 secre-
factor kappa-light-chain-enhancer of activated B cells (NF-𝜅B) pathway, tion and pyroptosis.262
which further triggers NLR family pyrin domain containing 3 (NLRP3)- Transient receptor potential ankyrin-1 (TRPA1) and TRP vanilloid-
mediated pyroptotic cell death in the bronchial epithelial cells.252 The 1 (TRPV1) are nonselective cation channels that act as chemosensors
clinical relevance of this pathway is underscored by the positive cor- for many exogenous irritants and endogenous ligands including proin-
relation observed between epithelial mucus content and epithelial SP flammatory mediators.263 , 264 Besides the C-fibers, TRPA1 and TRPV1
expression.253 Of interest, asthmatic subjects with Mycoplasma pneumo- are also expressed by nonneuronal cells including epithelial cells, ASM
niae, compared with those without, showed higher baseline epithelial cells and fibroblasts.265 , 266 An in vitro study claimed that although ei-
neurokinin 1 (NK1) expression, which was significantly reduced after ther TRPV1 or TRPA1 activation causes airway neurogenic inflamma-
antibiotic treatment.253 This infection-induced upregulation of NK1R tion, solely TRPA1 activation orchestrates an additional inflammatory
may amplify epithelial responses to SP, exacerbating airway inflamma- response which is not neurogenic.266 TRPA1 polymorphisms were cor-
tion. related with reduced asthma control.267 A relationship between higher
The ACh–M3 axis induces goblet cell metaplasia, ECM deposition, TRPA1 expression and activity and lower TRPV1 expression and activ-
and bronchoconstriction.254 In contrast, the ACh–𝛼7nAChR axis dimin- ity was recently described.268 The TRPV1 I585I/V genotype was as-
ishes the synthesis of TNF-𝛼, IL-1, and IL-6, attenuating lung inflamma- sociated with increased TRPA1 expression by primary airway epithe-
tion.255 Patients with asthma are more sensitive to M3 receptor signaling lial cells and with amplified responses to selected air pollution parti-
as compared to healthy subjects, partially due to an enhanced ability to cles in vitro. However, the TRPV1 I585I/V genotype was not associ-
open large Ca2+ channels in ASM.256 Consequently, in addition to bron- ated with worse asthma symptom control among children exposed to
chodilation, long acting antimuscarinic agents (LAMA) also exert anti- tobacco smoke, whereas other TRPA1 and TRPV1 variants were.268 Co-
inflammatory and anti-fibrotic effects by inhibiting muscarinic recep- exposure to polystyrene microplastics and di-(2-ethylhexyl) phthalate
tors present in neutrophils, macrophages, fibroblasts and ASM cells.254 was shown to amplify oxidative stress and inflammatory responses in
Unfortunately, 75% of severe asthmatics on triple therapy remain un- allergic asthma by activating the TRPA1–p38 mitogen-activated pro-
controlled.257 The relatively low success rate of LAMA in severe asthma tein kinase (MAPK) pathway.269 Both TRPV1 and TRPA1 function as
might arise from the lack of a phenotype-guided prescription. The vis- receptors for N-acyl homoserine lactones, quorum sensing molecules
ible properties of an asthma patient theratype benefiting from LAMA produced by Gram-negative bacteria.270 Another function of the TRPA1
addition were recently described.254 channel is to sense cold temperature.271 In a mouse model of cold-
Communication between local sensory neurons, immune cells, and induced exacerbation of allergic airway disease, blocking TRPA1 with
resident lung stromal cells appears to be a key driver of AHR, airway a selective antagonist resulted in reduced inflammation, airway remod-
obstruction, and inflammation.242 , 258 Lung-innervating neurons of the eling and AHR. This study highlighted a potential new mechanism of
jugular nodose complex express the high-affinity IgE receptor Fc epsilon cold-induced airway disease through TRPA1.272 Of note, TRPA1 is not
receptor (Fc𝜀R). Vagal nociceptor neurons expressing high-affinity im- involved in body temperature regulation at basal levels or under cold
munoglobulin epsilon receptor gamma subunit (Fc𝜀R1𝛾) are directly de- challenge, making it a viable target for cold-induced exacerbations of
polarized upon encountering allergen–IgE complexes, leading to action lung disease without unwanted temperature effects on the body.
potential firing, calcium influx, and release of SP.259 Increased in vivo Cysteine and serine proteases contribute to inflammation by activat-
circulating levels of IgE following allergen sensitization enhances the re- ing protease and Mas‑related G protein-coupled receptors (MRGPRs).
sponsiveness of Fc𝜀R1 to immune complexes in both mouse jugular no- Der p1, a major allergen molecule from the house dust mite, containing
dose complex neurons and human induced pluripotent stem cell-derived cysteine protease, activates protease-activated receptor 2 (PAR-2) and
nociceptors.259 SP released from these neurons can then act on local im- Mas-related G-protein coupled receptor member X1 (MRGPRX1) and in-

