Isabelle Honoré

High Prevalence of Azole-Resistant Aspergillus fumigatus in Adults with Cystic Fibrosis Exposed to Itraconazole

ABSTRACT Aspergillus fumigatus is the most frequent fungus found in the sputum of cystic fibrosis (CF) subjects. Itraconazole is prescribed for allergic bronchopulmonary aspergillosis (ABPA) or Aspergillus bronchitis in CF subjects. We hypothesized that A. fumigatus isolates in the sputum of CF subjects with previous exposure to itraconazole was associated with higher prevalence of azole resistance. From June 2010 to April 2011, sputum samples from adult CF subjects at Cochin University Hospital (France) were examined systematically for the detection of A. fumigatus. MICs of A. fumigatus isolates against azoles were screened using Etest, and reduced susceptibility to azoles was confirmed using the CLSI broth microdilution method. A. fumigatus was isolated from the sputum of 131/249 (52.6%) adult CF subjects, and 47/131 (35.9%) subjects had received previous treatment with itraconazole. Reduced A. fumigatus susceptibility to itraconazole (MIC, ≥2 mg/liter) was confirmed in 6/131 (4.6%) subjects. All 6 isolates also had reduced susceptibility to posaconazole (MIC, ≥0.5 mg/liter), and 3/6 isolates had reduced susceptibility to voriconazole (MIC, ≥2 mg/liter). Mutations in the cyp51A gene were detected at positions previously implicated to cause resistance in 5 isolates. Azole-resistant A. fumigatus isolates were found in 5/25 (20%) subjects exposed to itraconazole within the previous 3 years. High rates of azole-resistant A. fumigatus isolates were present in adult CF subjects and were associated with recent itraconazole exposure. Although the clinical implications of these findings will require further studies, the cautious use of itraconazole in adult CF subjects can be recommended.

Nasal airway ion transport is linked to the cystic fibrosis phenotype in adult patients.

Background: This study was conducted to determine whether the major nasal airway ion transport abnormalities in cystic fibrosis (that is, defective cAMP regulated chloride secretion and basal sodium hyperabsorption) are related to the clinical expression of cystic fibrosis and/or to the genotype. Methods: Nasal potential difference was measured in 79 adult patients with cystic fibrosis for whom clinical status, respiratory function, and CFTR genotype were determined. Results: In univariate and multivariate analysis, patients with pancreatic insufficiency were more likely to have low responses to low chloride (odds ratio (OR) 8.6 (95% CI 1.3 to 58.5), pu200a=u200a0.03) and isoproterenol (OR 11.2 (95% CI 1.3 to 93.9), pu200a=u200a0.03) solutions. Similarly, in univariate and multivariate analysis, patients with poor respiratory function (forced expiratory volume in 1 second <50% of predicted value) were more likely to have an enhanced response to amiloride solution (OR 3.7 (95% CI 1.3 to 11.0), pu200a=u200a0.02). However, there was no significant relationship between nasal potential difference and the severity of the genotype. Conclusions: Nasal epithelial ion transport in cystic fibrosis is linked to the clinical expression of the disease. The pancreatic status appears to be mostly related to the defect in epithelial chloride secretion whereas the respiratory status is mostly related to abnormal sodium transport and the regulatory function of the CFTR protein.

Reduced risk of nontuberculous mycobacteria in cystic fibrosis adults receiving long-term azithromycin

BACKGROUNDnAzithromycin reduces exacerbations in cystic fibrosis (CF) patients. Our aim was to investigate its association with nontuberculous mycobacteria isolation and macrolide susceptibility.nnnMETHODSnFrom 2006 to 2010, all adult CF subjects at Cochin Hospital (Paris, France) harboring at least one positive NTM isolate were identified (Cases). In a nested case-control study, each Case was individually matched for age and gender with up to 4 CF adults with no NTM isolate (Controls). Clinical data at the time of first NTM isolate (index date) in Cases were compared with those of Controls using multivariate conditional regression analysis.nnnRESULTSnCF subjects with positive NTM isolates (Cases, n=41) were matched to 155 Controls. Among Cases, 48.7% had isolates from Mycobacterium avium complex and 58.5% from Mycobacterium abscessus complex, and 31 Cases fulfilled the 2007 American Thoracic Society criteria for NTM infection (ATS+ Cases). Cases and ATS+ Cases were more likely to have low body mass index and colonization with Aspergillus fumigatus. Azithromycin was associated with a two-fold reduction in NTM isolates. Only one M. avium complex isolate had acquired macrolide resistance.nnnCONCLUSIONnThese data suggest that azithromycin is a primary prophylaxis for NTM infection in CF adults.

Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease

OBJECTIVEnTo investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting.nnnMETHODSnA multicentre observational study investigated adverse events, treatment discontinuation, FEV1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV1 below 40% predicted.nnnRESULTSnRespiratory adverse events (AEs) were reported by 27 of 53 subjects (51%) and 16 (30%) discontinued treatment. The mean absolute change in FEV1 was +2.06% after one month of treatment (P=0.086) and +3.19% after 3 months (P=0.009). BMI was unchanged.nnnCONCLUSIONSnTreatment with lumacaftor/ivacaftor in patients with CF and severe lung disease was discontinued more frequently than reported in clinical trials, due to respiratory AEs. Nevertheless, the patients who continued treatment had an increase in lung function comparable to what was observed in pivotal trials.

Prognostic value of six minute walk test in cystic fibrosis adults

BACKGROUNDnThe 6 min walk test (6MWT) provides prognostic information in various respiratory diseases, but limited data exist in cystic fibrosis (CF) adults.nnnMETHODSnConsecutive CF adults who performed 6MWT at Cochin Hospital (Paris, France) over 12 years were analyzed. The cut-off 6 min walking distance (6MWD) value that best predicted a combined endpoint (death without transplant or lung transplant) was established using a receiver operating curve. Determinants of low 6MWD or of desaturation (SpO2 ≤ 90%) during 6MWT were examined using multivariate logistic regressions. Prognostic value of these variables was assessed using Kaplan-Meier and Cox analyses.nnnRESULTSn6MWT was performed in 286 CF adults (median: age, 28 yr; FEV1, 45% predicted) of whom 14% (n = 40) had lung transplant and 6% (n = 18) died without transplant. 6MWD correlated with FEV1% predicted (r = 0.43; P < 0.001), but markedly differed in subjects within the same range of FEV1. A 6MWD ≤ 475 m predicted death or transplant and was mostly found in patients with FEV1 ≤ 60% predicted. Desaturation during the 6MWT occurred in 29% of patients, exclusively in subjects with FEV1 ≤ 60% predicted. Both 6MWD ≤ 475 m and desaturation during the 6MWT were independent predictors of death or transplant.nnnCONCLUSIONnThe 6MWT provides prognostic information in CF adults, especially in subjects with FEV1 ≤ 60% predicted.

Clinical characteristics, functional respiratory decline and follow-up in adult patients with primary ciliary dyskinesia

Introduction Primary ciliary dyskinesia (PCD) is a genetic disease characterised by abnormalities in ciliary function, responsible for chronic pulmonary and sinonasal diseases. Adult clinical features and outcome are poorly described. Objectives To assess the clinical characteristics and disease progression in adults with PCD. Methods Bicentric retrospective study, focusing on adults (≥18u2005years) with an asserted diagnosis of PCD based on the presence of bronchiectasis with typical ultrastructural defect of cilia and/or situs inversus (SI). Clinical symptoms, respiratory function, extent of bronchiectasis, microbiology and molecular analysis were assessed. Results are expressed as median (25th; 75th centile). Results 78 patients were included with a median follow-up of 8.1u2005years. 91% of patients had respiratory symptoms and 95% had chronic rhinosinusitis. Half of ultrastructural defects concerned dynein arms. Respiratory function was significantly lower in women (FEV1=60% predicted (50; 76), vs 77% (62; 95), p=0.009) and in patients with chronic airway Pseudomonas aeruginosa (PA, n=21) infection (FEV1=60% (48; 71) vs 75% (55; 89), p=0.04). FEV1 was associated with gender (regression coefficient for men =13.8, p=0.009), chest CT score (r=−0.42, p<0.001) but not with age at diagnosis, SI or body mass index. FEV1 decline was −13.4u2005mL/year (−42.8; +11.9) and was greater in women (−29.3u2005mL/year, (−59.7; −11.9), vs –2.0u2005mL/year (−26.9; +25.4), p=0.002). Three patients had severe respiratory failure. Conclusions Alteration of respiratory function in adults with PCD is heterogeneous and usually moderate but appears more severe in women and in patients with chronic PA infection. Only 4% of patients develop chronic respiratory failure.

Employment and work disability in adults with cystic fibrosis

BACKGROUNDnAs a result of prolonged survival, more patients with cystic fibrosis (CF) participate in the labour force. The aim of this study was to evaluate their education, occupation levels and risk factors for work disability.nnnMETHODn207 patients answered a self-administered questionnaire about their educational level and work status. Independently, medical records were reviewed for illness severity indicators.nnnRESULTSn39 patients (19%) were students, 117 (57%) were in the labour force, 13 (6%) were seeking employment and 38 (18%) were inactive. CF patients had a higher educational level and were more likely to hold skilled jobs and to work part time than the general population. FEV1 and educational level were the strongest predictive factors of disability.nnnCONCLUSIONnMany CF patients have access to professional life. Their higher educational levels improve the chances of attaining employment, which highlights the need for career counselling. Working part time helps to maintain employment despite declining health.

