UPDATE IN ASTHMA 2019

Sejal Saglani MRCPCH MD1, Juan P. Wisnivesky MD DrPH,2,3 Antonios Charokopos MD3,

Christopher D. Pascoe PhD4,5, Andrew J. Halayko PhD FCAHS4,5 and Adnan Custovic MD PhD1

1. National Heart and Lung Institute, Imperial College London, UK

2. Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New

York, NY

3. Division of Pulmonary and Critical Care Medicine, Icahn School of Medicine at Mount

Sinai, New York, NY

4. Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB,

Canada

5. Biology of Breathing Group, Children’s Hospital Research Institute of Manitoba,

Winnipeg, MB, Canada

Corresponding author: Professor Adnan Custovic MD PhD, Professor of Paediatric Allergy,

National Heart & Lung Institute, Imperial College London, UK.

tel: +44 020 7594 3274, email: a.custovic@imperial.ac.uk

Word count: 4,335

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In a recent review on childhood asthma, we proposed that knowledge gaps will only be

addressed by integrating technological advances and human knowledge across diverse

disciplines, with a patient at its center(1). So, how far have we come in turning “big data” into

actionable information to address some of the most important questions in asthma today,

including clinical and mechanistic insights about the architecture of asthma heterogeneity, to

inform personalized treatments? In this Update focusing on publications in the American

Thoracic Society journals, we review the progress made in 2019 on understanding asthma

epidemiology and risk factors, mechanisms underpinning different disease subtypes, therapeutic

options and prediction of treatment responses, and highlight areas for future research.

Burden of disease

Despite advances in treatment (most notably biologics), a significant proportion of patients fail to

achieve asthma control(2). The direct costs of uncontrolled asthma in adolescents and adults in

the US over the next 20 years is likely to be a staggering $1.5 trillion(3), emphasizing the

importance of devising and implementing effective strategies for long-term control(4). Whilst the

overall asthma-related mortality has declined in the United States from 1999 to 2015, the

mortality rate among children aged 1-14 years has not changed(5). Factors contributing to poor

asthma control, exacerbations and mortality include individual characteristics and environmental

exposures. Mortality continues to be higher in women (particularly African American)(5); thus,

we need to better understand these disparities to develop accurate risk-prediction tools.

Exacerbations remain one of the most troublesome aspects of asthma for patients and families,

and a major burden on healthcare resources. In a study of >50,000 asthmatics in England, one-

third had at least one confirmed exacerbation over an 8-year period between 2007 and 2015, but

<1% had yearly exacerbations(6). Although exacerbation frequency increased with asthma

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severity, they occurred across all severity levels, and more than half of frequent exacerbators had

mild/moderate disease. The best predictor of future exacerbations was a history of previous

exacerbation(6). This suggests that rather than being driven only by severity, the exacerbation

risk reflects specific susceptibility which may characterize an exacerbation-prone asthma

endotype(7). This is consistent with results from a birth cohort which identified two distinct

longitudinal trajectories of severe wheeze/asthma exacerbations in childhood, “infrequent” and

“early-onset frequent”, each with different risk factors and long-term outcomes(8). Lung

function was worse among patients with frequent severe exacerbations, and declined from age 8

to 16 years(8). Similar to the adult data(6), this population-based analysis identified a subgroup

of mild asthmatics, with good symptom control and normal lung function, who continued to

experience frequent exacerbations.

A significant unmet clinical need remains a reliable biomarker that predicts exacerbations to

avoid lung function decline(9). Although an attack within the last month is a major risk

factor(10), no available tool or intervention allows us to target high-risk patients among those

who had recent attacks. We therefore need to focus our efforts to identify other (bio)markers that

better predict the future risk. Reliable daily lung function monitoring is a potential option, and

home monitoring using forced oscillation technique in children revealed physiological

fingerprint that may inform management(11).

