Guillaume Lezmi

Airway Remodeling in Preschool Children with Severe Recurrent Wheeze.

RATIONALE Airway wall structure in preschoolers with severe recurrent wheeze is poorly described. OBJECTIVES To describe airway wall structure and inflammation in preschoolers with severe recurrent wheeze. METHODS Flexible bronchoscopy was performed in two groups of preschoolers with severe recurrent wheeze: group 1, less than or equal to 36 months (n = 20); group 2, 36-59 months (n = 29). We assessed airway inflammation, reticular basement membrane (RBM) thickness, airway smooth muscle (ASM), mucus gland area, vascularity, and epithelial integrity. Comparisons were then made with biopsies from 21 previously described schoolchildren with severe asthma (group 3, 5-11.2 yr). MEASUREMENTS AND MAIN RESULTS RBM thickness was lower in group 1 than in group 2 (3.3 vs. 3.9 μm; P = 0.02), was correlated with age (P < 0.01; ρ = 0.62), and was higher in schoolchildren than in preschoolers (6.8 vs. 3.8 μm; P < 0.01). ASM area was lower in preschoolers than in schoolchildren (9.8% vs. 16.5%; P < 0.01). Vascularity was higher in group 1 than in group 2 (P = 0.02) and group 3 (P < 0.05). Mucus gland area was higher in preschoolers than in schoolchildren (16.4% vs. 4.6%; P < 0.01). Inflammatory cell counts in biopsies were not correlated with airway wall structure. ASM area was higher in preschoolers with atopy than without atopy (13.1% vs. 7.7%; P = 0.01). Airway morphometrics and inflammation were similar in viral and multiple-trigger wheezers. CONCLUSIONS In preschoolers with severe recurrent wheeze, markers of remodeling and inflammation are unrelated, and atopy is associated with ASM. In the absence of control subjects, we cannot determine whether differences observed in RBM thickness and vascularity result from disease or normal age-related development.

Pleuroparenchymal fibroelastosis as a late complication of chemotherapy agents

To the Editor: We identified six patients with clinical, radiographic and physiological features typical of pleuroparenchymal fibroelastosis (PPFE). In the six cases, PPFE may have been causally related to prior alkylating drugs used to treat malignacy, namely cyclophosphamide in five of the cases and carmustine (BCNU (1,3-bis-(2-chloroethyl)-1-nitrosourea)) in one. Based on an extensive review of the literature, we suspect that similar cases may have already been reported in the past 4 decades but have not been recognised either as PPFE or as drug-induced in nature. In 2004, Frankel et al. [1] described a then-new clinicopathologic entity, which they termed “idiopathic PPFE”. The authors identified five patients who had a clinical presentation suggestive of chronic interstitial pneumonitis that did not fit any previously established category of idiopathic interstitial pneumonia. The patients were characterised by significant pleural involvement in the form of pleural thickening, which was more marked in both upper regions. In all five patients, surgical biopsy demonstrated prominent visceral pleural fibrosis with subpleural fibroelastosis and an abrupt transition between the fibrotic area and the near-normal adjoining lung. There was sparing of the underlying lung parenchyma at some depth from the pleural surface, and sparse fibroblast foci were present at the edge of the fibrotic area. Since that seminal report, several cases and small series have been reported that have demonstrated a strikingly similar clinical, radiological and pathological presentation, also characterised by difficult-to-treat pneumothoraces in a sizable fraction of affected patients. In the updated American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias [2], PPFE is included as a separate but well-defined category of rare entities. Little is known about the aetiology of PPFE and …

Epithelial inactivation of Yy1 abrogates lung branching morphogenesis

Yin Yang 1 (YY1) is a multifunctional zinc-finger-containing transcription factor that plays crucial roles in numerous biological processes by selectively activating or repressing transcription, depending upon promoter contextual differences and specific protein interactions. In mice, Yy1 null mutants die early in gestation whereas Yy1 hypomorphs die at birth from lung defects. We studied how the epithelial-specific inactivation of Yy1 impacts on lung development. The Yy1 mutation in lung epithelium resulted in neonatal death due to respiratory failure. It impaired tracheal cartilage formation, altered cell differentiation, abrogated lung branching and caused airway dilation similar to that seen in human congenital cystic lung diseases. The cystic lung phenotype in Yy1 mutants can be partly explained by the reduced expression of Shh, a transcriptional target of YY1, in lung endoderm, and the subsequent derepression of mesenchymal Fgf10 expression. Accordingly, SHH supplementation partially rescued the lung phenotype in vitro. Analysis of human lung tissues revealed decreased YY1 expression in children with pleuropulmonary blastoma (PPB), a rare pediatric lung tumor arising during fetal development and associated with DICER1 mutations. No evidence for a potential genetic interplay between murine Dicer and Yy1 genes during lung morphogenesis was observed. However, the cystic lung phenotype resulting from the epithelial inactivation of Dicer function mimics the Yy1 lung malformations with similar changes in Shh and Fgf10 expression. Together, our data demonstrate the crucial requirement for YY1 in lung morphogenesis and identify Yy1 mutant mice as a potential model for studying the genetic basis of PPB. Summary: Genetic ablation of the transcription factor YY1 in mouse lung epithelium disrupts lung branching and leads to cyst formation, a phenotype reminiscent of pleuropulmonary blastoma.