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I. Agache, S. Li, Y. Zheng et al. Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

Fig. 5. Type VII asthma induced by direct cell activation. Key pathways involved in Type VII hypersensitivity reactions in asthma according to the new EAACI
nomenclature. Direct activation of airway cells occurs through multiple non-immune mechanisms, including chemical pollutants (e.g., PFAS), environmental ir-
ritants (cold, mechanical stress, microplastics, Gram-negative bacteria), proteases (e.g., HDM Der p 1), epithelial cells and macrophages, and specific receptor
agonists. AEC, Airway epithelial cell; AIM2, Absent in melanoma 2; ASM, Airway smooth muscle; cAMP, Cyclic adenosine monophosphate; EAACI, European
Academy of Allergy and Clinical Immunology; HDM, House dust mite; IL, Interleukin; MФ, Macrophage; MC, Mast cell; MRGPR, Mas-related G protein-coupled
receptor; OR, Olfactory receptor; PAR, Protease-activated receptor; PFAS, Per- and polyfluoroalkyl substances; TAS2R, Type 2 taste receptor; TRP, Transient receptor
potential.

duces the release of the pro-inflammatory cytokine IL-6 from cells ex- drug development, as opposed to the 𝛽 2 AR, which has only one subtype.
pressing these receptors.273 , 274 Mas-related G-protein coupled receptor TAS2R agonists have been shown to exert pleiotropic effects on different
member X2 (MRGPRX2) is expressed predominantly on MCs.275 MCs airway cell types. In ASM cells, they significantly inhibit the develop-
are increased especially in the lungs of patients who died from asthma ment of AHR and the cell cycle progression by inhibiting PI3K-mediated
and have been related to AHR.276 A recent study showed that MRGPRX2 pro-mitogenic signaling.284 , 285 In MCs, stimulation with TAS2R ago-
expression is significantly upregulated in MCs from asthmatic lungs as nists decreases the release of pro-inflammatory mediators such as his-
compared to those from non-asthmatic lungs, and the main activator tamine and eicosanoids.278 In immune cells, TAS2R agonists also exert
of MRGPRX2 is the hemokinin-1, a neuropeptide produced by human anti-inflammatory effects. For instance, chloroquine may act on mono-
bronchial cells and macrophages resulting in ASM contraction.277 Thus, cytes, while azithromycin promotes macrophage polarization from M1
selective MRGPRX antagonists could serve as novel targets for the mod- pro-inflammatory phenotype to M2 anti-inflammatory/reparative phe-
ulation of T1 asthma (MRGPRX1) and of AHR/near-fatal asthma (MRG- notype.286 , 287
PRX2). Several human olfactory receptors (ORs) were identified on the ASM
Bitter taste receptors belong to type II taste receptors (TAS2R), a cells.229 Olfactory receptor family 1 subfamily D member 2 (OR1D2)
family of the seven transmembrane GPCRs expressed on a variety of and olfactory receptor family 2 subfamily AG member 1 (OR2AG1) are
cell types: Tuft cells, ciliated epithelial cells, mast cells, neutrophils, expressed at the RNA and protein levels in ASM cells.288 Specific ago-
monocytes, eosinophils, lymphocytes and ASM cells.278–280 There are 25 nists for OR2AG1 and OR1D2 trigger transient calcium increases in ASM
distinct TAS2R subtypes in humans.264 The nuances in signaling differ- via a cyclic adenosine monophosphate (cAMP)-dependent signal trans-
ences between TAS2R subtypes, if any, are unclear due to lack of recep- duction cascade. Furthermore, the activation of OR2AG1 inhibited the
tor subtype-specific ligands and expression of multiple TAS2R subtypes histamine-induced contraction of the ASM, whereas the stimulation of
on an individual cell. Their expression is increased in severe asthma.281 OR1D2 led to an increase in cell contractility.288 In addition, OR1D2
A seminal paper established the potential of targeting TAS2R to stimu- activation induced the secretion of IL-8 and GM-CSF.288 Overall, ORs
late ASM relaxation and bronchodilation.282 Critically, this therapeutic exert diverse and cell type-specific effects on ASM function. ORs do not
potential targeting TAS2R appears to be preserved even in the context uniformly promote bronchodilation; instead, they modulate a range of
of airway inflammation, since TAS2R expression and signaling, along cellular responses including cytoskeletal remodeling, contractility, and
with TAS2R-mediated ASM relaxation and bronchodilation, remain un- cytokine secretion—processes that collectively contribute to two cardi-
altered under inflammatory conditions.283 TAS2R-mediated ASM relax- nal features of asthma: airway remodeling and hyperplasia.289
ation is unaffected by tachyphylaxis, as opposed to 𝛽 2 -adrenergic re- A critical aspect of the biology of the lungs is its capacity to respond
ceptor (𝛽 2 AR), suggesting that in the conditions where asthmatics are to mechanical stretch. The sensing of the physical movements in the
refractory to beta agonist treatment, TAS2R agonists can be useful for lungs is regulated by mechanosensitive ion channels such as the TRP
stimulating bronchodilation. Further, ASM cells express multiple sub- superfamily and Piezo (PZ) channels (i.e., Piezo 1 and Piezo 2), both
types of TAS2Rs (at least 3–4 of them at a level higher than 𝛽 2 AR), all of which are widely expressed throughout the lungs.290 It was recently
of which are known to relax ASM. This presents an opportunity to ex- shown that pulmonary fibrosis could be driven by elevated mechanical
plore multiple subtypes of TAS2R either singularly or in combination for tension in alveolar type 2 cells inducing a TGF‐𝛽 signaling loop, lead-

