Michael C. Peters

Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts

BACKGROUND Severe asthma is a complex heterogeneous disease associated with older age and obesity. The presence of eosinophilic (type 2) inflammation in some but not all patients with severe asthma predicts responsiveness to current treatments, but new treatment approaches will require a better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation, which arises in subgroups of obese and older patients, increases the severity of asthma. Interleukin-6 (IL-6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the association between IL-6 concentrations, metabolic dysfunction, and asthma severity. METHODS In this cross-sectional analysis, patients were recruited from two cohorts: mainly non-severe asthmatics from the University of California San Francisco (UCSF) and mainly severe asthmatics from the Severe Asthma Research Program (SARP). We generated a reference range for plasma IL-6 in a cohort of healthy control patients. We compared the clinical characteristics of asthmatics with plasma IL-6 concentrations above (IL-6 high) and below (IL-6 low) the upper 95% centile value for plasma IL-6 concentration in the healthy cohort. We also compared how pulmonary function, frequency of asthma exacerbations, and frequency of severe asthma differed between IL-6 low and IL-6 high asthma populations in the two asthma cohorts. FINDINGS Between Jan 1, 2005, and Dec 31, 2014, we recruited 249 patients from UCSF and between Nov 1, 2012, and Oct 1, 2014, we recruited 387 patients from SARP. The upper 95th centile value for plasma IL-6 concentration in the healthy cohort (n=93) was 3·1 pg/mL, and 14% (36/249) of UCSF cohort and 26% (102/387) of the SARP cohort had plasma IL-6 concentrations above this upper limit. The IL-6 high patients in both asthma cohorts had a significantly higher average BMI (p<0·0001) and a higher prevalence of hypertension (p<0·0001) and diabetes (p=0·04) than the IL-6 low patients. IL-6 high patients also had significantly worse lung function and more frequent asthma exacerbations than IL-6 low patients (all p values <0·0001). Although 80% (111/138) of IL-6 high asthmatic patients were obese, 62% (178/289) of obese asthmatic patients were IL-6 low. Among obese patients, the forced expiratory volume in 1 s (FEV1) was significantly lower in IL-6 high than in IL-6 low patients (mean percent predicted FEV1=70·8% [SD 19·5] vs 78·3% [19·7]; p=0·002), and the percentage of patients reporting an asthma exacerbation in the past 1-2 years was higher in IL-6 high than in IL-6 low patients (66% [73/111] vs 48% [85/178]; p=0·003). Among non-obese asthmatics, FEV1 values and the frequency of asthma exacerbations within the past 1-2 years were also significantly worse in IL-6 high than in IL-6 low patients (mean FEV1 66·4% [SD 23·1] vs 83·2% [20·4] predicted; p<0·0001; 59% [16/27] vs 34% [108/320]; p=0·01). INTERPRETATION Systemic IL-6 inflammation and clinical features of metabolic dysfunction, which occur most commonly in a subset of obese asthma patients but also in a small subset of non-obese patients, are associated with more severe asthma. These data provide strong rationale to undertake clinical trials of IL-6 inhibitors or treatments that reduce metabolic dysfunction in a subset of patients with severe asthma. Plasma IL-6 is a biomarker that could guide patient stratification in these trials. FUNDING NIH and the Parker B Francis Foundation.

Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations

Rationale: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation‐prone asthma (EPA) remain incompletely defined. Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA. Methods: Baseline data from the NHLBI Severe Asthma Research Program (SARP)‐3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP‐1 + 2 cohort. Measurements and Main Results: Of 709 subjects in the SARP‐3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP‐3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP‐3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2‐2.1] for every log unit of eosinophils, 1.3 [1.1‐1.4] for every 10 body mass index units, and 1.2 [1.1‐1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4‐2.1] and 1.6 [1.3‐2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP‐1 + 2 multivariable model. Conclusions: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).

