A novel syndrome of silent rhinovirus-associated bronchoalveolitis in children with recurrent wheeze.

BACKGROUND: Rhinovirus (RV) infections trigger wheeze episodes in children. Thus, understanding of the lung inflammatory response to RV in children with wheeze is important. OBJECTIVES: This study sought to examine the associations of RV on bronchoalveolar lavage (BAL) granulocyte patterns and biomarkers of inflammation with age in children with treatment-refractory, recurrent wheeze (n = 616). METHODS: Children underwent BAL to examine viral nucleic acid sequences, bacterial cultures, granulocyte counts, and phlebotomy for both general and type-2 inflammatory markers. RESULTS: Despite the absence of cold symptoms, RV was the most common pathogen detected (30%), and when present, was accompanied by BAL granulocytosis in 75% of children. Compared to children with no BAL pathogens (n = 341), those with RV alone (n = 127) had greater (P < .05) isolated neutrophilia (43% vs 16%), mixed eosinophils and neutrophils (26% vs 11%), and less pauci-granulocytic (27% vs 61%) BAL. Children with RV alone furthermore had biomarkers of active infection with higher total blood neutrophils and serum C-reactive protein, but no differences in blood eosinophils or total IgE. With advancing age, the log odds of BAL RV alone were lower, 0.82 (5th-95th percentile CI: 0.76-0.88; P < .001), but higher, 1.58 (5th-95th percentile CI: 1.01-2.51; P = .04), with high-dose daily corticosteroid treatment. CONCLUSIONS: Children with severe recurrent wheeze often (22%) have a silent syndrome of lung RV infection with granulocytic bronchoalveolitis and elevated systemic markers of inflammation. The syndrome is less prevalent by school age and is not informed by markers of type-2 inflammation. The investigators speculate that dysregulated mucosal innate antiviral immunity is a responsible mechanism.

Further evidence of a type 2 inflammatory signature in chronic obstructive pulmonary disease or emphysema.

BACKGROUND: There is increasing recognition of a type 2 (T2) inflammatory pattern in a subset of patients with chronic obstructive pulmonary disease (COPD) or emphysema, characterized by blood and airway eosinophilia. The mechanism underlying this is not well established. The recognition that CD125 (interleukin [IL]-5 receptor alpha) is expressed on some lung neutrophils and eosinophils in patients with asthma led us to speculate that CD125 may also be expressed on lung neutrophils in patients with COPD or emphysema. OBJECTIVE: To interrogate the expression of CD125 on lung neutrophils (and, when present, eosinophils) in patients with COPD/emphysema and identify a meaningful biomarker to predict neutrophil CD125 expression, including other markers of T2 inflammation. METHODS: We obtained blood and bronchoalveolar lavage (BAL) samples from patients with physician-diagnosed COPD/emphysema undergoing a clinically indicated bronchoscopy. RESULTS: We found that a highly variable percentage of BAL neutrophils indeed expressed surface CD125 (0%-78.7%), with obvious clustering of CD125high and CD125low patterns. No correlation was found with clinical characteristics, blood or BAL eosinophil or neutrophil counts, BAL cytokines, or BAL eosinophil CD125 expression. CONCLUSION: We conclude that, similar to asthma, lung neutrophils from patients with COPD display interleukin-5 receptor alpha (CD125) on their surface. This along with the frequent presence of IL-4 and IL-5 in airway fluid further suggests a possible role of the T2 pathway in contributing to COPD severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03984799.

Interleukin-5 receptor alpha (CD125) expression on human blood and lung neutrophils.

