COPD patients with chronic bronchitis and higher sputum eosinophil counts show increased type-2 and PDE4 gene expression in sputum.

Chronic obstructive pulmonary disease (COPD) patients with higher eosinophil counts are associated with increased clinical response to phosphodiesterase-4-inhibitors (PDE4i). However, the underlying inflammatory mechanisms associated with this increased response is not yet elucidated. This post hoc analysis focused on sputum gene expression in patients with chronic bronchitis who underwent 32-day treatment with two doses of the inhaled PDE4i CHF6001 (tanimilast) or placebo on top of triple therapy. Biological characterization and treatment effects were assessed between patients with different sputum eosinophil levels (eosinophilhigh  ≥ 3%; eosinophillow  < 3%) at baseline (primary samples) or at the end of the treatment of the placebo arm (validation samples). Forty-one genes were differentially expressed in primary samples (p-adjusted for false discovery rate < 0.05); all up-regulated in eosinophilhigh patients and functionally enriched for type-2 and PDE4 inflammatory processes. Eleven out of nineteen genes having immune system biological processes annotations including IL5RA, ALOX15, IL1RL1, CLC, GATA1 and PDE4D were replicated using validation samples. The expression of a number of these inflammatory mediators was reduced by tanimilast treatment, with greater effects observed in eosinophilhigh patients. These findings suggest that type-2 and PDE4 overexpression in COPD patients with higher sputum eosinophil counts contribute to the differential clinical response to PDE4i observed in previous clinical trials.

Discrepant nasal and bronchial nitric oxide kinetics during early and late phase allergic reactions.

Late allergic reactions (LAR) following allergen challenge occur in different compartments. We studied the kinetics of nasal and bronchial nitric oxide (NO) in mild asthmatics after allergen challenge. Twelve males with intermittent asthma (28 yr, FEV1 97% of predicted, PC20methacholine <8 mg/ml) and known LAR after bronchial allergen challenge underwent nasal and bronchial allergen provocation using the same allergen separated by a washout of 3 weeks. Nasal and bronchial NO were measured before challenge, during early (EAR) and late phase reactions, and 24 h after allergen. The mean (sem) maximum fall of FEV1 at EAR was 31.9+/-3.2% (P=0.001), and 17.6+/-2.2% (P=0.004) during LAR. All patients developed nasal EAR (max. fall in nasal rhinomanometric flow 64.8+/-7.6% of baseline) after nasal challenge, and 10 patients demonstrated nasal LAR with a fall in nasal flow of 65.9+/-6.6% (both P=0.002, respectively). During EAR, there was stronger reduction of nasal (-19.2+/-6.2%,P=0.039) than bronchial NO (-6.9+/-5.2% of baseline, P=ns). In contrast, bronchial NO also tended to decrease during bronchial LAR (-8.8+/-6.8%,P=ns), while nasal NO slightly increased non-significantly (+17+/-10.8%, P=ns). After 24 h, bronchial NO was significantly elevated (+78.1+/-40.1%, P=0.039), whereas nasal NO was unchanged (+6.1+/-15.1%, P=ns). The intraindividual difference between bronchial and nasal changes of NO during LAR, but not EAR or after 24 h, was significant (lung vs. nose: -35.6+/-14.1% relative difference, P=0.039). Despite similar functional responses in nose and bronchi, nasal NO kinetics following allergen challenge differ from bronchial NO. The concise mechanisms accounting for this discrepancy warrant further investigations.