Asthma part 1: pathogenesis, diagnosis, and endotypes

Asthma
Suravat Homvises, MD.
Part 1: Pathogenesis, Diagnosis and Endotypes

Contents
• Definition of asthma
• Wheezing phenotypes
• Risk factors
• Diagnosis
• Asthma endotypes

Definition
• Asthma is a common, chronic respiratory disease affecting 1–29% of the population in different
countries.
• Characterized by variable symptoms of wheeze, shortness of breath, chest tightness and/or
cough, and by variable expiratory airflow limitation.
• Both symptoms and airflow limitation characteristically vary over time and in intensity.
• Variations are often triggered by factors such as exercise, allergen or irritant exposure, change
in weather, or viral respiratory infections.
2023 GINA Report, Global Strategy for Asthma Management and Prevention

Prevalence of asthma
Europe Outside Europe
Holgate ST. Middleton’s allergy, 9th edition

Chinratanapisit S, et al. Asian Pac J Allergy Immunol 2019;37:226-31.
• 7 primary schools and 6 secondary schools in Bangkok were randomly mapped, stratified.
• N = 3,074 for 6-7 years (parental completed questionnaires) and 3,217 for 13-14 years
(self-completed questionnaires)

• 4 wheezing phenotypes
• No wheeze
• Transient early wheeze: wheezed in first 3 years of life but not after age 3 years
• Late-onset wheeze: onset between 4-6 years of age
• Persistent wheeze: wheezed both before and after 3 years of age
Tucson Children's Respiratory Study (TCRS)
Martinez FD, et al. N Engl J Med 1995;332:133-8.

• Wheezing in early life and continued to wheeze at 6 years (Persistent wheeze) were more
likely than children who never wheezed to have diminished airway function and have elevated
serum IgE levels at age 6 years
• Wheezing before 3 years of age but not at 6 years (Transient early wheeze) had diminished
airway function both before age 1 year and 6 years but did not have elevated serum IgE levels
or skin-test reactivity Martinez FD, et al. N Engl J Med 1995;332:133-8.

• Never wheeze
• Transient early wheeze
• Prolonged early wheeze:
onset between 6-54 months of age
• Intermediate-onset wheeze:
onset between 18-42 months of age
• Late-onset wheeze
• Persistent wheeze
Avon Longitudinal Study of Parents and Children (ALSPAC)
Henderson J, et al. Thorax 2008;63:974-80.

• Transient and prolonged early wheeze: not associated with atopy but weakly associated with increased
airway responsiveness
• Intermediate onset (18 months) wheezing: strongest associations with atopy and impaired lung function
• Late onset wheezing (after 42 months): associated with atopy and airway responsiveness
• Persistent wheeze: intermediate associated with atopy and airway responsiveness
Henderson J, et al. Thorax 2008;63:974-80.

Manchester Asthma and Allergy Study (MAAS)
• Never wheeze
• Transient early wheeze
• Persistent controlled wheeze
• Persistent troublesome wheeze
Belgrave DCM, et al. J Allergy Clin Immunol 2013;132:575-83 e12.

• Persistent troublesome wheeze: markedly higher probability of severe asthma exacerbations
and hospitalizations, unscheduled visits, reduced lung function, higher bronchial hyperreactive
airways, and higher IgE levels to inhalant allergens
Belgrave DCM, et al. J Allergy Clin Immunol 2013;132:575-83 e12.

Urban Environment and Childhood Asthma (URECA)
• High-risk inner-city cohort
• Low wheeze/low atopy
• Low wheeze/high atopy
• Transient wheeze/low atopy
• High wheeze/low atopy
• High wheeze/high atopy
Bacharier LB, et al. Am J Respir Crit Care Med 2019;199:71-82.

• High wheeze group (both high- and low-atopy): associated with asthma and low early-life
aeroallergen exposure
• High wheeze-high atopy phenotype was linked to greater morbidity and low household
microbial richness and diversity
Bacharier LB, et al. Am J Respir Crit Care Med 2019;199:71-82.

Protection Against Allergy: Study in Rural Environments (PASTURE)
• No/infrequent wheeze
• Transient wheeze
• Intermediate wheeze
• Persistent wheeze
Depner M, et al. Am J Respir Crit Care Med 2014;189:129-38.

