Sejal Saglani

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

BACKGROUND The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood. OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

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

BACKGROUND 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. OBJECTIVE We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA. METHODS 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. RESULTS 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. CONCLUSION IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.

Increased airway smooth muscle in preschool wheezers who have asthma at school age

BACKGROUND Increased airway smooth muscle (ASM) is a feature of established asthma in schoolchildren, but nothing is known about ASM in preschool wheezers. OBJECTIVE We sought to determine endobronchial biopsy specimen ASM area fraction in preschool wheezers and its association with asthma at school age. METHODS ASM area, reticular basement membrane thickness, and mucosal eosinophil and ASM mast cell values were quantified in endobronchial biopsy specimens previously obtained from preschool children undergoing clinically indicated bronchoscopy: severe recurrent wheezers (n=47; median age, 26 months) and nonwheezing control subjects (n=21; median age, 15 months). Children were followed up, and asthma status was established at age 6 to 11 years. Preschool airway pathology was examined in relation to asthma at school age. RESULTS Forty-two (62%) of 68 children had 1 or more evaluable biopsy specimens for ASM. At school age, 51 of 68 children were followed up, and 15 (40%) of 37 preschool wheezers had asthma. Children who had asthma and an evaluable biopsy specimen had increased preschool ASM area fraction (n=8; median age, 8.2 years [range, 6-10.4 years]; median ASM, 0.12 [range, 0.08-0.16]) compared with that seen in children without asthma (n=24; median age, 7.3 years [range, 5.9-11 years]; median ASM, 0.07 [range, 0.02-0.23]; P=.007). However, preschool reticular basement membrane thickness and mucosal eosinophil or ASM mast cell values were not different between those who did or did not have asthma at school age. CONCLUSION Increased preschool ASM is associated with those children who have asthma at school age. Thus a focus on early changes in ASM might be important in understanding the subsequent development of childhood asthma.

T cells in asthma: Influences of genetics, environment, and T-cell plasticity

Asthma is classically considered the archetypal T(H)2 disease, with increased circulating IgE levels and eosinophilic inflammation being caused by increased levels of T(H)2-type cytokines. However, this paradigm has been challenged because of the realization that strategies designed to suppress T(H)2 function are not effective for all patients. The clinical phenotype of asthma is notoriously heterogeneous and is affected by genetic and environmental exposures in addition to interactions between airway structural cells, including epithelial cells, and the immune system, as well as contributions from cells other than T(H)2 cells. A combination of genetic and environmental factors is thought to influence whether inflammation resolves or progresses, and the pulmonary epithelium is increasingly recognized to play a key role in this process. This complex interplay has made it increasingly apparent that immune responses are tailored to the individual patient and determined by the weight of each influence, and thus the label of asthma as a T(H)2 disease is too conservative. Indeed, an important concept that needs to be addressed, both in animal models and clinically, is that of T-cell plasticity and how lymphocytic responses are determined by environmental influences.

EAACI position statement on asthma exacerbations and severe asthma

Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult‐to‐treat asthma and severe treatment‐resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment‐resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult‐to‐control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult‐to‐control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.

Intravenous salbutamol bolus compared with an aminophylline infusion in children with severe asthma: a randomised controlled trial

Background: The relative efficacies of aminophylline and salbutamol in severe acute childhood asthma are currently unclear. A single bolus of salbutamol was compared with a continuous aminophylline infusion in children with severe asthma in a randomised double blind study. Methods: Children aged 1–16 years with acute severe asthma were enrolled if they showed little improvement with three nebulisers (combined salbutamol and ipratropium) administered over an hour and systemic steroids. Subjects were randomised to receive either a short intravenous bolus of salbutamol (15 μg/kg over 20 minutes) followed by a saline infusion or an aminophylline infusion (5 mg/kg over 20 minutes) followed by 0.9 mg/kg/h. Results: Forty four subjects were enrolled, with 18 randomly allocated to receive salbutamol and 26 to receive aminophylline. The groups were well matched at baseline. An intention to treat analysis showed that there was no statistically significant difference in the asthma severity score (ASS) at 2 hours between the two groups (median (IQR) 6 (6, 8) and 6.5 (5, 8) for salbutamol and aminophylline respectively, p=0.93). A similar improvement in ASS to 2 hours was seen in the two groups (mean difference –0.08, 95% CI –0.97 to 0.80), there was a trend (p=0.07) towards a longer duration of oxygen therapy in the salbutamol group (17.8 hours (95% CI 8.5 to 37.5) v 7.0 hours (95% CI 3.4 to 14.2)), and a significantly (p=0.02) longer length of hospital stay in the salbutamol group (85.4 (95% CI 66.1 to 110.2) hours v 57.3 hours (95% CI 45.6 to 72.0)). There was no significant difference in adverse events between the two groups. Conclusions: This study suggests that, in severe childhood asthma, there is no significant difference in the effectiveness of a bolus of salbutamol and an aminophylline infusion in the first 2 hours of treatment. Overall, the aminophylline infusion was superior as it significantly reduced the length of stay in hospital.

Type 2 innate lymphoid cells in induced sputum from children with severe asthma

To The Editor: Innate lymphoid cells (ILCs) are characterized by their lymphoid morphology and absence of lymphocyte lineage surface markers. Group 2 ILCs (ILC2s) expressing CD127 and CRTH2 are induced by the epithelial cytokines IL-33 and IL-25 and are implicated in the pathogenesis of allergic airways disease in murine models. ILC2s have been identified in cord blood, tonsils, and nasal polyps from patients with chronic rhinoosinusitis and in peripheral blood and bronchoalveolar lavage (BAL) from adults with asthma. However, there are no reports of ILC2s in pediatric airways. We have shown increased submucosal expression of IL-33 in children with severe therapy-resistant asthma (STRA), which was related to the presence of airway remodeling. Furthermore, direct inhaled administration of IL-33 to neonatal mice resulted in increased pulmonary IL-13 producing ILCs concomitant with airway remodeling. Because an important role for IL-33 is apparent in pediatric STRA, we aimed to determine the presence of ILC2s in the airways of children with STRA to assess their potential role as therapeutic targets. Children with STRA and a disease control group of children with recurrent lower respiratory

Epithelial cytokines and pulmonary allergic inflammation

The triad of epithelial derived cytokines, IL-25, IL-33 and TSLP are important for the initiation and development of pulmonary immune responses to environmental stimuli. Data from experiments using mouse models provide compelling evidence for their involvement in both innate and adaptive immunity to drive type-2 responses, allergic inflammation and airway remodelling. These cytokines are known to be expressed in human lung tissue and immune cells, however their involvement in mediating allergic pulmonary responses in patients is less clear than in murine models of disease. This article focuses on evidence for the role of IL-25, IL-33 and TSLP in human allergic disease and discusses their potential as therapeutic targets for severe asthma.

Vitamin D deficiency induces Th2 skewing and eosinophilia in neonatal allergic airways disease

Associations between vitamin D status and childhood asthma are increasingly reported, but direct causation and mechanisms underlying an effect remain unknown. We investigated the effect of early‐life vitamin D deficiency on the development of murine neonatal allergic airways disease (AAD).

Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons

Background Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown. Objective We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients. Methods We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes. Results We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation–related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients. Conclusion We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.