Socioeconomic factors, air pollution and other environmental exposures

Socioeconomic factors play a critical role in asthma control. Analyzing data from children of

different Latino ethnicities, Puerto Rican children (versus Mexican), low-income or female had

lower adherence to inhaled corticosteroids (ICS) over a 12-month period(12, 13). Only 14-23%

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of children were adherent (>80% of the time) and one quarter had changing adherence patterns

over time, highlighting that medication adherence is not a fixed personal characteristic.

It is well established that outdoor air pollution contributes to worsening asthma control and

increased risk of exacerbations. In 2019, a new data linked air pollution to adverse outcomes

across the life-course, from increased risk of asthma deaths(14) and impaired lung function(15),

to higher risk of asthma development(16). A study in China investigated the association between

short-term exposure to air pollution and asthma mortality, using air monitoring data and

information on >7,000 asthma deaths between 2013 and 2018(14). Short-term exposures to fine

particulate matter <2.5 m in diameter (PM2.5), NO2, and O3 were significantly associated with

asthma mortality(14). Similarly, in Peruvian children, ambient air pollution (including PM2.5,

black carbon and NO2) negatively affected patient-centered outcomes such as asthma control and

quality of life(17, 18). These findings raise a possibility that reducing air pollution may decrease

asthma mortality worldwide(19), and highlight the need for enacting effective policy measures in

low- and middle-income countries affected by rising pollution. The impact of PM2.5 has attracted

a lot of attention, identifying this as potentially key pollutant. However, a recent double-blind

cross-over study amongst allergic asthmatics has shown that particle removal from diesel exhaust

which mimicked catalytic traps on cars resulted in a greater reduction in lung function after co-

challenge with allergen than standard diesel exhaust(15). The particle filtering reduced volatile

organic compounds (VOCs) but increased NO2, suggesting that NO2 may be the key component

of air pollution which interacts with allergens(20).

Air pollution interacts with other environmental exposures. For example, air pollutants and

indoor endotoxin exposure act synergistically to increase emergency room visits for asthma(21).

Importantly, the adverse health effects are observed at concentrations below current thresholds,

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suggesting that air quality standards need to be strengthened(22). Other interventions may also

be of help. For example, negative impact of PM2.5 on asthma severity may be modified by

consumption of fatty acids, with higher omega-3 polyunsaturated fatty acids (n3PUFA) reducing

the effect of exposure (but with the opposite effect of high omega-6 fatty acids)(23). This raises

the question of whether more holistic non-pharmacologic interventions which combine diet

changes(23), reduction in air pollution(24) and allergen avoidance(25) would be effective. We of

course must never forget hazards of tobacco, particularly as adverse effects of early-life exposure

on airway inflammation and lung function are measurable decades later(26). Occupational

exposures are also involved in asthma pathogenesis, and this year’s investigations brought forth

previously unrecognized associations(27).

Other environmental determinants of childhood asthma, whether stemming from in-utero or

early life exposures, have received considerable attention. Immigration at various ages offers an

opportunity to assess the contribution of genetic versus environmental factors on asthma

development. Administrative data from Ontario, Canada, was used to examine asthma incidence

in immigrants (>50% from Asia) compared to non-immigrants and their children (28).

Immigrants (including children below age 5 years) exhibited substantially lower age- and sex-

adjusted asthma incidence compared to non-immigrants. Conversely, Ontario-born children of

immigrants had higher asthma incidence than children of non-immigrants, suggesting a role for

the in-utero, gestational, or perinatal environment on asthma susceptibility. Maternal–fetal

interface is important for immune programming and long-term health, and maternal asthma and

preeclampsia during pregnancy synergistically increase the risk of asthma in offspring(29, 30).

At this point, the key question of whether we can use these observations to devise strategies for

asthma prevention remains unanswered(31). Systems biology may offer a potential roadmap to

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identify markers of early risk and elucidate underpinning pathways by interrogating

environmentally-responsive mechanisms which operate in the placenta(32).

