Pulmonary fibrosis (PF) is an uncommon manifestation observed in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). While patients with PF associated with AAV seem to have a worse prognosis, these patients have been described only in case reports or small retrospective case series. In this retrospective multicenter study, we report the main features and long-term outcomes of patients with PF associated with AAV, fulfilling the American College of Rheumatology criteria and/or Chapel Hill definitions. Forty-nine patients (30 men [61%]; median age at diagnosis of AAV, 68 [interquartile range, 58–73] years) with PF associated with AAV were identified. Forty (81.6%) patients had MPA and 9 (18.4%) had granulomatosis with polyangiitis. The diagnosis of PF preceded the onset of vasculitis in 22 (45%) patients. Usual interstitial pneumonia was the main radiologic pattern (n = 18, 43%). ANCA were mostly of antimyeloperoxidase specificity (88%). All patients were treated with glucocorticoids as induction therapy, combined with cyclophosphamide (CYC) (n = 36, 73.5%) or rituximab (RTX) (n = 1, 2%). Factors associated with mortality included occurrence of chronic respiratory insufficiency (hazard ratio [HR], 7.44; 95% confidence interval [CI], 1.6–34.5; p = 0.003), induction therapy with glucocorticoids alone (HR, 2.94; CI, 1.05–8.33; p = 0.04), and initial weigh loss (HR, 2.83; CI, 1.05–7.65; p = 0.041). The 3-year survival rate in patients treated with glucocorticoids alone or combined with an immunosuppressant (CYC or RTX) as induction therapy was 64% (95% CI, 41–99) and 94% (95% CI, 86–100), respectively (p = 0.03). After a median follow-up of 48 months [interquartile range, 14–88 mo], 18 (37%) patients died, including 11 related to respiratory insufficiency. PF is a rare manifestation of AAV with a very poor prognosis. Induction therapy with CYC might improve the outcome.

Given that in vivo telomere length reflects cellular turnover and exposure to oxidative and inflammatory damage, our data support accelerated aging in COPD.

Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive respiratory disorder resulting from defects of motile cilia. Various axonemal ultrastructural phenotypes have been observed, including one with so-called central-complex (CC) defects, whose molecular basis remains unexplained in most cases. To identify genes involved in this phenotype, whose diagnosis can be particularly difficult to establish, we combined homozygosity mapping and whole-exome sequencing in a consanguineous individual with CC defects. This identified a nonsense mutation in RSPH1, a gene whose ortholog in Chlamydomonas reinhardtii encodes a radial-spoke (RS)-head protein and is mainly expressed in respiratory and testis cells. Subsequent analyses of RSPH1 identified biallelic mutations in 10 of 48 independent families affected by CC defects. These mutations include splicing defects, as demonstrated by the study of RSPH1 transcripts obtained from airway cells of affected individuals. Wild-type RSPH1 localizes within cilia of airway cells, but we were unable to detect it in an individual with RSPH1 loss-of-function mutations. High-speed-videomicroscopy analyses revealed the coexistence of different ciliary beating patterns-cilia with a normal beat frequency but abnormal motion alongside immotile cilia or cilia with a slowed beat frequency-in each individual. This study shows that this gene is mutated in 20.8% of individuals with CC defects, whose diagnosis could now be improved by molecular screening. RSPH1 mutations thus appear as a major etiology for this PCD phenotype, which in fact includes RS defects, thereby unveiling the importance of RSPH1 in the proper building of CCs and RSs in humans.

Using clinical predictors, we evaluated clinical case definitions of influenza during the 1995-1996 outbreak in France. Thirty-five general practitioners collected virological specimens and clinical data. Predictors of influenza virus infection were selected with logistic regression models. The results varied with the influenza virus subtype: temperature of >38.2 degrees C, stiffness or myalgia, rhinorrhea, and cough were predictive of influenza A/H3N2, whereas fatigue, lacrimation or conjunctival injection, and the absence of stiffness or myalgia were predictive of influenza A/H1N1. On the basis of this analysis and data from the literature, 12 clinical case definitions were evaluated for their abilities to diagnose influenza virus infection. They were associated with positive predictive values of 27% to 40% and negative predictive values of 80% to 91%. We conclude that focused studies evaluating clinical case definitions of influenza with use of subsets of patients should accompany population-based disease surveillance for optimal estimates of the disease burden associated with influenza epidemics.

