Airway hyperresponsiveness, remodeling and inflammation in infants with wheeze.

BACKGROUND: The relationship of airway hyperresponsiveness to airway remodeling and inflammation in infants with wheeze is unclear. OBJECTIVE: To investigate airway hyperresponsiveness, remodeling and inflammation in infants with wheeze and troublesome breathing. METHODS: Inclusion criteria were as follows: full-term, 3-23 months of age; doctor -diagnosed wheeze and persistent recurrent troublesome breathing; without obvious structural defect, suspicion of ciliary dyskinesia, cystic fibrosis, immune deficiency or specified use of corticosteroids. Airway hyperresponsiveness (AHR) was evaluated by performing a methacholine bronchial challenge test combined with whole body plethysmography and rapid thoracoabdominal compression. Endobronchial biopsies were analysed for remodeling (thickness of reticular basement membrane and amount of airway smooth muscle) and for inflammation (numbers of inflammatory cells). Correlation analyses were performed. RESULTS: Forty-nine infants fulfilled the inclusion criteria for the present study. Median age was 1.06 years (IQR 0.6; 1.5). Lung function was impaired in 39/49 (80%) children, at the median age of 1.1 years. Methacholine challenge was successfully performed in 38/49 children. Impaired baseline lung function was correlated with AHR (P = .047, Spearman). In children with the most sensitive quartile of AHR, the percentage of median bronchial airway smooth muscle % and the number of bronchial mast cells in airway smooth muscle were not significantly higher compared to others (P = .057 and 0.056, respectively). No association was found between AHR and thickness of reticular basement membrane or inflammatory cells. Only a small group of children with both atopy and AHR (the most reactive quartile) had thicker airway smooth muscle area than non-atopics with AHR (P = .031). CONCLUSIONS AND CLINICAL RELEVANCE: These findings do not support the concept that AHR in very young children with wheeze is determined by eosinophilic inflammation or clear-cut remodeling although it is associated with impaired baseline lung function. The possible association of increased airway smooth muscle area among atopic children with AHR remains to be confirmed.

Monocytes accumulate in the airways of children with fatal asthma.

BACKGROUND: Activated T helper type 2 (Th2) cells are believed to play a pivotal role in allergic airway inflammation, but which cells attract and activate Th2 cells locally have not been fully determined. Recently, it was shown in an experimental human model of allergic rhinitis (AR) that activated monocytes rapidly accumulate in the nasal mucosa after local allergen challenge, where they promote recruitment of Th2 cells and eosinophils. OBJECTIVE: To investigate whether monocytes are recruited to the lungs in paediatric asthma. METHODS: Tissue samples obtained from children and adolescents with fatal asthma attack (n = 12), age-matched non-atopic controls (n = 9) and allergen-challenged AR patients (n = 8) were subjected to in situ immunostaining. RESULTS: Monocytes, identified as CD68+S100A8/A9+ cells, were significantly increased in the lower airway mucosa and in the alveoli of fatal asthma patients compared with control individuals. Interestingly, cellular aggregates containing CD68+S100A8/A9+ monocytes obstructing the lumen of bronchioles were found in asthmatics (8 out of 12) but not in controls. Analysing tissue specimens from challenged AR patients, we confirmed that co-staining with CD68 and S100A8/A9 was a valid method to identify recently recruited monocytes. We also showed that the vast majority of accumulating monocytes both in the lungs and in the nasal mucosa expressed matrix metalloproteinase 10, suggesting that this protein may be involved in their migration within the tissue. CONCLUSIONS AND CLINICAL RELEVANCE: Monocytes accumulated in the lungs of children and adolescents with fatal asthma attack. This finding strongly suggests that monocytes are directly involved in the immunopathology of asthma and that these pro-inflammatory cells are potential targets for therapy.

Lung function, airway remodeling, and inflammation in infants: outcome at 8 years.

BACKGROUND: Associations between early deficits of lung function, infant airway disease, and outcome at school age in symptomatic infants are still unclear. OBJECTIVE: To report follow-up data on a unique cohort of children investigated invasively in infancy to determine predictive value of airway disease for school-aged respiratory outcomes. METHODS: Fifty-three infants previously studied using bronchoscopy and airway conductance were approached at 8 years of age. Symptoms, lung volumes, and airway responsiveness were reassessed. Data on lifetime purchase of asthma medication were obtained. Lung function was compared with that of 63 healthy nonasthmatic children. RESULTS: Forty-seven children were reevaluated. Physician-diagnosed asthma was present in 39 children (83%). Twenty-five children (53%) had current and 14 children (30%) had past asthma. No pathologic feature in infancy correlated with any outcome parameter. As expected, study children had significantly reduced lung function and increased airway responsiveness compared with healthy controls, and very early symptoms were risk factors for reduced lung function. Current asthma was associated with reduced infant lung function and parental asthma. Reduced lung function in infancy was associated with purchase of inhaled corticosteroids when 6 to 8 and 0 to 8 years of age. CONCLUSION: The lack of predictive value of any pathologic measure in infancy, reported here for the first time to our knowledge, demonstrates that pathologic processes determining the inception of asthma, which are as yet undescribed, are different from the eosinophilic inflammation associated with ongoing disease.

