Severe Therapy-resistant Asthma Research Articles

Assessment of corticosteroid response in pediatric patients with severe asthma by using a multidomain approach

There is no agreed upon definition of systemic corticosteroid response in asthmatic children. Moreover, pediatric severe therapy-resistant asthma (STRA) is heterogeneous, and thus response to steroids is unlikely to be uniform in all patients. We sought to evaluate the utility of a multidomain approach incorporating symptoms, lung function, and inflammation to determine steroid responsiveness in pediatric patients with STRA. Eighty-two children (median age, 12years) with STRA received a clinically indicated dose of intramuscular steroid. Changes in 4 separate domains were assessed 4weeks after intramuscular triamcinolone acetonide: normalization of (1) symptoms (Asthma Control Test score, >19/25 or 50% increase), (2) spirometric results (FEV1 ≥80% of predicted value or ≥15% increase), (3) fraction of exhaled nitric oxide levels (<24ppb), and (4) sputum eosinophil counts (<2.5%). Fifty-four of 82 children had complete data in all 4 domains. Twenty-three (43%) of 54 children had a symptom response, 29 (54%) of 54 had a lung function response, 28 (52%) of 54 had a fraction of exhaled nitric oxide response, and 29 (54%) of 54 had a sputum eosinophil response. Although a similar proportion of children responded to systemic corticosteroids in each domain, there were no reliable predictors of a response pattern. Seven (13%) of 54 were complete responders (response in all domains), 8 (15%) of 54 were nonresponders (no response in any domain), and 39 (72%) of 54 were partial responders (response in ≥1 domain). A multidomain evaluation of systemic steroid responsiveness using pragmatic clinical assessments confirms childhood STRA is heterogeneous and that a complete response in symptoms and inflammatory and physiologic parameters is rare. Individual response patterns to systemic steroids might be useful in guiding the choice of add-on therapies in each child as a step toward achieving personalized medicine.

Ethnic Variation in Response to IM Triamcinolone in Children With Severe Therapy-Resistant Asthma

Although ethnicity may influence response to treatment of patients with asthma, this approach is controversial. The objective of this study was to determine if ethnicity influences the response to IM steroid use (eliminating adherence as an issue). Children with severe therapy-resistant asthma who had previously undergone a detailed assessment (including a nurse-led hospital and home visit in which potentially modifiable factors had been identified and addressed) were admitted for further evaluation; this evaluation included assessment of steroid response. Children were classified as white, black, Asian, or mixed white/black. Steroid responsiveness was defined according to symptoms (Asthma Control Test), inflammation (sputum eosinophil count and exhaled nitric oxide), and spirometry (FEV1); these variables were measured before and 4weeks after IM triamcinolone use. Data were collected regarding exacerbations. Fractional exhaled nitric oxide (Feno) response was defined as a decrease to< 24 parts per billion (ppb). Seventy-nine subjects were identified (white, n= 54 [68%]; black, n= 16 [20%]; Asian, n= 5 [6%]; and mixed white/black, n= 4 [5%]). After administration of triamcinolone, there was a significant drop in median Feno in white children (46.8 to 23.1 ppb; P< .001) but not in black children (52.2 to 34.5 ppb; P= .58). More black children than white children (86.7%) were Feno nonresponders (86.7%vs45.3%; P< .05), and more black children had exacerbations compared with white children (61%vs17%; P< .05). Black children with asthma were less likely to report an Feno response and had more exacerbations 4weeks after administration of triamcinolone than white children. Further research is needed to understand the mechanisms of these differences, but theycannot be due to differences in adherence or access to care.

The dark side of the moon: severe therapy-resistant asthma in children

Problematic severe asthma is the term used to describe children whose asthma is not responsive to standard therapy with high-dose inhaled corticosteroids and additional controllers. These children need to be assessed by a step-wise systematic protocol in order to confirm the diagnosis, evaluate co-morbidities, assess the adherence to treatment, and finally evaluate the basic management. More than half of these children have "difficult-to-treat asthma", which improves if the basic management is correct. Children whose asthma remains uncontrolled despite resolution of any reversible factors are termed "severe therapy-resistant" asthmatics; for them, an individualised treatment plan is developed after a detailed and invasive protocol of investigation. Therapeutic options for these patients can be divided into medications used in lower doses for children with less severe asthma, and those used in other pediatric diseases but not for asthma. Most treatments are unlicensed and there is a lack of high-quality evidence. Children with recurrent severe exacerbations, in particular in the context of good baseline asthma control, are particularly difficult to treat, and there is no evidence on which therapeutic option to recommend. International collaborations, using standard protocols of investigation, are needed to better understand mechanisms of severe therapy-resistant asthma and to deliver evidence-based treatments in the future.