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I. Agache, S. Li, Y. Zheng et al. Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

ing to impaired alveolar regeneration.291 Recent studies have revealed

cell type-specific and context-dependent roles for the mechanosensi-
tive Piezo channels in asthma pathogenesis. In lung fibroblasts, Piezo1
mediates mechanical stretch-induced ECM production via extracellular
signal-regulated kinase (ERK) phosphorylation and Ca2+ influx, suggest-
ing a role in airway remodeling.292 Similarly, in ASM cells, mechanical
stretch activates pro-inflammatory mechanisms through the interaction
between the mechanosensitive piezo channels and the key Ca2+ reg-
ulatory protein stromal interaction molecule 1 (STIM1), implicating a
role of Piezo in pro-inflammatory responses.293 In contrast to these pro-
inflammatory and pro-remodeling effects, Piezo1 serves as a negative
regulator of ILC2 function. Upon ILC2 activation, Piezo1 expression is
induced, which restrains ILC2 activity by suppressing cytokine produc-
tion and ultimately decreasing AHR.294 This dual functionality high-
lights the functional complexity of mechanical signaling in the airways.
Blocking mechanical pathways using inhibitors such as gadolinium (i.e.,
Piezo 1 inhibitor) has been shown to reduce inflammation and mucous
secretion.295 These findings underscore the need for cell type-specific
targeting strategies when considering Piezo channels as therapeutic tar-
gets in asthma.
Severe steroid-resistant asthma in adults is defined by the failure
to achieve a >15% improvement in FEV1 after 14 days of oral steroid
treatment.296 This condition affects 5–10% of patients with severe
asthma and represents a major unmet need in current asthma manage-
ment, contributing to the substantial healthcare burden resulting from
prolonged and frequent hospitalizations and complications associated
with OCS use.297 Steroid resistance can be either inherited (primary)
or acquired (secondary). Corticosteroids readily diffuse into the air-
Fig. 6. Mechanism of glucocorticoids resistance in severe asthma. Glucocorti-
way tissue, bind and activate cytosolic glucocorticoid receptors (GRs).
coids bind to cytosolic GR𝛼, inducing its nuclear translocation where the ligand-
The anti-inflammatory effects are mediated by the GR𝛼 isoform via activated GR𝛼 complex recruits HDAC2 to GRE, resulting in gene suppression
ligand-dependent transcription factors, while GR𝛽 acts as a dominant and anti-inflammatory effects. Resistance arises from multiple defects, includ-
inhibitor of GR𝛼. Defective GR𝛼 expression and activity impairs the anti- ing overexpression of the dominant-negative GR𝛽 isoform (○), 1 defective GR𝛼
inflammatory effects of glucocorticoids and plays important roles in the nuclear translocation (○),
2 reduced HDAC2 expression/activity (○), 3 cytokine-
induction of steroid resistance (Fig. 6). Conversely, one of the impor- induced alterations (IL-2, IL-4, IL-13) (○),
5 and competitive interference by pro-
tant molecular mechanisms contributing to primary corticosteroid re- inflammatory transcription factors (NF-𝜅B, NF-AT1, IRF1) (○). 6 GC, Glucocor-
sistance is the overexpression of the GR𝛽 isoform.298 Over 3000 single- ticoid; GR𝛼, Glucocorticoid receptor 𝛼; GR𝛽, Glucocorticoid receptor 𝛽; GRE,
nucleotide polymorphisms have been described for the gene encoding Glucocorticoid response element; HDAC2, Histone deacetylase 2; IL, Interleukin;
IRF1, Interferon regulatory factor 1; NF-AT1, Nuclear factor of activated T cells
GR.299 In addition, various GR protein isoforms result from 11 tran-
1; NF-𝜅B, Nuclear factor 𝜅B.