Very low birth weight and respiratory outcome: association between airway inflammation and hyperresponsiveness.

BACKGROUND: The respiratory outcomes after preterm birth have changed, and it is unclear whether increased airway hyperresponsiveness (AHR) later in childhood is associated with airway inflammation. OBJECTIVE: To investigate the association between AHR and fractional exhaled nitric oxide (FeNO), including the alveolar concentration of nitric oxide, in school-age children with very low birth weight (VLBW). METHODS: Twenty-nine children with VLBW, 33 children with a history of early wheeze, and 60 healthy controls underwent a FeNO measurement and bronchial challenge test with histamine. Atopy was assessed with skin prick tests. RESULTS: Children with VLBW had well-preserved baseline lung function but significantly increased AHR, expressed as the dose response slope (P < .001). Geometric mean FeNO levels were similar between VLBW children and healthy controls, and a history of bronchopulmonary dysplasia had no effect. In the VLBW and early wheeze groups, AHR was associated with FeNO (r = 0.47, P = .01, and r = 0.43, P = .013, respectively), but in a stratified analysis, this association was significant only in atopic individuals. By using the multiple flow FeNO technique, the bronchial nitric oxide flux rather than alveolar nitric oxide concentrations were associated with AHR in both children with early wheeze and VLBW. CONCLUSION: We conclude that in VLBW children AHR is related to FeNO but only in atopic individuals. Similar to children with early wheeze, this association is dependent on bronchial flux rather than alveolar nitric oxide concentration. It is likely that AHR is modified by atopic inflammation rather than by inflammatory process due to prematurity.

Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years.

BACKGROUND: Relationships between early deficits of lung function, infant airway pathology and outcome in symptomatic infants are unclear. A study was undertaken to determine the associations between early lung function, airway histology and inflammation in symptomatic infants with the continuance of respiratory symptoms, lung function and subsequent use of inhaled asthma medication at the age of 3 years. METHODS: 53 children who underwent lung function measurements and bronchoscopy following referral to a specialist children's hospital for recurrent lower respiratory symptoms at a mean age of 1 year were followed up at 3 years of age. Assessments were made of respiratory symptoms during the previous year, lung function by oscillometry and atopy by skin prick testing. Individual data on the purchase of asthma medications were obtained from the Social Insurance Institution for the 12 months preceding the follow-up visit. RESULTS: 50 children (94%) were re-evaluated, of whom 40 had ongoing airway symptoms. 11/39 (28%) who underwent successful oscillometry had reduced lung function, 31/50 (62%) used inhaled corticosteroids (ICS) regularly and 12/50 (24%) used ICS intermittently. Abnormal lung function at infancy was associated with ongoing airway symptoms (p<0.001) and with the purchase of ICS (p=0.009) and ß agonists (p=0.002). Reticular basement membrane thickness in infancy and the numbers of mucosal mast cells, but not eosinophils, correlated significantly with the amount of ICS purchased at 3 years (p=0.003 and p=0.018, respectively). CONCLUSIONS: Reduced lung function, thickening of the reticular basement membrane and increased density of mucosal mast cells in infancy are associated with respiratory morbidity and treatment needs at age 3 years in this highly selected group of children.

Characterisation of bronchus-associated lymphoid tissue and antigen-presenting cells in central airway mucosa of children.

BACKGROUND: Childhood represents an immunological window of vulnerability in which individuals are at increased risk for both serious infections and development of allergic diseases, particularly affecting the airways. However, little is known about how the airway mucosal immune system is organised and functions during early age. Here, the organisation of immune cells in bronchial mucosa of children was characterised. METHODS: Immunophenotyping was performed on mucosal samples obtained postmortem from nine children aged 2-15 years without any history of atopic manifestations or any signs of respiratory disease, who died from non-inflammatory causes. RESULTS: In all nine cases, isolated lymphoid follicles (ILFs), interpreted as bronchus-associated lymphoid tissue (BALT), were found, constituting an average frequency of 60 ILFs/cm(2) of airway mucosal surface. Outside these ILFs, dense networks of CD11c(+) myeloid dendritic cells (DCs), CD68(+) macrophages and CD3(+)CD45RA(-) memory T cells were found. Plasmacytoid DCs occurred in low numbers. Importantly, intraepithelial antigen-presenting cells were found to extend cellular projections into the airway lumen. CONCLUSION: The density and location of antigen-presenting cells and T cells in this age group are similar to those observed in adults. However, in contrast to adults, BALT appears to be a normal feature of the airway mucosa throughout childhood, suggesting that these structures contribute to regional immunity and homeostasis. This indicates that the local immune system in the airways of children has unique features which should be taken into account, not only when studying airway immunology and immunopathology, but also in the development of mucosal vaccines.