Vitamin D and respiratory disorder

Article type Review article The active form of vitamin D is synthesized in some body organs following sun exposure and dietary intake. Vitamin D exhibits its major and critical effects not only through regulation of calcium and phosphate metabolism but also by influencing on respiratory and immune system. Serum concentrations of 25-hydroxyvitamin D below the optimum limit lead to vitamin D insufficiency or maybe deficiency. These inappropriate concentrations of vitamin D lead to different types of pulmonary diseases such as viral and bacterial respiratory infection, asthma, chronic obstructive pulmonary disease, and cancer. In this review we described the association between vitamin D deficiency and severe therapy resistant asthma. We also reviewed the underlying molecular mechanism of vitamin D deficiency in children with severe- therapy resistant asthma. Based on current information, future clinical trial are needed to study the role of vitamin D supplementation on different groups of patients with severe asthma including infants, children of school age, and ethnic minorities.

Severe asthma in childhood

In the majority of cases, asthma in children may be easily controlled by available drugs. However, a substantial subset exists who remain “difficult to treat”. The burden of the disease for these children is enormous in terms of quality of life, social problems, resources expenditure and mortality. Over the last 15 years, several international committees have proposed different definitions for severe asthma. In order to revise such definition and provide guidance about the management of patients with severe asthma, a jointed ERS/ATS Task Force has recently published a document addressed to the specialists in respiratory medicine and allergy [1]. It is defined “severe”, asthma which requires treatment with guidelines suggested medications for GINA steps 4–5 asthma (high dose ICS and LABA or leukotriene modifier/theophylline) for the previous year or systemic CS foro 50% of the previous year to prevent it from becoming “uncontrolled” or which remains “uncontrolled” despite this therapy. Uncontrolled asthma defined as at least one of the following: 1) Poor symptom control: ACQ consistently >1.5, ACT 3 days each) in the previous year; 3) Serious exacerbations: at least one hospitalisation, ICU stay or mechanical ventilation in the previous year; 4) Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal); 5) Controlled asthma that worsens on tapering of these high doses of ICS or systemic CS (or additional biologics). Inherent in the definition of severe asthma is the exclusion of individuals who present with “difficult asthma” in whom appropriate diagnosis and/or treatment of confounders (comorbidity, adherence, psychosocial problems, etc.) improves their current condition. Therefore, it is recommended that patients presenting with “difficult asthma” have their asthma diagnosis confirmed and be evaluated by an asthma specialist for more than 3 months. Patients with confirmed severe asthma should receive an individualised treatment plan after a detailed and invasive protocol of investigations. Therapeutic options can be divided into medications used in lower doses for children with less severe asthma, and those used in other paediatric diseases but not for asthma. Most treatments are unlicensed and the evidence base is poor. International collaborations, using standard protocols of investigation, will be essential if the mechanisms of severe therapy resistant asthma are to be understood, and evidence-based treatment delivered.

Clinical characteristics of children and adolescents with severe therapy-resistant asthma in Brazil.