Alternative splicing of interleukin-33 and type 2 inflammation in asthma

Significance Type 2 inflammation occurs in a large subgroup of asthmatics and is the target of multiple novel therapies for asthma; however, the mechanisms that drive type 2 inflammation in chronic asthma are poorly understood. In this study, we identify a previously unidentified mechanism of IL-33 activity involving alternative RNA transcript splicing and provide evidence that mast cells and basophils are major cellular targets of IL-33 activity driving type 2 cytokine production in stable asthma. These data advance our understanding of the mechanisms of type 2-high asthma and guide the selection of asthmatics likely to benefit from IL-33 inhibitor therapies. Type 2 inflammation occurs in a large subgroup of asthmatics, and novel cytokine-directed therapies are being developed to treat this population. In mouse models, interleukin-33 (IL-33) activates lung resident innate lymphoid type 2 cells (ILC2s) to initiate airway type 2 inflammation. In human asthma, which is chronic and difficult to model, the role of IL-33 and the target cells responsible for persistent type 2 inflammation remain undefined. Full-length IL-33 is a nuclear protein and may function as an “alarmin” during cell death, a process that is uncommon in chronic stable asthma. We demonstrate a previously unidentified mechanism of IL-33 activity that involves alternative transcript splicing, which may operate in stable asthma. In human airway epithelial cells, alternative splicing of the IL-33 transcript is consistently present, and the deletion of exons 3 and 4 (Δ exon 3,4) confers cytoplasmic localization and facilitates extracellular secretion, while retaining signaling capacity. In nonexacerbating asthmatics, the expression of Δ exon 3,4 is strongly associated with airway type 2 inflammation, whereas full-length IL-33 is not. To further define the extracellular role of IL-33 in stable asthma, we sought to determine the cellular targets of its activity. Comprehensive flow cytometry and RNA sequencing of sputum cells suggest basophils and mast cells, not ILC2s, are the cellular sources of type 2 cytokines in chronic asthma. We conclude that IL-33 isoforms activate basophils and mast cells to drive type 2 inflammation in chronic stable asthma, and novel IL-33 inhibitors will need to block all biologically active isoforms.

Intelectin-1 Is a Prominent Protein Constituent of Pathologic Mucus Associated with Eosinophilic Airway Inflammation in Asthma

To the Editor: Intelectin-1 (ITLN-1) is an epithelial cell protein that is up-regulated in asthma (1). ITLN-1 is a pleotropic adipokine (also known as omentin-1) with roles in the gut ranging from host defense against pathogenic bacteria to promotion of insulin-stimulated glucose uptake (2–4). The host defense roles of ITLN-1 may result from its ability to bind structures expressed by microorganisms in a carbohydrate-dependent manner (5). ITLN-1 is also a binding partner for lactoferrin (6), and ITLN-1 may cooperate with lactoferrin in host defense (6, 7). Little is known about the function of ITLN-1 in human asthma. One possibility is that it participates in pathways of inflammation downstream of IL-13 (1). Indeed, studies in a mouse model of asthma suggest that ITLN-1 mediates IL-13–induced monocyte chemotactic protein-1 and -3 production in epithelial cells (8). Another possibility is that ITLN-1 is a component of airway mucus and contributes to pathologic mucus gel formation in disease. Supporting this possibility are studies in the gastrointestinal tract showing that ITLN-1 is a goblet cell protein that is secreted with mucus into the intestinal lumen (9). In addition, other studies in the intestine have suggested mucin–intelectin interactions that could alter the biophysical properties of mucus (10). Some of the results of these studies have been previously reported in the form of an abstract (11) Because mucus pathology causes mucus plugging and airway occlusion (12, 13), especially in fatal asthma (14), we set out to determine if ITLN-1 is a component of pathologic mucus in acute asthma. We first immunostained lung tissue sections from cases of fatal asthma and found prominent