Machine learning and bioinformatics

Advanced analytical techniques including machine learning approaches have been pioneered in

this journal(33). Such methods reveal structure within complex data sets and can provide new

insights into asthma mechanisms(34). An approach using unsupervised learning informed by the

prior biological knowledge within the Severe Asthma Research Program (SARP) triamcinolone

study discovered four clusters of corticosteroid responsiveness, and identified 12 variables which

predicted group assignment(35). The challenge now is to translate such findings into actionable

decision support tools to manage patients with severe asthma(36). Although application of

machine learning may provide pointers to potential mechanisms, careful methodological

consideration is needed, as the choice of variables, data transformations and algorithms have

major impact on results(37). Sample size, timing and frequency of data collection may also

impact the number and nature of discovered clusters(38). Data-driven analysis of pooled data

from five birth cohorts identified four temporal patterns (“phenotypes”) of wheezing among

>15,000 subjects followed until adolescence: two early-onset transient phenotypes (preschool

and mid-childhood remitting), persistent, and late-onset wheeze. All phenotypes (including the

transient) were associated with significantly lower lung function and increased odds of asthma in

adolescence compared to children who never wheezed, suggesting that commonly held view that

transient wheezing is benign may not be true(39, 40).

Asthma mechanisms and potential for novel treatments and biomarkers

Treatment failure remains a problem in asthma management. To address this, breakthroughs in

understanding of disease pathophysiology are essential to identify novel therapeutics, or/and

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support better targeting of current treatments. A specific role for the alarmin

S100A9/calprotectin to activate T-regulatory cells and suppress CD4+ T cells in response to

inhaled allergen has been uncovered(41), highlighting the potential role of calprotectin in a type

2–dominant settings(42). Alveolar macrophage ATP-binding cassette lipid transporter ABCGA1

was shown to control macrophage lipid uptake and decrease granuloma formation and

inflammation(43), identifying a new target to mitigate persistent inflammation(44). Surprisingly,

glucocorticoid exposure of airway smooth muscle (ASM) from severe asthmatics did not elicit

divergent global changes in cellular transcriptome compared to non-asthmatic donors; rather,

differences were observed for a limited number of genes, many with unknown roles in the

lung(45). Examples include cholecystokinin and premelanosome, which are differentially

induced in severe asthma, and may offer clues to decipher novel targets that may improve

glucocorticoid function in severe asthma(46). Mucus overproduction contributes to morbidity

and mortality in asthma, and there is compelling new evidence from studies in early-life non-

human primate asthma models and humans with asthma, that overproduction of γ-aminobutyric

acid (GABA) by pulmonary neuroendocrine cells plays an important role in mucus

overproduction(47). In asthmatics, this is correlated with elevated expression of a subset of

GABAα and GABAβ receptors in airway epithelium, and blockade of these receptors in vitro

reversed IL-13-induced MUC5AC expression and goblet cell proliferation.

The paradigm for paracrine effects of LTB-4, a potent neutrophil chemokine thought to be

chiefly synthesized by neutrophils, mononuclear phagocytes and airway epithelial cells, has been

re-tooled with the new findings that eosinophils express abundant leukotriene A4 hydrolase and

produce LTB4(48). This indicates that eosinophils may contribute to neutrophilia in severe

asthma. Although airway levels of LTB4 were higher in severe asthmatics, in vitro release of

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LTB4 was lower in stimulated and unstimulated peripheral blood eosinophils. The contribution

of an eosiniophil-LTB4 axis and its potential as a therapeutic target remains open, but the

potential for eosinophil-targeting anti-IL-5 biologics to reduce airway neutrophils may provide

an answer(49).

Transforming growth factor β1 (TGF1) has also emerged with a potential new role in the

resistance to bronchodilators in asthma(50). New evidence using in vitro model revealed TGF1

mitigates β-agonist activity in ASM by increasing the abundance of phosphodiesterase-4 and

limiting availability of intracellular cyclic AMP(51). Autophagy, a homeostatic process for

turnover of organelles and biomolecules that can also modulate immunity and cell survival, has

been associated with asthma risk for some years, but its role in pathophysiology was unclear(52).

New findings confirm that autophagy markers are expressed in ASM in asthma, that it modulates

TGF1-induced collagen biosynthesis in cultured ASM cells, and that a non-selective modulator

of autophagy, chloroquine, blunts asthma pathophysiology(53).