Objective: To describe the clinical characteristics, lung function, radiological findings, and the inflammatory cell profile in induced sputum in children and adolescents with severe therapy-resistant asthma (STRA) treated at a referral center in southern Brazil. Methods: We retrospectively analyzed children and adolescents (3-18 years of age) with uncontrolled STRA treated with high-dose inhaled corticosteroids and long-acting ß2 agonists. We prospectively collected data on disease control, lung function, skin test reactivity to allergens, the inflammatory cell profile in induced sputum, chest CT findings, and esophageal pH monitoring results. Results: We analyzed 21 patients (mean age, 9.2 ± 2.98 years). Of those, 18 (86%) were atopic. Most had uncontrolled asthma and near-normal baseline lung function. In 4 and 7, induced sputum was found to be eosinophilic and neutrophilic, respectively; the inflammatory cell profile in induced sputum having changed in 67% of those in whom induced sputum analysis was repeated. Of the 8 patients receiving treatment with omalizumab (an anti-IgE antibody), 7 (87.5%) showed significant improvement in quality of life, as well as significant reductions in the numbers of exacerbations and hospitalizations. Conclusions: Children with STRA present with near-normal lung function and a variable airway inflammatory pattern during clinical follow-up, showing a significant clinical response to omalizumab. In children, STRA differs from that seen in adults, further studies being required in order to gain a better understanding of the disease mechanisms.

Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33

BackgroundThe mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored.ObjectiveWe sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33.MethodsEighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model.ResultsChildren with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13+ innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2−/− mice lacking a functional receptor for IL-33.ConclusionPediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33–mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.

Severe Asthma in Children

Severe asthma in children is characterized by sustained symptoms despite treatment with high doses of inhaled corticosteroids or oral corticosteroids. Children with severe asthma may fall into 2 categories, difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities, or poor adherence due to adverse psychological or environmental factors. In contrast, treatment resistant is defined as difficult asthma despite management of these factors. It is increasingly recognized that severe asthma is a highly heterogeneous disorder associated with a number of clinical and inflammatory phenotypes that have been described in children with severe asthma. Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with long-acting β-agonists and other add-on therapies, such as antileukotrienes and methylxanthines. It is important to identify and address the influences that make asthma difficult to control, including reviewing the diagnosis and removing causal or aggravating factors. Better definition of the phenotypes and better targeting of therapy based upon individual patient phenotypes is likely to improve asthma treatment in the future.

Let-7a is differentially expressed in bronchial biopsies of patients with severe asthma.

Asthma is a chronic inflammatory disease. Around 5 to 10% of patients classified as having severe asthma can-not be adequately controlled despite the use of all currently available therapeutic approaches. Previous studies have revealed the potential important role of miRNAs in the regulation of a variety of inflammatory processes, including asthma. Expression of selected miRNAs, specifically let-7a, miR-21 and miR-223, that were shown to have important roles in asthma pathogenesis, were analyzed in bronchial biopsies of 24 patients with asthma, 12 mild and 12 severe and 10 controls with no chronic disease. We found significantly reduced expression of let-7a in bronchial biopsies from patients with severe asthma in comparison to patients with mild asthma as well as in comparison to the non-asthmatic controls. On the other hand, no significant differences in miR-21 and miR-223 expression were found between the different groups analyzed. Reduced let-7a levels in bronchial biopsies of patients with severe therapy-resistant asthma could not only be used as a potential biomarker to discriminate between different asthma phenotypes, but also might be a target for modulation of treatment at the inflammatory site for a group of patients that are most affected and still lack effective treatment.

GENE EXPRESSION DYNAMICS IN PATIENTS WITH SEVERE THERAPY-RESISTANT ASTHMA DURING TREATMENT PERIOD

Introduction: The leading mechanisms and causes of severe therapy resistant asthma are poorly understood. The aim of this study was to define global patterns of gene expression in adults with severe therapy-resistant asthma in dynamic during treatment period.Methods: Performed 24-week prospective interventional study in parallel groups. Severe asthma patients was aposterior divided at therapy sensitive and resistant patients according to ATS criteria. Global transcriptome profile was characterized using the Affymetrix HuGene ST1.0 chip. Cluster analysis was performed.Results and conclusion: According to our data several mechanisms of therapy resistance may be considered: increased levels of nitric oxide and beta2-agonists nitration, dysregulation of endogenous steroids secretion and involvement in the pathogenesis of Staphylococcus aureus. Absence of suppression of gene expression KEGG-pathway “asthma" may reflect the low efficiency or long period of anti-inflammatory therapy effect realization.

Pediatric Asthma – do we need more innovation for treatment?

Pediatric Asthma – do we need more innovation for treatment?

Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma

BackgroundUnderstanding of immune mechanisms underpinning asthma has emerged from studies in adults. It is increasingly recognised, both immunologically and in the development of novel therapies, that adult responses cannot be...

P88 Real-Life Experience of Omalizumab in Children with Severe Asthma

IntroductionTherapeutic options for children with severe asthma are limited. Clinical studies support the use of the anti-IgE antibody, omalizumab, in children with severe atopic asthma. However, children included in these...

IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma

TH2 cytokines are not responsible for the ongoing symptoms and pathology in children with severe therapy-resistant asthma (STRA). IL-33 induces airway hyperresponsiveness, but its role in airway remodeling and steroid resistance is unknown. We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA. IL-33 levels were quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodeling and IL-33 levels was assessed. HDM-induced allergic airways disease (AAD) in neonatal ST2(-/-) mice lacking the IL-33 receptor was assessed, together with collagen production after IL-33 administration. The effect of steroid therapy on IL-33 levels in patients with neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsy (EB) specimens from children with STRA and related to remodeling, and collagen production by airway fibroblasts from pediatric patients stimulated with IL-33 and budesonide was quantified. Blocking IL-13 after AAD was established in neonatal mice and did not reduce remodeling or IL-33 levels; airway hyperresponsiveness was only partially reduced. IL-33 promoted collagen synthesis both from asthmatic fibroblasts from pediatric patients and after intranasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in EB specimens from children with STRA, whereas remodeling was absent in HDM-exposed ST2(-/-) mice. IL-33 levels were maintained, whereas IL-13 levels were abrogated by steroid treatment in neonatal HDM-exposed mice and in EB specimens from children with STRA. IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.

Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma

The inflammatory phenotypes of severe asthma in adults may be reflected in peripheral blood. If this were true in children with severe therapy-resistant asthma (STRA), invasive tests could be avoided. At the moment there is no conclusive evidence in children. All patients underwent blood tests, exhaled nitric oxide (FeNO), sputum induction, bronchoalveolar lavage (BAL) and endobronchial biopsy (EB). Sixty-three (71.6%) patients had a normal blood profile and only 1/88 had a combined blood eosinophilia and neutrophilia. 76/88 (86%) had normal blood eosinophils, but of these, 84% had airway eosinophilia in either BAL (n = 43;66%) or EB (n = 41;79%). In children with STRA blood eosinophilia was associated with airway eosinophilia. However, normal blood eosinophil levels did not exclude airway eosinophilic inflammation. Peripheral blood counts are not reliable in characterising airway inflammation in severe asthmatic children exposed to high dose steroid therapy, therefore bronchoscopy with BAL should be considered.

Asthma diagnosis and treatment – 1003. Severe asthma: a comparison of clinical severity and lung function

Background Severe therapy resistant asthma is a relatively rare entity. This has been variously defined based on clinical and spirometric criteria. It has always been known that the correlation between clinical and physiological parameters is not very consistent and hence the difficulty in defining this entity. We have looked at our cohort of consecutive patients with severe and moderate asthma in trying to establish a correlation between clinical and spirometric parameters. Methods We looked at 850 consecutive patients with diagnosis of asthma based on Spirometric criteria (GINA guidelines). These were patients were compliance to medications was ensured and technique was optimised by trained healthcare personnel. We then selected the ones who had “Severe” & “Moderate” asthma basedon Spirometry. We now looked at these patients and correlated their Spirometry with thesymptomatology (use of rescue medication, night time awakening, exercise induced symptoms) and exacerbation rates (unscheduled GP visits, number of courses of OCS, emergency visits, hospitals and ICU admissions). Results Only 79 (9.29%) patients out of 850 had severe asthma & 352 (41.41%) patients had moderate asthma based on Spirometric criteria. We found that Spirometric findings correlated with clinical parameters in 69.4% patients with Severe Asthma & 86% patients with Moderate Asthma. Conclusions Only a small but significant percentage of patients in our population satisfy the Spirometric criteria of Severe Asthma (less than 10%). Even in this population there is lack of homogeneity between clinical parameters (symptoms & exacerbations) and physiological parameters (Spirometry). This correlation was much more consistent in patients with Moderate Asthma. Interestingly, we found more severe the asthma based on Spirometry, less was the correlation with symptomatology and exacerbations. This phenomenon and its causation needs to be studied in greater detail in longitudinal studies.

Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics

The causes of severe childhood asthma are poorly understood. Our aim was to define global patterns of gene expression in children with severe therapy-resistant and controlled asthma. White blood cells were isolated and the global transcriptome profile was characterised using the Affymetrix Human Gene ST 1.0 chip in children with severe, therapy-resistant asthma (n=17), controlled asthma (n=19) and healthy controls (n=18). Receptor expression was studied in separated leukocyte fractions from asthmatic adults (n=12). Overall, 1378 genes were differentially expressed between children with severe/controlled asthma and controls. Three significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways were represented: natural killer cell-mediated cytotoxicity (upregulated in controlled asthma); N-glycan biosynthesis (downregulated in severe asthma); and bitter taste transduction receptors (TAS2Rs) (upregulated in severe asthma). Quantitative PCR experiments confirmed upregulation of TAS2Rs in severe asthmatics. TAS2R expression was replicated in leukocytes from adult asthmatics, in which TAS2R agonists also inhibited LPS-induced cytokine release. Significant correlations between expression of TAS2Rs and clinical markers of asthma severity were found in both adults and children. In conclusion, specific gene expression patterns were observed in children with severe, therapy-resistant asthma. The increased expression of bronchodilatory TAS2Rs suggests a new target for the treatment of asthma.

Impaired innate interferon induction in severe therapy resistant atopic asthmatic children.

Deficient type I interferon-β and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.

Long-term effectiveness of a staged assessment for paediatric problematic severe asthma

To the Editors: The recently proposed term “problematic severe asthma” (PSA) [1] describes children with persistent symptoms and/or severe exacerbations despite high dose treatment [2]. They suffer significant morbidity and consume a disproportionate amount of healthcare resources. Children with PSA are heterogeneous with respect to lung function [3] and asthma phenotype [4] and warrant careful evaluation. PSA [5] encompasses 1) wrong diagnosis; 2) significant comorbidities; 3) difficult asthma with potentially reversible factors such as poor inhaler technique, ongoing allergen exposure or poor adherence to treatment [6]; and 4) severe therapy-resistant asthma (STRA) that is refractory to maximal treatment despite optimised standard management [7]. PSA children were enrolled in a staged assessment protocol to differentiate difficult asthma from STRA [6]. The different stages were as follows. Stage 1: a detailed re-evaluation of the child including a nurse-led outpatient assessment with evaluation of inhaler device and technique, psychosocial questionnaire, a home and school visit, an assessment of adherence including prescription uptake check and a final multidisciplinary team discussion to decide whether the child had difficult asthma or STRA [6]. Stages 2 and 3: children identified as STRA progressed to invasive investigations including bronchoscopy and assessment of steroid response [7]. Differentiating difficult asthma from STRA is important to avoid unnecessary invasive procedures and side effects from additional treatments such as methotrexate. Furthermore, the healthcare costs of these approaches cannot be justified if simply improving basic management may improve asthma control. There have been no longitudinal studies that have assessed the long-term efficacy of a staged assessment of paediatric PSA. We hypothesised that the stage 1 assessment distinguishes difficult asthma from STRA and results in …

Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines

The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood. We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the T(H)2 cytokines IL-4, IL-5, and IL-13. Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen T(H)2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation. Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P < .001; biopsy specimen, P < .01); within the STRA group, there was marked between-patient variability in eosinophilia. Submucosal mast cell, neutrophil, and lymphocyte counts were similar in both groups. Reticular basement membrane thickness and airway smooth muscle were increased in patients with STRA compared with those found in control subjects (P < .0001 and P < .001, respectively). There was no increase in BAL fluid IL-4, IL-5, or IL-13 levels in patients with STRA compared with control subjects, and these cytokines were rarely detected in induced sputum. Biopsy IL-5(+) and IL-13(+) cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid T(H)2 cytokines had significantly lower lung function than those with undetectable BAL fluid T(H)2 cytokines. STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the T(H)2 mediators that are thought to drive allergic asthma were mostly absent.