Circulating IL-17-producing mucosal-associated invariant T cells (MAIT) are associated with symptoms in children with asthma

IL-17 and mucosal-associated invariant T (MAIT) cells have been involved in asthma pathogenesis. However, IL-17-producing MAIT cells (MAIT-17) were not evidenced. We aimed to determine whether circulating MAIT-17 were detectable in children with asthma, and whether they correlated with asthma symptoms or lung function. Children from the SPASM cohort of preschoolers with severe wheeze were reassessed for asthma at school age, and categorized as exacerbators (1 or more severe exacerbations in the previous 12months) or non-exacerbators. Nineteen children (10.9years) were included (9 non-exacerbators, 10 exacerbators). Circulating MAIT-17 were detected by flow cytometry. Their frequency was higher in exacerbators than in non-exacerbators (1.9 [1.01-3.55] vs 0.58 [0.46-1.15], p<0.01). MAIT-17 correlated with the number of severe exacerbations (r=0.68, p<0.001), and correlated negatively with the ACT score (r=-0.55, p=0.01). In summary, MAIT-17 are present in children with asthma and associated with asthma symptoms.

Non-immediate-reading skin tests and prolonged challenges in non-immediate hypersensitivity to beta-lactams in children

A minority of children reporting non‐immediate reactions to beta‐lactams (BLs) are allergic. Allergy workup usually includes late‐reading (48‐72 hours) skin tests (ST) and short (1‐3 days) drug provocation tests (DPT), regardless of the chronology of the index reaction. The sensitivity of hyper‐late‐reading (≥6‐7 days) ST and of prolonged DPT for the diagnosis of non‐immediate hypersensitivity to BLs is yet to be determined.

Mast cells are associated with exacerbations and eosinophilia in children with severe asthma

The role of mast cells in the pathogenesis of childhood asthma is poorly understood. We aimed to estimate the implication of airway mucosal mast cells in severe asthma and their relationship with clinical, functional, inflammatory and remodelling parameters. Bronchial biopsies were performed in 36 children (5–18 years) with severe asthma: 24 had frequent severe exacerbations and/or daily symptoms in the previous year (symptomatic group), and 12 had few symptoms and a persistent obstructive pattern (paucisymptomatic group). Nine children without asthma were included as control subjects. We assessed mast cells in the submucosa and airway smooth muscle using c-kit antibodies and in the entire biopsy area using Giemsa. The number of submucosal mast cells was higher in the symptomatic group than in the paucisymptomatic group (p=0.02). The number of submucosal mast cells correlated with the number of severe exacerbations (p=0.02, r=0.37). There were positive correlations between the number of submucosal mast cells (p<0.01, r=0.44), airway smooth muscle mast cells (p=0.02, r= 0.40), mast cells stained by Giemsa (p<0.01, r=0.44) and submucosal eosinophils. Mast cells are associated with severe exacerbations and submucosal eosinophilic inflammation in children with severe asthma. Submucosal mast cells are associated with exacerbations and submucosal eosinophilia in children with severe asthma http://ow.ly/uwly302J5mE

Multifocal Fixed Drug Eruption to ceftazidime in a child with cystic fibrosis

Fixed drug eruption (FDE) is a cutaneous adverse drug reaction characterized by well-delimited pigmented lesions of the skin and/or mucosa [1,2]. FDE is rare and frequently misdiagnosed leading to recurrent eruptions after the offending drug is re-administered [1,2]. The diagnosis hallmark is its recurrence in previously affected sites leading to a residual hyperpigmentation, however some cases without residual pigmentation have been described [2]. Many drugs have been shown to induce FDE, especially antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) [3]. To our knowledge, there is no report of FDE to ceftazidime. This article is protected by copyright. All rights reserved.

Comment on “Development of Asthma in Inner-City Children: Possible Roles of MAIT Cells and Variation in the Home Environment”

We read with interest the paper of Chandra et al. ([1][1]) reporting the frequency of invariant NKT (iNKT) and mucosal-associated invariant T (MAIT) cells in blood samples obtained from children at age 1 y and their possible correlation with recurrent wheezing, allergen sensitization, and asthma at

Assessment of airway inflammation and remodeling in children with severe asthma: The next challenge