Human rhinoviruses (HRV) are principal triggers of asthma exacerbations. One emerging

approach prevent exacerbations is to stabilize the half-life of host defense mediators generated

by airway epithelium, such as NO and S-nitrosoglutathione. Studies using human airway

epithelial cells (HAECs) have shown inhibition of replication and inflammation associated with

HRV-16 using a selective inhibitor of S-nitrosoglutathione reductase(54). Secretoglobin family

1A member 1 (SCGB1A1), secreted by non-ciliated airway club cells and the most abundant

protein in airway lining fluid, is inhibited by viral infection(55). It is an important defense

molecule, and lower levels of SCGB1A1 have been detected in BAL, serum, and urine of

individuals with asthma. New evidence indicates Th2 cytokines and viral infections may drive

asthma pathophysiology via epithelial loss of SCGB1A1 through blocking FOXA2, a

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transcriptional inducer of SCGB1A1(56). Polymorphisms on chromosome 17q21 have been

consistently associated with childhood-onset asthma in association with HRV infections, but the

functional relevance has yet to be determined. Silencing ORMDL3 led to reduced levels of IL-6

and IL-8, and knockdown reduced expression of the HRV receptor ICAM1(57). The latter is of

particular importance in explaining the significant interaction between ORMDL3 and rhinovirus

induced wheezing illnesses in infants(58) and subsequent progression of wheezing illnesses to

childhood asthma(59).

Exosomes (extracellular nanovesicles that can be actively formed and released to transport

proteins, lipids and miRNA for internalization by target cells) may play a role in airway

remodeling. miRNA cargo in exosomes from cultured HAECs, and their association with

regulating the secretion of a diverse array of innate protective proteins and pathology-associated

proteins, including mucins MUC5AC and MUC5B, was published(60). Cultured HAECs were

also shown to secrete enzymatically active inositol polyphosphate 4-phosphatase type I A

(INPP4A), a lipid phosphatase, in extracellular vesicles as a homeostatic loop that dampened

local airway fibroblast growth(61). In patients with asthma and allergen challenged mice,

extracellular airway INPP4A was significantly reduced, underpinning a mechanism creating a

permissive environment for persistent inflammation and remodeling.

Targeting airway remodeling

Current treatments for asthma do not specifically target airway remodeling(62). The role of

remodeling in both childhood and adult asthma was demonstrated using nonlinear optimal

microscopy to show airway remodeling involves the progressive accumulation of disorganized

fibrillar collagen by airway fibroblasts(63). Novel analytical techniques have shown the impact

of routine asthma treatments on airway cell gene expression and transcriptomics analyses.

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Bronchoalveolar lavage (BAL) cell gene expression was influenced by beta-agonist therapy(64),

while sputum cell transcriptomics analysis showed persistence of T2 inflammation associated

with complex innate and adaptive immunity gene networks despite steroid therapy(65). An ultra-

T2 high group was identified using RNA-seq in addition to a T2 low sub-group characterized by

genes with decreased expression, especially of CD8 T-cells(65). However, limitations related to

the small sample and cross-sectional design limit applicability(66), with additional limitation that

data was generated from a mixed cells population(67). Moreover, the cost and complexity of

these analyses are barriers to adoption into routine clinical practice(66, 67).

Targeting persistent airway inflammation and ASM migration offers novel targets to limit the

remodeling. New understanding comes from the delineation of a role for glia maturation factor

gamma (GMFγ) to promote ASM migration(68). GMFγ is elevated in the asthmatic lung, and

has the capacity to regulate focal adhesion dynamics and promote ASM migration(69). A large

family of extra-oral bitter taste receptors (TAS2R) expressed in ASM has been a target for new

bronchodilators for a decade, but new work reveals that ligands for these receptors are also

capable of inhibiting ASM proliferation by diminishing phosphorylated extracellular signal–

regulated kinase 1/2(70). These findings offer potential for biased TAS2R ligand development to

relax ASM, and/or decrease ASM proliferation, to blunt airway wall thickening(71).