Pathogenesis
• Cellular inflammation
• Epithelial damage
• Subepithelial basement membrane thickening
• Smooth muscle increase

Cellular inflammation
• Persistent airway inflammation
• Increased airway smooth muscle
• Thickening of the subepithelial lamina reticularis (reticular lamina)
• Matrix deposition throughout the airway wall (between muscle bundles)
• Increase in micro-vessels and neural networks
• Mucous metaplasia of the epithelium with increased submucosal glands
• Mucus plug
• Composed of mucins, serum proteins, inflammatory cells, and cellular debris
• Desquamated epithelial cells and macrophages

• A 71-year-old woman with a history of asthma presented with a productive cough, fever, and
shortness of breath
• Centrifuged sample of her bronchoalveolar-lavage specimen contained microscopic structures
identified as Curschmann's spirals
• Associated with production of excess mucus in conditions such as asthma and bronchitis
Vezza PR, Montgomery EA. N Engl J Med 1998;339:1043.

• In early onset allergic asthma, Th2 cells are activated during allergen exposure, inducing an
inflammatory cascade results in eosinophilic airway inflammation
• In past 5 years, innate lymphoid type 2 cells (ILC2s) have been identified as possible drivers of
eosinophilic airway inflammation, leading to shift in denomination from eosinophilic versus non-
eosinophilic asthma to type 2 high and type-2-low asthma
Porsbjerg C, et al. Lancet 2023;401:858-73.

• Allergen uptake by DCs drives expansion of Th2 cells that secrete pro-allergic cytokines
(IL-4, IL-5, IL-9 and IL-13).
• Cytokines are also produced by ILC2 cells that differentiate from progenitor cells in presence of
alarmins such as thymic stromal lymphopoietin (TSLP), IL-33 and IL-25
• Both Th2 and ILC2 cells express the IL-33 receptor ST2 as well as the PGD2 receptor (CRTH2)
Eyerich S, et al. Allergy 2020;75:546-60.

• Goblet cell hyperplasia in epithelial cell lining
• Sub-basement membrane thickening with
collagen deposition in the mucosal area
• Cellular infiltrate
• Subject without asthma

• Airway wall thickness
• Increased from 50% to 300% in fatal asthma and from 10% to 100% in nonfatal asthma
• Results from increase in most tissue compartments, such as inflammatory edema and
entrapment of water by proteoglycans
• Goblet cell hyperplasia and hypertrophy
• Effects of IL-4, IL-9, and IL-13
• Response to epithelial stress and injury through secretion of epidermal growth factor
family (EGF, amphiregulin, transforming growth factor α [TGF- α], and heparin binding
EGF-like growth factor [HB-EGF])
• Increase in microvessels driven by fibroblast growth factor (FGF)-1, FGF-2, and vascular
endothelial growth factor (VEGF)-1

• Cellular infiltration
• Results from both activation of resident cells and recruitment of circulating inflammatory
cells into airway
• Majority of types of inflammatory cell: Eosinophils
• Primary lysis of eosinophils to liberate free eosinophil granules (FEGs) containing their
toxic proteins in association with epithelial damage
• Different asthma sub-phenotypes: neutrophils, lymphocytes, macrophages and mononuclear
cells, and mast cells
• Mucosal mast cells: T cell-dependent tryptase+ type (MCT)
• Deeper in airway wall and between the smooth muscle bundles: Mast cells containing
both tryptase, chymase, and carboxypeptidase A (MCTC)
• More severe and chronic asthma: MCTC numbers increase in epithelium, submucosa,
smooth muscle, and peripheral airways

Epithelial Damage
• Epithelial damage and shedding in conducting airways result from separation of columnar cells
from basal cells, which are more resistant to detachment in asthma even in presence of
extensive inflammation
• Desquamated epithelial cells expectorated in sputum of asthmatic patients are known as
“Creola bodies”

Subepithelial Basement Membrane Thickening
• Basement membrane region of asthmatic patients is twice as thick as in non-asthmatic airways
• Confined to the lamina reticularis, with unaltered overlying lamina rara and lamina densa
• Collagenous proteins are the major constituent of the extracellular matrix (ECM)
• Collagen types I, III, V, and VI
• Collagen IV is the major constituent of normal basement membrane
• Thickened reticular layer is largely composed of collagen III, V and lesser extent type I and
fibronectin
- Holgate ST. Middleton’s allergy, 9th edition
- Izuhara K, et al. Allergol Int 2015;64 Suppl:S3-10.