scription start sites, and differential mRNA splicing leads to further GR
protein variants; each can be modified post-translationally and alter
steroid responsiveness. Furthermore, some GR isoforms are expressed
in a cell-type-specific manner or in a sub-cellular location. Defective Conclusion
nuclear translocation of GRs reduces expression and activity of histone
deacetylase (HDAC) 2 in patients with asthma,300 and this reduction is The current stratified approach in asthma using a few available
associated with steroid insensitivity and more severe disease.300 Dys- biomarkers measured at the point-of-care leads to a significant over-
regulation of GR signaling pathways, including changes in GR phospho- lap between endotype classification. It also did not solve the signif-
rylation, makes a substantial contribution to the inherent glucocorti- icant incomplete response rate to biologicals targeting the T2 path-
coid resistance in severe asthma.301 Higher levels of IL-2, IL-4 and IL-13 way. Machine-learning models combining precision immunology data
expression result in local cytokine secretion which further alters GR𝛼 with imaging biomarkers and deep phenotyping provide an unbiased
translocation. Pro-inflammatory transcription factors, including NF-𝜅B, novel view on asthma pathogenetic pathways and related biomarker
activator protein-1, and IFN regulatory factor-1, competitively interact signatures guiding personalized management of asthma patients. Dig-
with GR for binding sites on DNA as well as for transcriptional coacti- ital health technology can impact asthma care by identifying and ed-
vators. Such competitive interaction limits GR’s ability to suppress the ucating about environmental triggers, prompting earlier recognition of
production of pro-inflammatory cytokines.299 In severe asthma, there is asthma symptoms, and improving medication adherence and inhaler de-
a dysregulation of the NF-𝜅B and MAPK pathways, whereby the ASM vice technique. The new EAACI nomenclature introducing the V, VI and
cells can proliferate and contribute to airway remodeling despite cor- VII hypersensitivity reactions provides the basis for defining new asthma
ticosteroid treatment.302 In addition, exposure to smoke or pollutants theratypes.
increases oxidative stress, which further compromises GR signaling and However, there are still ongoing and future challenges we have to
contributes to corticosteroid resistance.303 PI3K-delta inhibitors that confront in asthma diagnosis and treatment, including the standardiza-
reestablish HDAC2 function together with p38 MAPK inhibitors decreas- tion of multi-omics for clinical use, the development of cost-effective
ing GR phosphorylation, are currently in clinical development.304 , 305 point-of-care biomarker panels and therapies for non-T2 targets, and
Understanding how to tackle the complex pathogenetic pathways the integration of digital health data into the decision-making process.
classified as type V, VI or VII asthma opens novel opportunities for per- These underscore the need to prioritize the integration of diverse data
sonalized asthma management. This approach complements current bi- streams into asthma theratypes-based clinical decision-support systems
ologicals targeting the T2 pathway and brings us closer to achieving to achieve clinical remission of asthma,307 and ultimately improve pa-
biological remission in asthma (Table 1). tient outcomes.

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I. Agache, S. Li, Y. Zheng et al. Chinese Medical Journal Pulmonary and Critical Care Medicine 4 (2026) 19–38

Table 1
Novel asthma theratypes uncovered by the concept of type V, VI and VII asthma.