A new generation of highly selective inhibitors of bromodomain-containing protein 4 (BRD4),

an atypical histone acetyltransferase that binds to NF-κB/RelA to trigger neutrophilic

inflammation, may be promising therapies to mitigate airway remodeling(72). The novel BRD4

inhibitors reduced collagen deposition, airway myofibroblast transition and the development of

AHR and lung stiffness in a murine model of repeated toll-like receptor 3 agonist challenge(73).

This role of bromodomain and extraterminal (BET) proteins, and an increased half-life for these

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BRD4-selective inhibitors, suggest accelerated clinical development of this class of drugs is

warranted(73). A role of interleukin-4 in airway remodeling was suggested using human nasal

epithelial cells (via induced cell migration that disrupted barrier integrity through activation of

the focal adhesion integrins, αvβ5 and αvβ6, and focal adhesion kinase signaling)

(74). This suggests that strategies linked to IL-4 pathobiology may have

impact on airway remodeling(75).

Asthma treatments: From standard drugs to personalized therapy and biologics

The placebo effect in asthma has long been recognized. In an analysis of five randomized trials,

patients with uncontrolled asthma in the placebo arm had significant decreases in healthcare

utilization, improved lung function and symptom control(76), implying that either a

“sham/placebo effect” or the study protocol-dictated structured asthma regimen could explain

these changes(76). The ‘real life’ effectiveness and toxicity of ICS in older asthmatics (>66

years) was evaluated in Ontario, Canada. In this population, ICS use was associated with fewer

asthma-related hospitalizations, but importantly not with an increased risk of pneumonia(77).

Repurposing therapies offers another avenue to achieve better asthma control. In a cohort of

adults with diabetes and asthma, patients treated with metformin had fewer exacerbations and

less acute resource utilization compared to propensity-matched controls(78, 79). The anti-

inflammatory potential of n3PUFA was investigated in a randomized trial of obese patients with

uncontrolled asthma(80, 81); six-months n3PUFA treatment improved mononuclear cell n3/n6

PUFA ratio, but did not change urinary leukotrienes, asthma control, lung function or

exacerbations(81).

From a social policy perspective, the impact of Affordable Care Act’s Medicaid expansion on

outcomes of patients with chronic respiratory conditions, including asthma was assessed(82, 83).

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Medicaid expansion was associated with a decline in mechanical ventilation rates among

uninsured and chronic respiratory condition-related hospitalizations (including asthma);

however, there were no changes in intensive care use or in-hospital mortality(82).

Treatment decisions for patients with severe eosinophilic asthma are becoming increasingly

complex because of the number of available add-on therapies. The use of remote FeNO testing

has been proposed as a way to identify non-adherence to ICS in difficult-to control asthmatics to

avoid inappropriate escalation to add-on biologics(84). The need for adherence monitoring

(beyond relying on change in FeNO or blood eosinophils as proxy measures) was emphasized in

an accompanying editorial(85), and clinical trials which exclude patients with difficult-to-control

asthma prior to consideration of biologic therapy are essential(86). A post hoc analysis of the

DREAM and QUEST trials, which investigated the efficacy of ani-IL5 and anti-IL4 receptor-

antibodies, has suggested combined use of blood eosinophils and FeNO to predict response(87).

However, head-to-head trials that incorporate such predictive scores are required prior to clinical

application. Additional parameters have been assessed as predictors of response to the anti-IL5

antibody Reslizumab(88). Asthma Control Questionnaire, Asthma Quality of Life Questionnaire,

FEV1 and number of asthma exacerbations during the year before enrolment into a 16-week

efficacy trial compared to the first 16 weeks of treatment, were evaluated for their ability to

predict efficacy at 52 weeks. An algorithm with these parameters generated at 16 weeks

predicted responders, but did not reliably identify non-responders. Evidence from patients treated

in routine care is needed before adoption into practice(89).