Subepithelial Basement Membrane Thickening
• Subepithelial collagen is produced by myofibroblasts lying beneath the epithelium, with their
numbers correlating with the extent of collagen thickness
• Epithelium is potent source of growth factors capable of driving both fibrosis and smooth muscle
proliferation, including periostin, platelet-derived growth factors (PDGFs), bFGF, transforming
growth factor β (TGF-β), and epidermal growth factor receptor (EGFR) family
- Holgate ST. Middleton’s allergy, 9th edition
- Izuhara K, et al. Allergol Int 2015;64 Suppl:S3-10.

Smooth Muscle Increase
• Smooth muscle alterations in asthma are best characterized as hyperplasia
• Increase in airway smooth muscle (ASM) mass from hyperplasia when confined to larger airways,
whereas hypertrophy predominates when smaller airways become involved in more severe disease
• Greater narrowing effect on the caliber of the airways in the distal bronchi and bronchioles
than on the larger airways
• Cause for increased muscle mass in asthma still remains largely unknown
• Continuous irritation by mediators and growth factors
• Hyperplasia caused by repeated episodes of bronchoconstriction
• Loss of inhibitory control with unopposed myogenic activity

Fahy JV. Nat Rev Immunol 2015;15:57-65.

Porsbjerg C, et al. Lancet 2023;401:858-73.

• Perturbation of epithelium with infection and pollutants provides initial danger signal and
activates innate signaling receptors
• Chemokine secretion from airway epithelial cells and trafficking of immature DCs to mucosal
epithelium
• Maturation to competent antigen-presenting myeloid-type DCs
• Mature DCs process allergens detected then migrate to local lymph nodes, where they interact
with naïve T cells via TCR, MHC-II, and costimulatory molecules >> T cells differentiation
• Epithelial-derived cytokines and chemokines such as IL-33, IL-25, CCL17, and CCL22 influence
DC activation and Th2 maturation and migration into the mucosa
Pathogenesis

• Regulatory T cells
• Suppression of DCs involved in
programming effector T cells
• Direct inhibition of Th1, Th2, and Th17 cells
• Suppression of allergen specific IgE and
induction of IgG4
• Inhibition of mast cells, basophils, and
eosinophils
• Prevention of effector T cell migration into
the target tissue
Pathogenesis

Risk factors for the development of asthma
• Genetic factors
• Prenatal and perinatal factors
• Maternal smoking
• Maternal asthma
• Maternal obesity and weight gain
• Maternal vitamin D supplementation
• Maternal diet
• Breastfeeding
• Allergic sensitization
• Air pollution
• Respiratory viruses
• Microbial factors

Genetics factors
• Genome-wide association studies (GWASs) in large groups of people with and without asthma
• ORMDL3/GSDMB was first published in 2007 by Moffatt and colleagues
• Genetic variation at chromosome 17q12–21 is associated with childhood asthma
El-Husseini ZW, et al. Lancet Respir Med 2020;8:1045-56.

• Effect allele of certain genetic variant could be associated with protection or risk of different
asthma-related phenotypes in different environmental settings
• Influence of environmental factors on asthma may be modified by genetic composition
Genetics factors
Hernandez-Pacheco N, et al. Pediatr Allergy Immunol 2022;33:e13780.

• Epigenetic regulation
• DNA methylation
• Histone modifications
• Non-coding RNAs (microRNAs)
Genetics factors
Miteva D, et al. 2023;3:115-33.