BACKGROUND: Our previous studies revealed the presence of interleukin-5 (IL-5) receptor alpha chain (IL-5Rα, CD125) on neutrophils in a murine model of influenza and in the lung fluid of children with severe asthma. OBJECTIVE: To further evaluate the functional characteristics and effects of clinical factors and inflammatory variables on neutrophil surface IL-5Rα abundance in lung fluid and blood. METHODS: IL-5Rα expression was quantified by flow cytometry performed on purified neutrophils from blood and bronchoalveolar lavage fluid samples obtained from healthy controls and individuals with asthma. Expression was further confirmed by immunohistochemistry. Functional signaling through the IL-5Rα was evaluated by measurement of IL-5-inducible modulation of neutrophil surface CD62L and IL-5Rα expression. RESULTS: IL-5Rα was consistently present but at a variable magnitude on blood and lung neutrophils. Expression on lung neutrophils was significantly higher than that on blood cells (p"?>P < .001) where their expression was higher in the presence of airway pathogens, especially with respiratory viruses. Increased receptor expression occurred in response to the translocation of preformed receptors from intracellular stores. Receptors were functional as revealed by IL-5-mediated down-regulation of CD62L and the feed-forward up-regulation of reception expression. CONCLUSION: In addition to the expression on eosinophils and basophils, the IL-5Rα is consistently and abundantly expressed on the surface of blood and especially air space neutrophils. These observations support the concept that some of the efficacy of IL-5/IL-5R-targeting biologics observed in asthma may reflect their ability to target neutrophilic air space inflammation.

Novel Treatment-Refractory Preschool Wheeze Phenotypes Identified by Cluster Analysis of Lung Lavage Constituents.

BACKGROUND: Preschool children with treatment-refractory wheeze often require unscheduled acute care. Current guidelines advise treatment of persistent wheeze with inhaled corticosteroids. Alternative treatments targeting structural abnormalities and specific inflammatory patterns could be more effective. OBJECTIVE: To apply unsupervised analysis of lung lavage (bronchoalveolar lavage [BAL]) variables to identify clusters of preschool children with treatment-refractory wheeze. METHODS: A total of 155 children 6 years or younger underwent bronchoscopy with BAL for evaluation of airway structure, inflammatory markers, and pathogens. Variables were screened with factor analysis and sorted into clusters by Ward's method, and membership was confirmed by discriminant analysis. RESULTS: The model was repeatable in a 48-case validation sample and accurately classified 86% of cases. Cluster 1 (n = 60) had early-onset wheeze, 85% with structural abnormalities, mostly tracheamalacia, with low total IgE and agranulocytic BAL. Cluster 2 (n = 42) had later-onset wheeze, the highest prevalence of gastroesophageal reflux, little atopy, and two-third had increased BAL lipid-laden macrophages. Cluster 3 (n = 46) had mid-onset wheeze, low total IgE, and two-third had BAL viral transcripts, predominately human rhinovirus, with BAL neutrophilia. Cluster 4 (n = 7) was older, with high total IgE, blood eosinophilia, and mixed BAL eosinophils and neutrophils. CONCLUSIONS: Preschool children with recurrent wheeze refractory to inhaled corticosteroid treatment include 4 clusters: airway malacia, gastroesophageal reflux, indolent human rhinovirus bronchoalveolitis, and type-2high inflammation. The results support the risk and cost of invasive bronchoscopy to diagnose causes of treatment-refractory wheeze and develop novel therapies targeting airway malacia, human rhinovirus infection, and BAL neutrophilia in preschool children.

Measures of ventilation heterogeneity mapped with hyperpolarized helium-3 MRI demonstrate a T2-high phenotype in asthma.

BACKGROUND: Hyperpolarized gas with helium (HHe-3) MR (magnetic resonance) is a noninvasive imaging method which maps and quantifies regions of ventilation heterogeneity (VH) in the lung. VH is an important feature of asthma, but little is known as to how VH informs patient phenotypes. PURPOSE: To determine if VH indicators quantified by HHe-3 MR imaging (MRI) predict phenotypic characteristics and map to regions of inflammation in children with problematic wheeze or asthma. METHODS: Sixty children with poorly-controlled wheeze or asthma underwent HHe-3 MRI, including 22 with bronchoalveolar lavage (BAL). The HHe-3 signal intensity defined four ventilation compartments. The non-ventilated and hypoventilated compartments divided by the total lung volume defined a VH index (VHI %). RESULTS: Children with VHI % in the upper quartile had significantly greater airflow limitation, bronchodilator responsiveness, blood eosinophils, expired nitric oxide (FeNO), and BAL eosinophilic or neutrophilic granulocyte patterns compared to children with VHI % in the lower quartile. Lavage return from hypoventilated bronchial segments had greater eosinophil % than from ventilated segments. CONCLUSION: In children with asthma, greater VHI % as measured by HHe-3 MRI identifies a severe phenotype with higher type 2 inflammatory markers, and maps to regions of lung eosinophilia. Listed on ClinicalTrials. gov (NCT02577497).