Target Interventions by asthma type Clinical impacts

Chronic inflammation Fruit, fibers and vegetable intake, reduced animal product consumption, and Asthma associated with
weight management170 , 197 , 198 , 229 , 230 (Type VI) obesity/metabolic syndrome
Long-acting antimuscarinic agents254 , 255 (Type VI)
Metformin, glucagon-like peptide-1 receptor agonists212 , 213 (Type VI)
Nebulized dehydroepiandrosterone-3-sulfate204 (Type VI)
Inhibition of the renin-angiotensin system215 (Type VI)
Mucosal bacterial immunotherapy240 (Type VI)
Innate immune cells trained with specific stimuli (e.g., allergoid-mannan
conjugates)241 (Type VI)
Decreased release of mediators from MCs with TAS2R agonists278 (Type VI)
Anti-inflammatory actions on monocytes with bitter taste receptor agonists
(chloroquine)286 (Type VI)
Phenotypic shift in macrophages to an anti-inflammatory/reparative phenotype
with TAS2R agonists such as macrolides287 (Type VI)
TRPA1 inhibitors266 (Type VII)
T1 asthma Selective MRGPRX1 antagonists273 , 274 , 277 (Type VII) Non-eosinophilic asthma
AHR/near-fatal asthma (MCs Selective MRGPRX2 antagonists275–277 (Type VII) AHR/near-fatal asthma
driven)
Cold-induced respiratory TRPA1 inhibitors271 , 272 (Type VII) Cold exposure as major trigger of
disease asthma symptoms or exacerbations
Airway obstruction Mucosal bacterial immunotherapy240 (Type VI) Fixed airway obstruction
Long-acting antimuscarinic agents254 (Type VI) Asthmatics refractory to 𝛽- agonist
TAS2R agonists in asthmatics refractory to beta agonist treatment282 (Type VII) treatment
Airway hyperreactivity Long-acting antimuscarinic agents254 (Type VI) Asthmatics refractory to 𝛽- agonist
Piezo1 activation restrains ILC2 activity by reducing cytokine production, treatment
resulting in decreased AHR294 (Type VII)
TAS2R agonists282 (Type VII)
Restoration of the epithelial Topical steroids111 , 131 (Type VII) Benefits to all asthma phenotypes as
barrier function and AIT restoring the antiviral interferon response306 (Type VII) epithelial barrier function and
integrity Cannabinoids (WIN55212-2) restoring rhinovirus-induced epithelial barrier integrity is a major protective factor
disruption241 (Type VI)
Epithelial derived cytokines Anti TSLP and anti-IL-33 biologics7 , 99 (Type VII) Non-eosinophilic asthma
Mucous secretion Long-acting antimuscarinic agents254 (Type VI) High mucus burden (HRCT score) not
Antibodies directed against key epitopes of the CLC crystallization interface146 responding to T2 -targeting biologics
(Type VII)
Mucolytic approaches that involve disruption of disulfide bonds or weakening of
non-covalent mucin interactions145 (Type VI)
Gene or transcript directed therapies that target each mucin145 (Type V)
Fucosyltransferase 2 inhibitors to inhibit mucin fucosylation145 (Type V)
Blocking mechanical pathways using the Piezo 1 inhibitor gadolinium290–292
(Type VII)
Cytoskeletal remodeling and Long-acting antimuscarinic agents254 (Type VI) Asthma with fixed airway obstruction
hyperplasia Inhibition of the renin-angiotensin system215 (Type VI) or with accelerated lung function
Specific agonists of the olfactory receptors OR2AG1 and OR1D2288 (Type VII) decline
TAS2R agonists (inhibition of the cell cycle progression by inhibiting
phosphoinositide 3-kinase-mediated pro-mitogenic signaling in ASM cells)285
(Type VII)
Communication between Bronchial thermoplasty significantly reduced or interrupted the signaling Asthma with fixed airway obstruction
local sensory neurons, between PNECs and other cells by interfering with their secretion and synapse or with accelerated lung function
immune cells, and resident formation246 (Type VI) decline
lung stromal cells
Corticosteroid resistance Phosphoinositide 3-kinase-delta inhibitors that reestablish HDAC2 function Asthma needing maintenance OCS
(Type VII)
p38 mitogen-activated protein kinase inhibitors decreasing GR
phosphorylation304 , 305 (Type VII)
AIT, Allergen immunotherapy; AHR, Airway hyperreactivity; ASM, Airway smooth muscle; CLC, Charcot-Leyden crystals; GR, Glucocorticoid receptor; HDAC,
Histone deacetylase; HRCT, High-resolution computed tomography; IL, Interleukin; ILC, Innate lymphoid cells; MCs, Mast cells; MRGPR, Mas-related G protein-
coupled receptor; OCS, Oral corticosteroids; OR, Olfactory receptors; PNEC, Pulmonary neuro-endocrine cells; TAS2R, Type 2 taste receptor; TSLP, Thymic stromal
lymphopoietin; TRP, Transient receptor potential.

Declaration of competing interest alization, Project administration. Yadong Gao: Writing – review & edit-
ing, Visualization, Project administration.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence References
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