Prenatal and perinatal factors
• Exposures that have adverse impacts on lung growth and immune development and increase
the risk of lower respiratory infections and allergic sensitization in early life
• Environmental exposures resulting in low lung function at birth
• Decreased somatic growth and decreased airway growth
• Development of airway tree is completed by 16-18 weeks’ gestation
• Exposures occurring before this period may have adverse impact on airway growth and
on lung function at birth

• Pooled analysis was performed from 8 European birth cohorts
• Maternal smoking only during pregnancy was associated with wheeze and asthma at 4-6 years of
age, with aOR of 1.39 (95% CI 1.08–1.77) and 1.65 (95% CI,1.18–2.31), respectively
• Likelihood to develop wheeze and asthma increased statistically significantly in linear dose-dependent
manner in relation to maternal daily cigarette consumption during the first trimester of pregnancy
Maternal smoking
Neuman A, et al. Am J Respir Crit Care Med 2012;186:1037-43.

• Systematic review and meta-analysis on 43 prospective
birth cohorts
• Maternal prenatal smoking was associated with increased
risk of wheezing in <6-year-olds (OR 1.36, 95%CI 1.19-
1.55) and wheezing or asthma in ≥6-year-olds (OR 1.22,
95%CI 1.03-1.44)
• Postnatal exposures to maternal/parental smoking were
associated with wheezing in <6-year-olds (OR: 1.21; 95%CI
1.13-1.31 and OR 1.30; 95%CI 1.13-1.51)
Maternal smoking
Silvestri M, et al. Pediatr Pulmonol 2015;50:353-62.

• Perth cohort: Infants of mothers who smoked during pregnancy had impaired TLR-mediated
immune responses and reduced production of cytokines such as IL-6, IL-10, and TNF-α,
increasing subsequent risk of respiratory infections and asthma
• Decreased lung function and airway hyperresponsiveness of infants with intrauterine smoke
exposure
• Nicotine (key constituent of cigarette smoke)
• Across placenta and interact with nicotinic acetylcholine receptors of fetal lung, interfering
with lung development
• Affect epithelial differentiation and sustained activation of immune cells through epigenetic
alterations, such as DNA methylation or changed microRNA expression
Xing Y, Leung AS, Wong GW. Pediatr Allergy Immunol 2023;34:e14049.
Maternal smoking

• Primary and secondary care electronic medical records between 2007 and 2017 from UK
Clinical Practice Research Datalink (CPRD-GOLD)
• Mothers requiring asthma relievers during pregnancy (aHR 1.17, 95%CI 1.09-1.26), Mothers
requiring asthma preventers during pregnancy (aHR 1.32, 95%CI 1.18-1.48), and Mothers
whose asthma worsened during pregnancy (aHR 1.53, 95%CI 1.36-1.71) were at greater risk of
having offspring with preschool wheezing progressed to asthma at 5–8 years
Maternal smoking
Bloom CI, et al. J Allergy Clin Immunol 2021;147:1949-58.

• Meta-analysis from 33 studies
• Odds ratio for asthma in children of asthmatic mothers
compared with non-asthmatic mothers was significantly
increased at 3.04 (95% CI 2.59–3.56)
• Maternal asthma conferred greater risk of disease than
paternal asthma (3.04 vs. 2.44, p=0.037)
Maternal asthma
Gallagher C, et al. Pediatr Allergy Immunol 2024;35:e14081.

• 14 observational studies
• Maternal obesity in pregnancy was associated
with higher odds of asthma or wheeze ever
(OR 1.31; 95%CI 1.16–1.49) or current
(OR 1.21; 95% CI 1.07–1.37)
• Each 1-kg/m2 increase in maternal BMI was
associated with 2-3% increase in odds of childhood
asthma
Maternal obesity and weight gain
Forno E, et al. Pediatrics 2014;134:e535-46.

Breastfeeding
• Systematic review and meta-analysis of 42 studies
• Children with longer duration/more breastfeeding compared to shorter duration/less
breastfeeding have a lower risk of asthma (OR 0.84, 95% CI 0.75–0.93; I2 = 62.4%)
• Lower risk of asthma was found in children who had more exclusive breastfeeding versus less
exclusive breastfeeding (OR 0.81, 95% CI 0.72–0.91; I2 =44%)
Xue M, et al. ERJ Open Res 2021;7.