The utility of mepolizumab in mild asthma to prevent exacerbations is of increasing interest. A

study in mild asthmatics investigated the immune mechanisms underlying the effect of

mepolizumab in RV16-induced exacerbations(90). A single dose of mepolizumab attenuated

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circulating and airway eosinophils at baseline (before RV16 challenge), but did not lead to

further reductions after challenge. Interestingly, in response to RV16, mepolizumab attenuated

neutrophil activation, enhanced sIgA production, and prevented attenuation of B-cell and

macrophage numbers. However, mepolizumab-treated patients had higher viral load, suggesting

that the overall immune responses to mepolizumab resulted in a pro-infective state(91). Of note,

the anti-IgE antibody, omalizumab, in children with mild asthma resulted in enhanced innate

immune responses to rhinovirus(92) suggesting different anti-viral effects due to blocking

eosinophils vs. IgE, and highlighting the potential protective role of eosinophils in milder

disease(91).

Therapies for Non-type2 asthma

Treatments for asthma that is not predominantly driven by type-2 immune responses remain an

unmet need. A previous trial showed reduced exacerbations with the macrolide antibiotic

azithromycin(93), but potential impact on bacterial colonization or antibiotic resistance had not

been investigated. Subsequent study has shown that long-term azithromycin treatment had no

impact on the overall bacterial load, airway microbiota, pathogen abundance and antibiotic

resistance, but selectively reduced Haemophilus influenzae load(94). There was also a significant

increase in macrolide resistance. Therefore, the broad use of long-term antibiotics in chronic

airway diseases must be carefully considered, and the only feasible strategy may be to use non-

antibiotic macrolides(95).

Identification of mechanisms underpinning neutrophil-dominant asthma, and whether neutrophils

in this phenotype are inflammatory, are important questions. The role of activated neutrophils

was characterized in induced sputum from patients with severe asthma by measurement of

neutrophil extracellular traps (NETs) and assessment of the inflammasome(96). A subset of

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patients with high sputum extracellular DNA levels with associated obesity, neutrophilic

inflammation, increased NET formation and inflammasome activation was found(97). It was

suggested that a more accurate method of detecting extracellular DNA levels may be to use

synthetic absorptive matrix to collect nasal or airway secretions (nasosorption and

sputosorption). Both were shown to be minimally invasive, performed rapidly and permitted

measurement of cytokines which reflected lower airway sputum eosinophilia(98).

Bronchial thermoplasty has been approved for adult severe asthma, but little is known about the

mechanism of action. Effects on the bronchial epithelium, mucus-producing cells, basal cells and

epithelial proliferation were reported 3 weeks and 12 months after thermoplasty(99). Sustained

reduction in MUC5AC epithelial staining and improved epithelial integrity were observed,

suggesting an impact on epithelial structure in addition to smooth muscle(99).

Understanding mechanisms of asthma risk

Understanding mechanisms of how environmental exposures modify asthma risk, severity and

exacerbations, and interact with genetic predisposition, remains key priority. For example,

organophosphorus pesticide exposure may impact the risk by induction of NF-κβ-dependent pro-

inflammatory TNF-α and IL-1β from alveolar macrophages(100). A polymorphism in cadherin-

related family member 3 (CDHR3) gene, rs6967330 GA, has previously been linked with

early-onset childhood asthma with severe exacerbations(101). The same variant is associated

with increased CDHR3 protein expression and rhinovirus-C binding and replication in airway

epithelial cells(102), offering a new therapeutic target to reduce exacerbation risk. The lung

microbiome differs between healthy and asthmatic subjects, and research on horses with natural

asthma revealed a complex interaction between environmental allergen exposures, disease status,

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and lung microbiome(103). The microbiome can be altered and the severity of lung inflammation

attenuated by dietary supplementation of fermentable fiber(104).