Background-The serotonin transporter (5-HTT) is involved in the pulmonary artery smooth muscle hyperplasia that leads to pulmonary hypertension (PH). Because hypoxia and 5-HTT gene polymorphism control 5-HTT expression, we examined 5-HTT gene polymorphism and PH in hypoxemic patients with advanced chronic obstructive pulmonary disease (COPD). Methods and Results-In 103 patients with COPD recruited in France (nϭ67) and the UK (nϭ36), we determined 5-HTT gene polymorphism and pulmonary artery pressure (PAP) measured during right heart catheterization (France) or Doppler echocardiography (UK). Ninety-eight subjects from the 2 countries served as control subjects. The distribution of 5-HTT gene polymorphism did not differ between patients and control subjects. In patients carrying the LL genotype, which is associated with higher levels of 5-HTT expression in pulmonary artery smooth muscle cells than the LS and SS genotypes, PH was more severe than in LS or SS patients. Mean PAP values in patients from France with the LL, LS, and SS genotypes were 34Ϯ3, 23Ϯ1, and 22Ϯ2 mm Hg (meanϮSEM), respectively (PϽ0.01). Corresponding systolic PAP values in the UK were 40Ϯ3, 28Ϯ3, and 24Ϯ3 mm Hg, respectively (PϽ0.01). Compared with control subjects, platelet 5-HTT protein was increased in COPD patients in proportion to the hypoxemia level, and strong 5-HTT immunostaining was observed in remodeled pulmonary arteries from COPD patients. Conclusions-5-HTT gene polymorphism appears to determine the severity of PH in hypoxemic patients with COPD.Because PH is an important prognostic factor in this disease, recognition of patients at risk for PH should be helpful in

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Fiberoptic bronchoscopy (FOB) may worsen oxygenation and clinical status in severely hypoxemic patients. We conducted a prospective, randomized double-blind trial to compare the delivery of continuous positive airway pressure (CPAP) as a tool for maintaining oxygenation during FOB, to the delivery of oxygen only. Thirty consecutive patients who needed FOB for diagnostic purposes were enrolled. Their arterial oxygen pressure (Pa(O(2))) to inspired oxygen fraction (FI(O(2))) ratio was below 300 mm Hg. CPAP was generated by a simple new device open to the atmosphere. During FOB and the 30 min thereafter, pulse oximetry values (Sp(O(2))) were significantly higher in the CPAP than the Oxygen group (95.7 +/- 1.9% versus 92.6 +/- 3.1, p = 0.02). The lowest Sp(O(2)) values were observed in the Oxygen group (93.5 +/- 2.4% versus 88.6 +/- 3.4, p = 0.002). Arterial blood gases 15 min after FOB showed that Pa(O(2)) had increased in the CPAP group and decreased in the Oxygen group (DeltaPa(O(2)) = +10.5% +/- 16.9 versus -15% +/- 16.6, p = 0.01). Five patients in the Oxygen group, but none in the CPAP group, developed respiratory failure in the 6 h after FOB and required ventilatory assistance (p = 0.03). We conclude that in hypoxemic patients, the use of a new CPAP device during FOB allowed minimal alterations in gas exchange and prevented subsequent respiratory failure.

Vascular endothelial growth factor (VEGF) is a potent endothelial cell growth and permeability factor highly expressed in rodent alveolar epithelium after injury and repair. To investigate VEGF synthesis in human lung epithelial cells, we examined VEGF expression by cultured cells under basal conditions and after cytokine treatment or oxidative stress. Basal VEGF expression was detected in transformed human epithelial cell lines (A549 and 1HAEo-) and in primary human bronchial epithelial cells with RT-PCR, Western blot, and immunocytochemistry. Among the cytokines tested, only transforming growth factor-beta1 increased the levels of excreted VEGF(165) as measured by ELISA. Under hypoxia (0% O(2) for 24 h), the VEGF(165) level increased fivefold, and this effect was O(2) concentration dependent. VEGF concentrations in the medium of all the cell types studied reached values similar to those found in bronchoalveolar lavage fluids from normal patients. Endothelial cells (human umbilical vein endothelial cells) exposed to conditioned medium from primary bronchial epithelial cell cultures showed an increased growth rate, which was inhibited in the presence of a specific neutralizing antibody to VEGF. These results suggest that lung epithelial cells participate in the endothelial repair and angiogenesis that follow lung injury through the synthesis of VEGF.