• VDAART (N = 806) and COPSAC2010 (N = 581)
randomized pregnant women to daily high dose vitamin D3
(4,000 IU/d and 2,400 IU/d, respectively) or placebo
• High dose vitamin D3 supplementation had 25% reduced
risk of asthma/recurrent wheeze at 0-3 years
[aOR=0.74 (95%CI, 0.57-0.96)]
• Effect was strongest among women with 25(OH)D level
≥30 ng/ml at study entry [aOR=0.54 (0.33–0.88)]
• Loss of benefit at 6 years’ analysis
Maternal vitamin D supplementation
Wolsk HM, et al. PLoS One 2017;12:e0186657.

Brustad N, et al. Pediatr Allergy Immunol 2023;34:e13984.

Brustad N, et al. Pediatr Allergy Immunol 2023;34:e13984.
Maternal diet

• MAAS birth cohort
• Sensitization to multiple aeroallergens significantly increased risk of wheezing, asthma,
and exacerbations, resulting in hospitalization
Simpson A, et al. Am J Respir Crit Care Med 2010;181:1200-6.
Allergic sensitization

• Risk of current wheeze significantly increased with increasing levels of specific IgE to mite, cat,
and dog in preschool children
• PASTURE study: Excessive serum IgE production was associated with impaired lung function
and increased future asthma risk
• 680 children of MAS
• 766 children of PASTURE
Hose AJ, et al. J Allergy Clin Immunol 2017;139:1935-45 e12.

Hose AJ, et al. J Allergy Clin Immunol 2017;139:1935-45 e12.

• Mechanisms of the Development of ALLergy (MeDALL) study
• 14 European birth cohorts
• Polysensitization is associated with earlier onset of wheezing symptoms and multimorbidity
of allergic disorders in comparison with monosensitization
Anto JM, et al. J Allergy Clin Immunol 2017;139:388-99.

• Systematic review of 18 studies
• Associations between prenatal exposures to NO2, SO2, and PM10 and the risk of wheezing and
asthma development in childhood
Air pollution
Hehua Z, et al. Environ Res 2017;159:519-30.

Air pollution
• US Birth cohorts recruited between 1987 and 2007, and followed up through age 11 years
• Mean values of pollutants over the first 3 years of life were associated with asthma incidence
Zanobetti A, et al. JAMA Netw Open 2024;7:e240535.

Air pollution
• 1 IQR increase in PM2.5 (3.4 mcg/m3 ) was associated with increased asthma incidence among
children younger than 5 years (HR 1.31 [95%CI 1.04-1.66]) and children younger than 11 years
(OR 1.23 [95%CI 1.01-1.50])
• 1 IQR increase in NO2 (6.1 mcg/m3) was associated with increased asthma incidence among
children younger than 5 years (HR, 1.25 [95%CI 1.03-1.52]) and children younger than 11 years
(HR 1.22 [95%CI 1.04-1.44])
Zanobetti A, et al. JAMA Netw Open 2024;7:e240535.

Respiratory viruses
• Rhinovirus (RV) is the dominant agent associated with wheezing in children
• Young children who wheeze with RV are more likely to develop recurrent wheezing and later asthma
- Xing Y, Leung AS, Wong GW. Pediatr Allergy Immunol 2023;34:e14049.
- Makrinioti H, et al. Pediatr Allergy Immunol 2022;33:e13741.
RV
RSV
• Meta-analysis of 8 studies showed that the RV-bronchiolitis group were more likely to develop
recurrent wheeze than the RSV-bronchiolitis group

• Human rhinovirus is classified into 3 species, RV-A and RV-C are more commonly associated
with wheezing and severe illness compared with RV-B
• Carrying risk allele of cadherin-related family member 3, cellular receptor of RV-C, were more
susceptible to RV-C infections and develop recurrent wheezing and severe early-onset asthma
• COAST study:
• State 1: No wheeze/No allergic sensitization
• State 2: Wheeze/No allergic sensitization
• State 3: No wheeze/Allergic sensitization
• State 4: Wheeze/Allergic sensitization
• Allergic sensitization led to increased risk of wheezing illnesses caused by human rhinovirus
Human rhinovirus
- Jackson DJ, et al. Am J Respir Crit Care Med. 2012 Feb 1;185(3):281-5.