ITLN-1 immunostaining in the pathologic mucus plugs that occlude the airways (Figures 1A–1C). The cellular source of the ITLN-1 appears to be goblet cells (Figure 1C). We next measured ITLN-1 protein in sputum from 11 patients with acute severe asthma and two control groups (35 subjects with chronic stable asthma and 11 healthy control subjects) (Table 1). We found that ITLN-1 protein levels in the subgroup of patients with asthma in exacerbation were significantly higher than in stable asthma and in healthy control subjects (Figure 1D). We also noted that the increase in ITLN-1 in acute asthma was driven by the subgroup with increased sputum eosinophils (>2%) (Figure 1E), a finding that is consistent with ITLN-1’s regulation by IL-13 in airway epithelial cells (1). ITLN-1 up-regulation is thus a feature of “Th2-high” asthma, and the known pathologic characteristics of this disease endotype can be extended to include high ITLN-1 protein concentrations in mucus forming during disease exacerbations. Figure 1. Intelectin-1 (ITLN-1) protein in airway biospecimens and binding of ITLN-1 to airway mucins and lactoferrin. Sections of lung tissue from lungs of patients with fatal asthma were stained with an anti–ITLN-1 antibody or peptide blocking control. ... Table 1: Subject Characteristics The prominent immunostaining for ITLN-1 in mucus plugs in fatal asthma and the high concentrations of ITLN-1 in sputum in acute severe asthma prompted us to explore if ITLN-1 can bind to human airway mucins. ITLN-1 is a lectin with known specificity for galactosyl structures, especially the galactofuranosyl sugars expressed by microorganisms (5). To determine if ITLN-1 binds to human airway mucin glycans, we developed a plate-based binding assay using high-molecular-weight mucin preparations that we purified from induced sputum samples from subjects with chronic stable asthma (“mucin study”; Table 1). Specifically, we used biotinylated recombinant ITLN-1 to probe mucin coated on microtiter plates (see online supplement). Biotinylated jacalin, a tetrameric plant seed lectin with specificity for galactose, was used as a positive control. Although jacalin showed binding to mucin, ITLN-1 did not (Figure 1F). It is possible that ITLN-1 cannot recognize the pyranosyl forms of galactose in human mucin, but another possibility is that mucin glycans prevent binding through steric hindrance. It could also be that the plate assay is suboptimal for measuring ITLN-1 binding to mucin because other proteins or cofactors involved in an ITLN-1–mucin interaction in vivo are not represented in vitro. Because ITLN-1 has been characterized as the lactoferrin receptor (6, 7), we considered if ITLN-1 interacts with lactoferrin in airway mucus in acute asthma. We found that lactoferrin levels in sputum from patients with acute severe asthma are significantly higher than in control samples (Figure 1G). Notably, the concentration of lactoferrin ranged from 500 to 1,000 μg/ml in some of these sputum samples, a 1,000-fold higher concentration than ITLN-1. This large amount of lactoferrin in asthmatic mucus may bind and concentrate ITLN-1 in mucus. To examine the binding of ITLN-1 to lactoferrin, we used a plate-binding assay similar to the one we used for mucin-ITLN-1 binding. In this way, we found that biotinylated ITLN-1 binds avidly to immobilized lactoferrin (Figure 1H). This binding was inhibited by heparin, suggesting a charge-based interaction between ITLN-1 and lactoferrin’s basic N-terminal region (15), and increased by methyl galactofuranoside. Galactofuranoside is found in many microbial polysaccharides and is recognized as a preferred glycan ligand for ITLN-1 (7, 16). Our data suggest that ITLN-1 binding to galactofuranosyl residues on microorganisms might improve its ability to bind lactoferrin and target it to regions of high microorganism burden. We conclude that ITLN-1 is a prominent protein component of pathologic mucus in fatal asthma and in acute severe asthma, especially in the context of eosinophilic airway inflammation. The binding of ITLN-1 to lactoferrin is increased by galactofuranoside providing a mechanism by which ITLN-1 can cooperate with lactoferrin to defend against microbes.