Severe Asthma (SA) in children is relatively rare, affecting 2-5% of the asthmatic pediatric population. However, its burden is disproportionally high, as children with SA experience frequent asthma attacks, have a reduced quality of life, and account for approximately half of pediatric asthma healthcare costs. Asthma is now considered to encompass multiple conditions characterized by common symptoms (wheeze, cough, shortness of breath, chest tightness), variable degrees of airflow limitation, and various patterns of inflammation. Little data are available concerning airway inflammation (AI) and airway remodeling (AR) in pediatric asthma and the pathogenesis of pediatric SA cannot be completely extrapolated from adult studies. For example, although eosinophilic airway inflammation is a key feature of SA in schoolchildren, there is no evidence for the presence of Th2-type cytokines in bronchial mucosa or bronchoalveolar lavage (BAL) in this population. In this issue of Pediatric Pulmonology, Castro-Rodriguez et al4) present an extensive review of the intervention studies conducted in children with SA symptoms, in which direct analysis of AI and/or AR has been performed on BAL and/or bronchial biopsy. The authors sought to analyze the relationship between inflammation and remodeling and determine whether remodeling affects lung function (LF). AR has long been thought to result from repeated acute and chronic inflammation. However, this paradigm has been challenged by findings showing that some remodeling markers, especially increased reticular basement membrane (RBM) thickness, and airway smooth muscle (ASM) area can be observed early in the course of asthma, as early as in the preschool years, and that remodeling and inflammation appear to be unrelated in preschoolers with SA symptoms. AI can be assessed directly by bronchial biopsy or BAL. However, CastroRodriguez et al found only seven studies in which AI was analyzed in both BAL and biopsy. The extent to which the inflammatory cell counts in BAL correlate with those in the bronchial mucosa is unclear. Lex et al found that the eosinophil counts in BAL and bronchial mucosa were unrelated in children and adolescents with SA. The most reliable samples for analyzing AI in children with SA are those obtained from the bronchial mucosa, because they are collected directly from the pathological organ. In addition, most published biopsy studies have reported eosinophilic and neutrophilic infiltration of the bronchial mucosa, with a few focusing on other inflammatory cells, such as mast cells, lymphocytes, and macrophages. An important limitation of endoscopy studies in children is that they cannot include control subjects without any airway diseases for obvious ethical reasons. In many cases, the control subjects have upper or lower airway diseases other than asthma, whereas in others, no control subjects are included. It is therefore difficult to determine whether the observed features are pathological and specific to SA. This, along with the use of different technical procedures, limits the relevance of comparing studies and interpretation of the data. As expected, the authors showed that the datawere insufficient to make conclusions concerning potential influence of inflammation on remodeling in children with SA. However, they highlight that eosinophilic inflammation of the airways is always accompanied by the presence of remodeling markers. This does not mean that eosinophils cause remodeling, nor that inflammation precedes it. However, this is of major importance, because the presence of eosinophilsmay indicate an ongoing active inflammatory process in the airways, despite the use of high doses of inhaled steroids. Evidence suggest that AI in preschoolers with SA symptoms is more neutrophilic than eosinophilic, whereas SA in schoolchildren is more eosinophilic. This raises the question of whether SA in preschool and school-age children is based on a common pathological process, or whether they represent two different types of asthma. Interestingly, our group recently showed that some preschoolers with SA symptoms may display both eosinophilic and neutrophilic inflammation, and that those with more eosinophils at preschool age may be at increased risk of frequent severe exacerbations at school age. Analysis of the relationship between remodeling and LF showed an inverse correlation between ASM area and RBM thickness and FEV1 or FEV1/FVC. These findings are not surprising and support that 50% of children with asthma show a reduced increase in LF during childhood, with only 25% reaching 26 years of age with normal LF. However, most studies have focused only on RBM thickness and/or ASMarea, and the other remodelingmarkers, such asmucus gland area and epithelial integrity and vascularity are rarely described in children with SA. Their potential influence on LF or, more generally, on asthma is still poorly understood. Interventional studies with biopsy and extensive analysis of all AR markers are therefore needed to improve our understanding of how histological changes within the airway wall may affect the disease. For example, high vascularity in preschoolers with SA symptomsmay be associatedwith poor LF at school age.We have shown that there may be a substantial overlap between AR markers in preschoolers and school children, including RBM thickness, ASM, and mucus gland area, and epithelial integrity and vascularity. This finding suggests that the remodeling process may be progressive,

Invariant Natural Killer T and Mucosal-Associated Invariant T Cells in Asthmatic Patients

Recent studies have highlighted the heterogeneity of asthma. Distinct patient phenotypes (symptoms, age at onset, atopy, and lung function) may result from different pathogenic mechanisms, including airway inflammation, remodeling, and immune and metabolic pathways in a specific microbial environment. These features, which define the asthma endotype, may have significant consequences for the development and progression of the disease. Asthma is generally associated with Th2 cells, which produce a panel of cytokines (IL-4, IL-5, IL-13) that act in synergy to drive lung inflammatory responses, mucus secretion, IgE production, and fibrosis, causing the characteristic symptoms of asthma. In addition to conventional CD4+ T lymphocytes, other T-cell types can produce Th2 or Th17 cytokines rapidly. Promising candidate cells for studies of the mechanisms underlying the pathophysiology of asthma are unconventional T lymphocytes, such as invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells. This review provides an overview of our current understanding of the impact of iNKT and MAIT cells on asthmatic inflammation, focusing particularly on pediatric asthma.