2 Key factors
• Impaired antiviral responses
• MAAS cohort: Children with the highest risk of developing asthma exhibited lowest levels of
interferon in combination with high proinflammatory cytokines in response to RV infection
• Picornaviridae (mostly RV) and bacteriophage Siphoviridae is correlated with low innate
interferon responses
Human rhinovirus

• Excessive Th2 inflammation by RV induction
• RV infects respiratory epithelium, leading to release of epithelial-derived cytokines IL-25, IL-33,
and TSLP, which drives downstream release of IL-4, IL-5, and IL-13 from Th2 cells and ILC2s
Jackson DJ, Gern JE. J Allergy Clin Immunol Pract 2022;10:673-81.

• RSV is the most common viral pathogen causing bronchiolitis in infancy
• Prophylactic treatment of RSV with palivizumab greatly reduced recurrent wheezing in healthy
preterm infants even outside the RSV season
• MAKI trial: randomly assigned 429 healthy preterm infants born at GA 33-35 weeks to
receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during
RSV season
Respiratory syncytial virus
- Blanken MO, et al. N Engl J Med. 2013; 368(19): 1791-1799.

• Infants infected with RSV had downregulated interferon (IFN) responses and upregulated Th2
and Th17 pathways, which were associated with recurrent wheeze in succeeding 2 years
RV
RSV
Turi KN, et al. Am J Respir Crit Care Med 2018;198:1064-73.

• COAST study
• Development of persistent wheezing phenotype in children, or childhood asthma, requires at
least 2 factors at critical time-point in development of immune system or lung
(two-hit hypothesis)
• Dysregulation of cytokine responses at birth (genetic factor)
• Development of clinically significant lower respiratory tract viral infection (primarily
RSV bronchiolitis) (environmental factor)
Respiratory syncytial virus
Lemanske RF, Jr. Pediatr Allergy Immunol 2002;13:38-43.

Microbial effects
• COPSAC cohort: Neonates with bacterial pathogens colonized in hypopharyngeal region were
at increased risk of recurrent wheezing and childhood asthma
• S. pneumoniae
• M. catarrhalis
• H. influenzae

Microbial effects
• COAST study: High levels of RV and Moraxella during a wheezing attack and/or a high
abundance of Staphylococcus aureus in first 6 months of life were found to predict persistent
asthma
Tang HHF, et al. J Allergy Clin Immunol 2021;147:1683-91.

• Infants hospitalized for RSV infection had distinct nasopharyngeal microbiota profile,
characterized by high abundance of Haemophilus influenzae, which was associated with
mucosal CXCL8 responses and increased severity of wheezing attacks
• Integrated-omics endotyping: RV-C infection and Moraxella-dominated microbiome, with high
Th2 cytokine response, correlated with highest risk for recurrent wheezing and childhood asthma
Microbial effects
Raita Y, et al. J Allergy Clin Immunol 2021;147:2108-17.

• Host-microbiome dominated by commensals may reduce risk of viral wheeze and asthma
• Intranasal administration of Bifidobacterium or its cell wall extract significantly reduced viral
load within lung and protected against airway inflammation in murine models
• Microbial components derived from bacteria commensals such as lipopolysaccharides,
polysaccharide A, and extracellular polysaccharides can alter asthma risk through anti-
inflammatory responses
Microbial effects

Diagnosis

Diagnosis
• Typical variable respiratory
symptoms
• Confirmed variable expiratory
airflow limitation
• Age ≥6 years

แนวทางการรักษาโรคหืดสาหรับผู้ใหญ่ในประเทศไทย 2565
Diagnosis (Thai)

Differential diagnosis

Diagnosis in children 5 years and younger

• Suggestive features
Diagnosis in children 5 years and younger

Differential diagnosis (5 years and younger)

Asthma predictive index
Chang TS, et al. J Allergy Clin Immunol Pract 2013;1:152-6.

• Unselected: Tucson Children’s Respiratory Study cohort
• High risk: High-risk COAST cohort
Asthma predictive index
Chang TS, et al. J Allergy Clin Immunol Pract 2013;1:152-6.