Infertility in an adult cohort with primary ciliary dyskinesia: phenotype–gene association

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder (prevalence 1:10u200a000 to 1:40u200a000 births) characterised by impaired mucociliary clearance because of abnormal motile ciliary function [1, 2]. Five main ultrastructural PCD phenotypes have been described. Most result from a lack of dynein arms (DAs): no outer and inner DAs (2DAs), outer DAs alone (ODA) or inner DAs with microtubular disorganisation (IDA/MTD); or defects yielding an abnormal central complex (CC). Some patients with genetically confirmed PCD have apparently normal ciliary structure on electron microscopy (nEM). More than 30 genes encoding proteins involved in the structure or assembly of the axoneme, the ciliary internal cytoskeleton, are implicated in PCD [3]; their analysis enables identification of bi-allelic disease-causing mutations in 50–75% of patients. Approximately half of PCD cases are associated with situs inversus, thereby defining Kartageners syndrome. Moreover, because motile cilia and sperm flagella share common axonemal structures, most PCD-affected males are thought to be infertile [4]. According to the literature, male infertility is caused by severe or total asthenozoospermia and is currently treated by recourse to in vitro fertilisation or intracytoplasmic sperm injection [5, 6]. However, spontaneous fatherhood of PCD patients has been reported. Infertility, observed in 75% of male and 61% of female PCD patients, is dependent on ultrastructural and gene defects http://ow.ly/P4K030fPnPp

Complications of peripherally inserted central catheters in adults with cystic fibrosis or bronchiectasis.

Background Peripherally inserted central catheters (PICCs) are increasingly used in patients with cystic fibrosis (CF) or with non-CF bronchiectasis, but little data exist on catheter-related complications in this setting. Methods Prospective follow-up of consecutive PICCs inserted for intravenous (IV) antibiotics in adults with CF or with non-CF bronchiectasis at Cochin Hospital (Paris, France). Results Between March 2009 and December 2011, 182 PICCs were prescribed in 117 adults (67 CF and 50 non-CF patients). Ultrasound-guided placement of catheter was successful in 174/182 (95.6%) procedures; no insertion complication occurred. The mean ± SD catheter dwell time was 15 ± 9 days. No catheter-associated bloodstream infection occurred; main complications were symptomatic upper limb deep vein thrombosis (2%), catheter obstruction (18%) and persistent pain after catheter insertion (18%). Patients satisfaction was high and PICC could be used to perform antibiotic courses in most patients. Conclusions PICCs were generally safe for performing IV antibiotic courses in patients with CF or non-CF bronchiectasis, but prolonged pain and/or catheter obstruction occurred in approximately 20% of cases.

A prospective analysis of unplanned patient-initiated contacts in an adult cystic fibrosis centre

BACKGROUNDnTimely response should be provided when patients contact the cystic fibrosis (CF) centre in between scheduled visits. Little data exist on unplanned patient-initiated contacts in CF adults.nnnMETHODSnA two-stage prospective study was undertaken from 1 January to 31 December 2015 at Cochin Hospital, Paris (France). The first stage included all adults (≥18u202fyears) who initiated unplanned contacts to the CF centre over four months. Four physicians and three nurses systematically recorded unplanned patient-initiated contacts. The data was analysed to determine why and how patients contacted the CF centre and time spent responding to their request(s). The second stage (one physician, three nurses) lasted twelve months and explored whether high contact frequency was associated with disease severity, using multivariate logistic regression.nnnRESULTSnIn the first stage, 259 of 410 patients (63%) initiated at least one unplanned contact, corresponding to 1067 contacts over 4u202fmonths. Patients favoured email with physicians (61% of contacts) and telephone with nurses (87% of contacts). Total time spent by the 7 caregivers on providing responses was 8u202fh/work week. Reasons for contacting the CF centre varied greatly, but <20% of contacts were directly related to symptom management. In the second stage, 180 of 212 patients (85%) initiated 1876 contacts over 12u202fmonths. Factors associated with ≥5u202fcontacts/year were female sex, FEV1u202f≤u202f30% predicted, ≥5 physician visits/year, andu202f≥u202f1 hospital admission/year.nnnCONCLUSIONSnAnswering unplanned patient-initiated contacts represented a significant workload for CF caregivers. Increased disease severity was associated with high contact frequency.