Longitudinal follow-up of bronchial inflammation, respiratory symptoms, and pulmonary function in adolescents after repair of esophageal atresia with tracheoesophageal fistula.

OBJECTIVE: To characterize symptoms, pulmonary function tests (PFT) and bronchial responsiveness (BR) in adolescents after repaired esophageal atresia with tracheoesophageal fistula and correlate these with endobronchial biopsy findings. STUDY DESIGN: After a primary operation, 31 patients underwent endoscopies and bronchoscopies at the age of <3, 3 to 7, and >7 years. A questionnaire on respiratory and esophageal symptoms was sent to patients at a mean age of 13.7 years (range, 9.7-19.4). The questionnaire was completed by 27 of 31 patients (87%), and 25 of the 31 patients (81%) underwent clinical examination and pulmonary functioning tests. Endobronchial biopsies were analyzed for reticular basement membrane (RBM) thickness and inflammatory cells. RESULTS: The prevalence of current respiratory and esophageal symptoms was 41% and 44%, respectively. "Doctor-diagnosed asthma" was present in 22% of patients. A restrictive and obstructive spirometric defect was observed in 32% and 30% of patients, respectively. Increased bronchial responsiveness, detected in 24% of patients, was weakly associated with current respiratory symptoms and low forced vital capacity. Mean exhaled nitric oxide was within predicted range. RBM thickness increased slightly with age, whereas inflammatory cell counts varied from normal to moderate, with intraindividual variation. CONCLUSION: Inflammation of the airways in adolescents with a history of tracheoesophageal fistula, even in the presence of atopy, does not lead, in most cases, to the type of chronic inflammation and RBM changes seen in asthma.

Human rhinovirus in bronchial epithelium of infants with recurrent respiratory symptoms.

BACKGROUND: Human rhinoviruses (HRVs) are a common cause of upper respiratory tract infections. There is growing evidence that HRVs are also important in lower respiratory tract infections and often induce asthma exacerbations. OBJECTIVE: We evaluated the presence of HRV in the lower respiratory tract by obtaining bronchial biopsies from infants with recurrent asthmalike respiratory symptoms. METHODS: A total of 201 steroid-naive infants age 3 to 26 months with recurrent respiratory symptoms for at least 4 weeks within the preceding 2 months were studied for lung function using body plethysmography. Bronchoscopy was performed in 68 children, and bronchial biopsies were available from 59 infants for HRV detection with in situ hybridization. RESULTS: Human rhinovirus was detected in 21 of 47 (45%) specimens. Abnormal lung function (decreased airways conductance) was found in 18 of 21 (86%) HRV(+) infants and in 15 of 26 (58%) HRV(-) infants (P = .037). Occurrence of a respiratory infection in the 6 weeks preceding bronchoscopy correlated with HRV positivity (P = .036). CONCLUSION: Human rhinovirus is frequently found in the lower airways in infants with recurrent respiratory symptoms, and the majority of these HRV(+) infants also showed increased airway resistance. CLINICAL IMPLICATIONS: Human rhinovirus is a common pathogen causing upper and lower respiratory symptoms. Follow-up of these infants will reveal whether the presence of HRV in the bronchial biopsy and abnormal lung function with recurrent respiratory symptoms predicts subsequent asthma.

Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction.

RATIONALE: We hypothesized that the epithelial reticular basement membrane (RBM) thickening and eosinophilic inflammation characteristic of asthma would be present in symptomatic infants with reversible airflow obstruction. METHODS: RBM thickness and numbers of inflammatory cells were determined in ultrathin sections of endobronchial biopsies obtained from 53 infants during clinical bronchoscopy for severe wheeze and/or cough. Group A: 16 infants with a median age of 12 months (range 3.4-26 months), with decreased specific airway conductance (sGaw) and bronchodilator reversibility; Group B: 22 infants with a median age of 12.4 months (5.1-25.9 months), with decreased sGaw but without bronchodilator reversibility; and Group C: 15 infants with a median age of 11.5 months (3.4-24.3 months) with normal sGaw. Additional comparisons were made with the following groups. Group D: 17 children, median age 10.3 years (6-16 years), with difficult asthma; Group E: 10 pediatric control subjects without asthma, median age 10 years (6-16 years); and Group F: nine adult normal, healthy control subjects, median age 27 years (21-42 years). MAIN RESULTS: There were no significant differences in RBM thickness or inflammatory cell number between the infant groups. RBM thickness was similar in the infants and Groups E and F. However, the RBM in all infant groups (Group A: median 4.3 microm [range 2.8-9.2 microm]; Group B: median 4.15 microm [range 2.7-5.8 microm]; Group C: median 3.8 microm [range 2.7-5.5 microm]) was significantly less thick than that in the older children with asthma (Group D: median 8.3 microm [range 5.3-12.7 microm]; p < 0.001). CONCLUSION: RBM thickening and the eosinophilic inflammation characteristic of asthma in older children and adults are not present in symptomatic infants with reversible airflow obstruction, even in the presence of atopy.