Asthma endotypes
• Endotyping refines based on pathophysiologic mechanisms
• T2-Low Asthma
• Neutrophils, Th1 and Th17 cells
• Specific mediators: IL-8, IL-23, IL-17, and IL-23
• Patients tend not to respond to corticosteroids
• T2-High Asthma
• Th2 cells, type 2 innate lymphoid cells (ILC2), mast cells, natural killer T cells
• Specific mediators: IL-4, IL-5, IL-13, IL-33, IL-25, and thymic stromal lymphopoietin (TSLP),
immunoglobulin E (IgE)
Kuruvilla ME, et al. Clin Rev Allergy Immunol 2019;56:219-33.

T2-High asthma
• Dysregulated epithelial barrier
• Alarmins (TSLP, IL-25, IL-33)
• ILC2 cells
• Produce IL-5 and IL-13
• Remodeling and repair of damaged
tissue of asthma
• Th2 cells
• Secrete IL-4, IL-5, and IL-13
• High IgE antibody titers and eosinophilia

T2-High asthma
• Eosinophils
• Release cytokines (IL-13, IL-5), chemokines
(eotaxins), granule mediators, cysteinyl
leukotrienes (LTC4, LTD4, LTE4)
• CysLTs: potent bronchoconstrictors
• Eosinophil cytotoxic proteins: major basic
protein (MBP), eosinophil peroxidase (EPX),
eosinophil cationic protein (ECP), and
eosinophil-derived neurotoxin (EDN)
• Activate bronchial fibroblasts
• remodeling, thickening of BM

T2-High asthma
• Mast Cells and Basophils
• Express high-affinity IgE receptor
(FcεR1) and ST2 on their surfaces and
are activated by IgE cross-linking
• Secrete histamine and lipid mediators
(PGD2) and CysLTs
• Tryptase and proteases (mast cells)

T2-High asthma
• IgE
• Allergen exposure binds to high-affinity
receptor FcεRI on mast cells and low-
affinity receptor FcεRII or CD23 on APCs
• Facilitates antigen presentation by B cells
and DCs
• IgE-dependent mast cells activation cause
increase in vascular damage and
inflammatory cells infiltration that may
contribute to airway remodeling

T2-High asthma
• Prostaglandin 2
• MCs produce PGD2 which induces
vasodilation and increased vascular
permeability
• PGD2-high MCs strongly predict poorly
controlled T2 high asthma and are
associated with more severe disease

• Early-onset allergic asthma
• Late-onset eosinophilic asthma
• Aspirin-exacerbated respiratory disease (AERD)
T2-High asthma classification

(1) Early-onset allergic asthma
• Extrinsic allergic asthma
• Presentation ranges from mild to severe
• Positive allergy skin tests and increased serum-specific IgE

(2) Late-onset eosinophilic asthma
• Adult-onset disease
• Steroid-resistant eosinophilic phenotype of unknown molecular mechanism
• More severe asthma with fixed airflow obstruction
• Comorbid CRSwNP which generally precedes asthma development
• Prominent blood and sputum eosinophilia refractory to inhaled/oral corticosteroid treatment
• No evidence of atopy, but characterized by intense ILC2-driven production of IL-5 and IL-13
• Recent cluster analysis identified endotype of asthma with CRSwNP that highly
expresses Staphylococcus aureus enterotoxin (SE) sIgE and high levels of IL-5 and IgE

(3) Aspirin-Exacerbated Respiratory Disease (AERD)
• Asthma, CRSwNP, and COX-1 inhibitor-induced respiratory reactions
• Dysregulated arachidonic acid metabolism and cysLT production
• Baseline levels of PGE2 levels are markedly deficient
• Loss of homeostatic PGE2 expression removes negative feedback on 5-lipoxygenase
(5-LOX) pathway and upregulates constitutive cysLT synthesis
• CysLTs including LTC4, LTD4, and LTE4 are potent bronchoconstrictors
• Regulate the alarmin/ILC2/IL-5/IL-13 pathway, which drives profound tissue and blood eosinophilia

• Host Genetic Factors
• Variations at chromosome 17q21
• Viral Etiologies
• Respiratory viruses (esp. rhinovirus) are the most common trigger of asthma exacerbations
• Deficient local innate antiviral immune responses, upregulated pro-T2 response with
increased production of Th2 cytokines
• AECs in these patients demonstrate deficient type I and type III interferon (IFN) production
in response to viral infections
T2-High asthma clinical correlations