Sex and obesity are emerging as interacting factor and determinants of response to

environmental insult. In adult females, asthma severity is greater and more prone to

corticosteroid resistance(105, 106). Sex hormones may play an important role in these

differences. Activating estrogen receptor-β mitigated allergic airway inflammation and

remodeling in female mice(107). However, the disparity in pathophysiology between males and

females appears far more complex than can be explained by sex hormones alone. For example,

studies in mouse model suggest that microbiome may influence sex differences in ozone-induced

AHR. Gut microbiome from obese mice exacerbates ozone-induced AHR and

inflammation(108). More severe AHR was observed in male mice in response to ozone

exposure, which was abrogated after ablation of gut microbiome, and augmented by diet

enriched in short-chain fatty acids in male, but not female pups(109). The evidence directly

linking obesity, dietary fat intake, and altered innate immune responses in asthma(110)

motivated studies to investigate mechanisms underpinning these associations. A synergistic

effect of respiratory infection and dietary ω-6 PUFAs and saturated fatty acids on airway

inflammation was described using viral mimetic poly(I:C), bacterial lipoteichoic acid or

rhinovirus, mechanistically operating via p38 MAP kinase regulated synthesis of cytokines

associated with severe asthma, IL-6 and CXCL8(111). This begins to clarify how altered innate

immune responses to infections may be linked to obesity, and how obesity associates with more

frequent asthma exacerbations(112).

Neonates are exposed to hyperoxia during treatment of respiratory distress, and this represents a

unique but important environmental challenge. Cultured fetal ASM cells exposed to moderate,

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clinically relevant hyperoxia exhibited a phenotype consistent with cellular senescence,

including hypersecretion of proinflammatory and profibrotic mediators, and this was propagated

through paracrine mechanisms to promote inflammatory, fibrotic, and contractile responses in

ASM cells(113). This is of direct relevance to neonatal pulmonary medicine as it suggests

clinical interventions trigger processes leading to lung cell senescence and early life airway

remodeling and risk for chronic airway disease(114).

How to distinguish phenotypes and differentiate asthma from other pulmonary conditions?

Diagnosing asthma can be challenging in preschool children because lung function testing is not

always feasible or reliable. The multiple breath washout (MBW) test which measures ventilation

heterogeneity can aid in the diagnosis in preschool children. Compared to spirometry and

plethysmography, MBW was not sensitive in identifying children with asthma/persistent-

wheeze, but was able to differentiate children with asthma and severe exacerbations from non-

asthmatic controls(115). This suggests that this test may help identify young children with more

severe phenotypes(116).

Asthma-COPD overlap (ACO) is characterized by persistent airflow limitation and features of

both asthma and COPD. Patients with ACO have increased symptoms and higher exacerbation

rates than those with asthma or COPD alone. In a British primary care database, estimated

prevalence of ACO was 20.5%, 14.4% and 32.1% among those with COPD alone, asthma alone,

or both asthma and COPD, emphasizing the need for better diagnostic characterization of this

condition(117).

Development of tests that would allow identification of asthma phenotypes and enable

personalized therapy, and that can be used routinely in the clinic, is of great importance. VOCs

in breath were compared to exhaled nitric oxide (FeNO), blood and sputum biomarkers and lung

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function(118). VOCs were superior to FeNO and blood eosinophils as a marker of airway

eosinophilia. Breath analysis was also able to identify a neutrophilic phenotype. Moreover, the

combination of FeNO, blood eosinophils and VOCs in breath gave a strong prediction model for

eosinophilic asthma(118, 119). Exhaled breath condensate (EBC) was used to quantify ezrin, a

membrane cytoskeleton protein involved in epithelial barrier function(120). Levels of ezrin were

lower in EBC and serum from asthma patients, being lowest in those with poor control and low

lung function. This sets the scene for additional studies to confirm the potential of using ezrin as

a biomarker of airway damage(121). A relationship between circulating levels of CC16 (club cell

secretory protein 16) at age 11 years and sustained development of airway hyperresponsiveness

(AHR) has been shown(122). Despite the limitations of in vitro data, this study provides an

intriguing circulating biomarker and potential therapeutic target for early-life airway

remodeling(123).

Conclusions

Despite many advances in 2019 in our understanding of asthma heterogeneity and life-course

trajectory, the underlying pathophysiology and treatment modalities, there is still a long way to

go to deliver personalized treatments. We believe that step-changes in knowledge can be

achieved by fostering a multidisciplinary community of scientists, bringing them together around

technological advances, to allow treatments to move away from symptom-based, towards

mechanism-based.

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