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

Severe asthma is characterized by decreased NK cell cytotoxicity, and corticosteroids further disable NK cell function. NK cells in severe asthma—Failed resolution Anti-inflammatory corticosteroids are a first line of defense against many types of asthma, but patients with severe asthma do not frequently respond to this therapy. Duvall et al. now report that this lack of response may be due in part to defects in natural killer (NK) cells, which are important mediators of inflammation resolution. They found that NK cells from patients with severe asthma had impaired killing and that corticosteroid exposure further inhibited the function of these cells, whereas the proresolving mediator LXA4 preserved NK cell effector mechanisms. Therefore, corticosteroids may be a counterproductive therapy in patients with severe asthma, and specifically activating NK cells may provide an alternate therapeutic target. Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6−CCR4− T helper 1–enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4–exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.

Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age

BACKGROUND The effect of age on asthma severity is poorly understood. OBJECTIVES The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features. METHODS SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity. RESULTS Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma. CONCLUSIONS The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.

Type 2 Immune Responses in Obese Individuals with Asthma

The incidence of obesity has doubled in the United States in the past 20 years, and nearly 70% of adults are now either overweight or obese (1). Obesity is an independent risk factor for the development of asthma (2), and this means that obese patients with asthma comprise two types of patient: one who developed asthma before becoming obese, and a second who developed obesity before developing asthma. Asthma is more severe in obese patients than in lean patients (3), but the mechanisms of this disease modification are unknown. Themost common form of inflammation in asthma is T helper type 2 (Th2) inflammation characterized by accumulation of Th2 cytokine–producing cells and eosinophils. Although CD4 Th2 cells have been considered the dominant source of Th2 cytokines in asthma, innate helper type 2 cells (ILC2 cells) have recently emerged as an important cellular source (4). IL-33 is an epithelial cell–derived cytokine that can activate ILC2 cells to secrete IL-5 and IL-13, and there is now intense interest in evaluating the role of IL-33 and ILC2 cells in asthma, especially given the consistent appearance of IL-33 on gene lists emerging from genome-wide association studies in asthma (5). In the context of obesity and asthma, it is notable that recent studies in mouse models reveal key roles for IL-33, IL-4, IL-5, and eosinophils in regulating the metabolism of visceral adipose tissue cells. Specifically, a regulatory program has been uncovered in adipose tissue in which IL-33 activates ILC2 cells to secrete IL-5 and promote eosinophil accumulation (6). Eosinophils then secrete IL-4 and other mediators to cause alternative activation of macrophages, and macrophage products promote insulin sensitivity and optimal metabolic homeostasis (7). This metabolic role for type 2 immune responses in visceral adipose tissue is enhanced by parasite infection. Mice infected with parasites tolerate a high-fat diet without becoming obese, whereas mice without augmented type 2 immune responses do not (8). Taken together, these data suggest that a decrease in type 2 immunity in visceral adipose tissue may be a mechanism of obesity. In support of this possibility, it is known that pathologic adipose tissue is not characterized by type 2 immune responses but by the presence of CD4 Th1 cells, CD8 T cells, neutrophils, and proinflammatory macrophages (9, 10). The increased blood concentrations of tumor necrosis factor-a and IL-6 found consistently in obese patients (11, 12) may reflect the protein products of these inflammatory cell types in adipose tissue. If a pathologic reduction in type 2 immune responses in visceral adipose tissue is a possible mechanism of obesity, might obese individuals with asthma be characterized by a relative absence of Th2 inflammation in their airways? Prior to any knowledge of a role for type 2 immunity in adipose tissue, this question was of interest because of speculation that obesity-associated asthma represents a distinct “Th2-low” asthma endotype (13). In support of such an endotype, cluster analyses of large asthma cohorts have revealed a cluster of female obese individuals withasthma who have decreased markers of Th2 inflammation (14, 15). This cluster is small, however, and most of the obese subjects in these cohorts populate other phenotypic clusters. In addition, many obese individuals with asthma—especially those with more severe disease—have evidence of Th2 inflammation. For example, in a recent clinical trial of dupilumab (an IL-4 receptor inhibitor) in moderate to severe asthma (16), which enrolled only patients with asthma with systemic eosinophilia, the average body mass index of the patients was 31.5. In the current issue of the Journal, Desai and colleagues (pp. 657– 663) directly tackle the issue of eosinophilic airway inflammation in obese asthma (17). In two cohorts of patients with severe asthma, they measured eosinophil numbers and IL-5 in sputum samples and eosinophil numbers in tissue sections from endobronchial biopsies. They found that sputum IL-5 levels and biopsy eosinophil numbers are higher in obese severe asthma than in nonobese asthma. Examination of their data, which is presented so that individual data points can be seen, is notable for the considerable variation in eosinophil numbers and IL-5 cytokine concentrations among subjects. Across all asthma subgroups, there are sizable numbers of patients both with and without elevations in eosinophil and IL-5 measures. Thus, obese asthma—as in other asthma phenotypes—has subgroups who have and who do not have airway Th2 inflammation. As drugs such as dupilumab and other inhibitors of type 2 inflammation are deployed, it will be important to target them to the patient subgroups that will benefit. Clearly, large subgroups of obese individuals with asthma have Th2 inflammation and stand to benefit from these treatments. Advancing methods for more easily identifying Th2-high and Th2-low subgroups of patients remains of great interest, because sputumand bronchoscopy-based methods are not easily deployed in the community.

Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction

BACKGROUND. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS. In clinical studies, we developed and applied a bronchopulmonary segment–based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%–80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION. Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. FUNDING. NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

IL1RL1 asthma risk variants regulate airway type 2 inflammation

Genome-wide association studies of asthma have identified genetic variants in the IL1RL1 gene, but the molecular mechanisms conferring risk are unknown. IL1RL1 encodes the ST2 receptor (ST2L) for IL-33 and an inhibitory decoy receptor (sST2). IL-33 promotes type 2 inflammation, which is present in some but not all asthmatics. We find that two single nucleotide polymorphisms (SNPs) in IL1RL1 - rs1420101 and rs11685480 - are strongly associated with plasma sST2 levels, though neither is an expression quantitative trait locus (eQTL) in whole blood. Rather, rs1420101 and rs11685480 mark eQTLs in airway epithelial cells and distal lung parenchyma, respectively. We find that the genetically determined plasma sST2 reservoir, derived from the lung, neutralizes IL-33 activity, and these eQTL SNPs additively increase the risk of airway type 2 inflammation among asthmatics. These risk variants define a population of asthmatics at risk of IL-33-driven type 2 inflammation.

Biomarkers of Airway Type-2 Inflammation and Integrating Complex Phenotypes to Endotypes in Asthma

Purpose of ReviewOver the past decade, the most important advance in the field of asthma has been the widespread recognition that asthma is a heterogeneous disease driven by multiple molecular processes.Recent FindingsThe most well-established molecular mechanism in asthma is increased airway type-2 inflammation, and consequently, non-invasive biomarkers of increased airway type-2 inflammation, such as blood eosinophil counts or blood periostin levels, have proven important in stratifying asthma patients in clinical trials of type-2 cytokine inhibitors. However, it remains ambiguous how well these non-invasive biomarkers represent airway measures of type-2 inflammation in asthma. As a result, the utility of these biomarkers to assist with asthma management or as research tools to better understand asthma pathogenesis remains unclear.SummaryThis article reviews primary data assessing biomarkers of airway type-2 inflammation in asthma and describes how the use of biomarkers can advance a precision medicine approach to asthma treatment.