• Air Pollution
• Ozone and particulate matter
• Diesel exhaust particles (DEPs) augment primary IgE sensitization to allergens
• Neurogenic Inflammation
• Transient receptor potential vanilloid 1 (TRPV1) regulates activation and inflammatory
properties of CD4 T cells and modulates inflammatory and structural changes in chronic
asthma
• Nerve growth factor (NGF) is neurotrophins that mediates neuroplasticity
• High expression levels of NGF enhance the activity of eosinophils, allergen-mediated
eosinophil inflammation, and consequently airway hyperreactivity
T2-High asthma clinical correlations

T2-Low asthma
• Absence of markers of T2-high disease, such as eosinophilia
• Characterized by neutrophilic (sputum neutrophils > 40–60%) or paucigranulocytic (normal
sputum levels of both eosinophils and neutrophils) inflammation and lack of response to
corticosteroid therapy
• Associated with chronic infection with atypical bacteria, obesity, smoking, and poorly understood
underlying smooth muscle abnormalities
• Imbalance of Th17/Treg cells in steroid-resistant, severe, and neutrophilic asthma
• Activation of NLRP3 inflammasome and elevated IL-1β

• Th1-High Inflammatory Signature
• Elevated IFN-γ was associated with high airway resistance, increased inflammatory infiltrates,
and corticosteroid refractoriness
• IFN-γ-induced downregulation of secretory leukocyte protease inhibitor (SLPI) in AECs is
responsible for increased AHR
• Th17-High Inflammatory Signature
• Increased levels of IL-17A and IL-17F found in the bronchial walls of severe asthmatics and
associated with neutrophilic infiltration, AHR, and steroid resistance
• IL-17A/IL-22 increases smooth muscle cell proliferation and IL-17A drives collagen deposition
• IL-17 activity manifests as neutrophilic inflammation and IL-8 drives neutrophil recruitment
T2-Low asthma

• Obesity Associated
• Smoking Associated
• Very Late Onset
T2-Low asthma classification

(1) Obesity Associated
• Non-atopic, middle-aged woman with severe symptoms despite moderately preserved lung function
• Obesity biases CD4 cells toward Th1 differentiation, which associated with steroid refractory asthma
• ILC3 express both IL-17 and IL-22 and have been associated with obesity-related asthma
• IL-6 causes systemic inflammation in a subgroup of asthma patients with obesity and severe disease

(2) Smoking Associated
• Oxidative stress mediates epigenetic modifications and causes neutrophil and macrophage activation
• Smoking increases risk of sensitization to allergens and increases total IgE
• Asthma-COPD overlap syndrome (ACOS)
• Patients with significant smoking history and consequent airflow obstruction but also have
overlapping features of asthma (bronchodilator reversibility, eosinophilia, atopy)

(3) Very Late Onset
• Age cutoff for the diagnosis defined as > 50 years or > 65 years (depend on study)
• Aging lung is associated with decreased lung function due to loss of elastic recoil and
mechanical disadvantages
• Mechanisms have not been fully elucidated
• Increased sputum neutrophilia secondary to Th1 and Th17 inflammation

Asthma endotypes
Seys SF, Long MB. Eur Respir J 2022;59.
• Inflammation can be assessed using simple cellular responses by quantitative cytometry in sputum
• Sputum cell count identifies eosinophilic, neutrophilic, both eosinophilic and neutrophilic (mixed), and
paucigranulocytic types of asthma

• Cut-off values for the different induced sputum inflammatory phenotypes
Asthma endotypes
Guida G, et al. Front Med (Lausanne) 2022;9:969243.
Eosinophilic Neutrophilic Mixed Paucigranulocytic
Eosinophils(%) ≥1-3% <1-3% ≥1-3% <1-3%
Neutrophils (%) <40-76% ≥40-76% ≥40-76% <40-76%

• No specific therapies have shown any clinical
benefits in patients with asthma that is
associated with a non-T2 inflammatory process
• It remains to identify treatments to target that
endotype
Clinical applications
Sze E, et al. Allergy 2020;75:311-25.

To be continued
• Assessment of asthma
• Asthma management
• Asthma medications
• Difficult-to-treat and severe asthma
• Asthma exacerbations

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