Lung Lavage Granulocyte Patterns and Clinical Phenotypes in Children with Severe, Therapy-Resistant Asthma.

BACKGROUND: Children with severe asthma have frequent exacerbations despite guidelines-based treatment with high-dose corticosteroids. The importance of refractory lung inflammation and infectious species as factors contributing to poorly controlled asthma in children is poorly understood. OBJECTIVE: To identify prevalent granulocyte patterns and potential pathogens as targets for revised treatment, 126 children with severe asthma underwent clinically indicated bronchoscopy. METHODS: Diagnostic tests included bronchoalveolar lavage (BAL) for cell count and differential, bacterial and viral studies, spirometry, and measurements of blood eosinophils, total IgE, and allergen-specific IgE. Outcomes were compared among 4 BAL granulocyte patterns. RESULTS: Pauci-granulocytic BAL was the most prevalent granulocyte category (52%), and children with pauci-granulocytic BAL had less postbronchodilator airflow limitation, less blood eosinophilia, and less detection of BAL enterovirus compared with children with mixed granulocytic BAL. Children with isolated neutrophilia BAL were differentiated by less blood eosinophilia than those with mixed granulocytic BAL, but greater prevalence of potential bacterial pathogens compared with those with pauci-granulocytic BAL. Children with isolated eosinophilia BAL had features similar to those with mixed granulocytic BAL. Children with mixed granulocytic BAL took more maintenance prednisone, and had greater blood eosinophilia and allergen sensitization compared with those with pauci-granulocytic BAL. CONCLUSIONS: In children with severe, therapy-resistant asthma, BAL granulocyte patterns and infectious species are associated with novel phenotypic features that can inform pathway-specific revisions in treatment. In 32% of children evaluated, BAL revealed corticosteroid-refractory eosinophilic infiltration amenable to anti-TH2 biological therapies, and in 12%, a treatable bacterial pathogen.

Hyperpolarized helium-3 magnetic resonance lung imaging of non-sedated infants and young children: a proof-of-concept study.

PURPOSE: To develop and evaluate a protocol for hyperpolarized helium-3 (HHe) ventilation magnetic resonance imaging (MRI) of the lungs of non-sedated infants and children. MATERIALS AND METHODS: HHe ventilation MRI was performed on seven children ≤4years old. Contiguous 2D-spiral helium-3 images were acquired sequentially with a scan time of ≤0.2s/slice. RESULTS: Motion-artifact-free, high signal-to-noise ratio (SNR) images of lung ventilation were obtained. Gas was homogeneously distributed in healthy individuals; focal ventilation defects were found in patients with respiratory diseases. CONCLUSION: HHe ventilation MRI can aid assessment of pediatric lung disease even at a young age.

Hyperpolarized Helium-3 Diffusion-weighted Magnetic Resonance Imaging Detects Abnormalities of Lung Structure in Children With Bronchopulmonary Dysplasia.

PURPOSE: The aim of the study was to determine whether hyperpolarized He diffusion-weighted magnetic resonance imaging detects abnormalities in the lungs in children with bronchopulmonary dysplasia (BPD) as compared with age-matched normal children. MATERIALS AND METHODS: All experiments were compliant with Health Insurance Portability and Accountability Act (HIPAA) and performed with Food and Drug Administration approval under an IND application. The protocol was approved by our Institutional Review Board, and written informed consent was obtained. Hyperpolarized He diffusion-weighted magnetic resonance imaging was performed in 16 subjects with a history of preterm birth complicated by BPD (age range, 6.8 to 13.5 y; mean, 9.0 y) and in 29 healthy term-birth subjects (age range, 4.5-14.7 y; mean, 9.2 y) using a gradient-echo sequence with bipolar diffusion gradients and with measurements at 2 b values (0 and 1.6 s/cm). Age-related comparison of the whole-lung mean apparent diffusion coefficient (ADC), 90th percentile ADC, and percentage of whole-lung volume with ADC>0.2 cm/s between the 2 groups was examined using ordinary least-squares multiple regression. RESULTS: The mean ADC was significantly greater in subjects with BPD (0.187 vs. 0.152 cm/s, P<0.001). The 90th percentile ADC and mean percentage lung volume with ADC>0.2 cm/s were also higher in the BPD group (0.258 vs. 0.215 cm/s, 30.3% vs. 11.9%, P<0.001 for both). The body surface area-adjusted ventilated lung volume was similar in the 2 groups (1.93 vs. 1.91 L, P=0.90). CONCLUSIONS: Children with BPD had higher ADCs and the same lung volumes when compared with age-matched healthy subjects, suggesting that children with BPD have enlarged alveoli that are reduced in number.

Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis.

OBJECTIVE: To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection. DESIGN: Randomized controlled trial. SETTING: Multicenter trial in the United States. PARTICIPANTS: Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection. INTERVENTIONS: Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures. MAIN OUTCOME MEASURES: The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures. RESULTS: The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio, 0.95; 95% confidence interval [CI], 0.54-1.66) or ciprofloxacin and placebo (hazard ratio, 1.45; 95% CI, 0.82-2.54). The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups. CONCLUSIONS: No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00097773.

Hyperpolarized HHe 3 MRI of the lung in cystic fibrosis: assessment at baseline and after bronchodilator and airway clearance treatment.

RATIONALE AND OBJECTIVES: The purpose of this study is to determine hyperpolarized helium 3 (HHe) magnetic resonance (MR) findings of the lung in patients with cystic fibrosis (CF) compared with healthy subjects and determine whether HHe MR can detect changes after bronchodilator therapy or mechanical airway mucus clearance treatment. MATERIALS AND METHODS: Thirty-one subjects, 16 healthy volunteers and 15 patients with CF, underwent HHe lung ventilation MR imaging and spirometry at baseline. Eight patients with CF then were treated with nebulized albuterol, after which a follow-up HHe MR scan was obtained. Subsequently, recombinant human deoxyribonuclease (DNase) treatment and chest physical therapy were performed in these eight subjects, followed by a third HHe MR scan. For each MR study, the number of ventilation defects was scored by a human reader. RESULTS: Patients with CF had significantly more HHe MR ventilation defects per image than healthy subjects (mean, 8.2 defects in patients with CF vs 1.6 defects in healthy subjects; P < .05). Even the four subjects with CF with a normal forced expiratory volume in 1 second had significantly more ventilation defects than healthy subjects (mean, 6.5 defects in these patients with CF; P = .0002). After treatment with albuterol, there was a small, but statistically significant, decrease in number of ventilation defects (mean, 9.6-8.0 defects; P = .025). After DNase and chest physical therapy, there was a trend toward increasing ventilation defects (mean, 8.3 defects; P = .096), but with a residual net improvement relative to baseline. CONCLUSION: In patients with CF, HHe MR ventilation defects correlate with spirometry, change with treatment, and are elevated in number in patients with CF with normal spirometry results. Thus, HHe MR appears to possess many of the characteristics required of a biomarker for pulmonary CF and may be useful in the evaluation of CF pulmonary disease severity or progression.