Rationale: Targeted lung denervation (TLD) is a bronchoscopic radiofrequency ablation therapy for chronic obstructive pulmonary disease (COPD), which durably disrupts parasympathetic pulmonary nerves to decrease airway resistance and mucus hypersecretion.Objectives: To determine the safety and impact of TLD on respiratory adverse events.Methods: We conducted a multicenter, randomized, sham bronchoscopy–controlled, double-blind trial in patients with symptomatic (modified Medical Research Council dyspnea scale score, ≥2; or COPD Assessment Test score, ≥10) COPD (FEV1, 30–60% predicted). The primary endpoint was the rate of respiratory adverse events between 3 and 6.5 months after randomization (defined as COPD exacerbation, tachypnea, wheezing, worsening bronchitis, worsening dyspnea, influenza, pneumonia, other respiratory infections, respiratory failure, or airway effects requiring therapeutic intervention). Blinding was maintained through 12.5 months.Measurements and Main Results: Eighty-two patients (50% female; mean ± SD: age, 63.7 ± 6.8 yr; FEV1, 41.6 ± 7.3% predicted; modified Medical Research Council dyspnea scale score, 2.2 ± 0.7; COPD Assessment Test score, 18.4 ± 6.1) were randomized 1:1. During the predefined 3- to 6.5-month window, patients in the TLD group experienced significantly fewer respiratory adverse events than those in the sham group (32% vs. 71%, P = 0.008; odds ratio, 0.19; 95% confidence interval, 0.0750–0.4923, P = 0.0006). Between 0 and 12.5 months, these findings were not different (83% vs. 90%; P = 0.52). The risk of COPD exacerbation requiring hospitalization in the 0- to 12.5-month window was significantly lower in the TLD group than in the sham group (hazard ratio, 0.35; 95% confidence interval, 0.13–0.99; P = 0.039). There was no statistical difference in the time to first moderate or severe COPD exacerbation, patient-reported symptoms, or other physiologic measures over the 12.5 months of follow-up.Conclusions: Patients with symptomatic COPD treated with TLD combined with optimal pharmacotherapy had fewer study-defined respiratory adverse events, including hospitalizations for COPD exacerbation.Clinical trial registered with www.clinicaltrials.gov (NCT02058459).

Trichosporon mycotoxinivorans is a novel pathogen recently found in cystic fibrosis patients. We report the first case of a disseminated fatal infection with T. mycotoxinivorans associated with invasive Aspergillus fumigatus and Scedosporium apiospermum infection after lung and liver transplantation in a cystic fibrosis patient. CASE REPORTA 35-year-old man with cystic fibrosis (CF) was admitted for rapid respiratory deterioration and high-level oxygen requirements with respiratory acidosis. He was a nonsmoker and was still working actively as a farmer until a few days before his admission. His past medical history included sinonasal polyposis and diabetes mellitus. He was in good general condition despite a severe obstructive pulmonary disease that had been stable over the previous 5 years, with a forced expiratory volume in the first second at 20% of that predicted. He also had a 5-year bronchial colonization with Pseudomonas aeruginosa and Aspergillus fumigatus.Because of respiratory deterioration despite noninvasive ventilation and antibiotics, an extracorporeal membrane oxygenation, inotropic support, and hemodialysis were started and an emergency double lung transplantation (LT) was performed. The immunosuppression included basiliximab and high-dose methylprednisolone for induction, a standard dose of tacrolimus, mycofenolate mofetil, and methylprednisolone for maintenance. Due to immediate postoperative acute liver failure, an emergency liver transplantation was performed on day 2 post-LT. Another dose of basiliximab and high dose of methylprednisolone were given. Antifungal prophylaxis with caspofungin (70 mg) started on the day of LT was discontinued the next day due to liver dysfunction. Amyloidosis AA (deposition of amyloid protein A) was diagnosed on explanted liver. The patient's condition remained stable, although invasive ventilation and hemodialysis were maintained. Routine bronchoalveolar lavage specimens at days 1 and 6 post-LT were positive for P. aeruginosa (treated with ceftazidime, ciprofloxacin, and meropenem) and A. fumigatus. Caspofungin was resumed (50 mg daily) at day 6 post-LT because an Aspergillus galactomannan detection test (Platelia Aspergillus antigen; Bio-Rad) became positive in serum.On day 9 post-LT, nonfebrile sleepiness was noted. Within 4 days, the neurologic condition worsened, with tetraparesis and coma. Cerebral magnetic resonance imaging (MRI) showed multiple foci of cortical, subcortical, and periventricular hyperinten-

BackgroundHomeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling.ObjectiveThis study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation.MethodsMicrobiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture.ResultsWe identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition.ConclusionsHost-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.

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