R. Kanaan

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.

Characteristics and consequences of airway colonization by filamentous fungi in 201 adult patients with cystic fibrosis in France

A total of 657 sputum samples from 201 cystic fibrosis adult patients were collected during a 24-month period (2005-2006). We retrospectively analyzed the fungal colonization of the respiratory tract of these individuals by linking medical records and microbiological data. Filamentous fungi were isolated from specimens of 65.6% of the patients, with Aspergillus fumigatus being the predominant species recovered as it was found in specimens of 56.7% of the patients. We observed no difference for gender, pancreatic status and cirrhosis in patients with or without A. fumigatus colonization. We found a higher percentage of recovery of Pseudomonas aeruginosa, Stenotrophomonas maltophilia and nontuberculous mycobacteria in patients with A. fumigatus colonization. During the follow-up period of the study, 8.9% of the patients were diagnosed with allergic bronchopulmonary aspergillosis (ABPA). By a multivariate analysis we demonstrated that Scedosporium apiospermum was significantly associated with ABPA (Odds ratio = 13 [2-80]) as opposed to A. fumigatus (Odds ratio = 1.58 [0.49-5.05]).

Liver disease in adult patients with cystic fibrosis: A frequent and independent prognostic factor associated with death or lung transplantation

BACKGROUND & AIMS Increased life expectancy in patients with cystic fibrosis (CF) allows better knowledge of non-pulmonary complications like liver disease (CFLD). However, few data have been published in large adult cohorts. The aim of this study was to estimate the prevalence and the prognosis of CFLD in adult CF patients. METHODS A retrospective analysis of a monocentric cohort of adult CF patients prospectively followed, at least every year, was performed. CFLD was diagnosed using published composite criteria. If cirrhosis was suspected, upper digestive endoscopy was realized to assess the presence of portal hypertension. RESULTS A cohort of 285 adult CF patients was followed during 4.8 ± 3.6 years. Among them, 90 had CFLD at the beginning of follow-up and 23 a suspicion of cirrhosis. Factors independently associated with liver disease at baseline were history of meconium ileus, pancreatic insufficiency, chronic colonization with Burkholderia cepacia and the number of IV antibiotic courses per year. Nine patients developed liver decompensation during follow-up, all with a suspicion of cirrhosis at baseline. Six patients underwent liver transplantation alone and three patients combined liver and lung transplantation. Factors independently associated with death or lung transplantation at baseline were liver disease, BMI, forced expiratory volume in 1 second and number of IV antibiotic courses per year. CONCLUSIONS CFLD was present at baseline in one third of adult patients with CF with a marked risk of liver decompensation during follow-up. Moreover, CFLD at baseline appears as an independent factor associated with death or lung transplantation.

Causes of death in French cystic fibrosis patients: The need for improvement in transplantation referral strategies!

BACKGROUND Little data exist on causes of death in cystic fibrosis (CF) patients in the era of lung transplantation. METHODS Deaths in CF patients in France (2007-2010) were identified using the French CF Registry and causes of deaths were determined based on medical files by a mortality adjudication committee. RESULTS Of 256 deaths, half occurred after lung transplantation and were related to early or late complications of transplantation, whereas half occurred in patients who did not receive lung transplantation and were primarily related to respiratory failure or massive hemoptysis. Among patients who did not receive lung transplantation, only 19% died while waiting on a lung transplantation list. Lack of listing for lung transplantation was primarily related to late, or to lack of transplantation referral, rather than to contraindication to transplantation. CONCLUSIONS These data suggest that improvement in transplantation referral strategies may result in transplantation-related survival benefits.

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

BACKGROUND Azithromycin reduces exacerbations in cystic fibrosis (CF) patients. Our aim was to investigate its association with nontuberculous mycobacteria isolation and macrolide susceptibility. METHODS From 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. RESULTS CF 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. CONCLUSION These 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

OBJECTIVE To 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. METHODS A 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. RESULTS Respiratory 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. CONCLUSIONS Treatment 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

BACKGROUND The 6 min walk test (6MWT) provides prognostic information in various respiratory diseases, but limited data exist in cystic fibrosis (CF) adults. METHODS Consecutive 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. RESULTS 6MWT 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. CONCLUSION The 6MWT provides prognostic information in CF adults, especially in subjects with FEV1 ≤ 60% predicted.

Employment and work disability in adults with cystic fibrosis

BACKGROUND As 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. METHOD 207 patients answered a self-administered questionnaire about their educational level and work status. Independently, medical records were reviewed for illness severity indicators. RESULTS 39 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. CONCLUSION Many 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.

Déshydratation sévère, conséquence de la canicule d’août 2003 sur une cohorte d’adultes atteints de mucoviscidose

Resume Objectif Etudier les consequences de la canicule d’aout 2003, en termes de deshydratation, sur une population d’adultes atteints de mucoviscidose. Methode Etude retrospective portant sur les appels telephoniques recus et les hospitalisations concernant tous les patients (245) regulierement suivis par le Centre de ressources et de competences, hopital Cochin a Paris. Resultats Six patients ont eu une deshydratation extracellulaire avec insuffisance renale fonctionnelle associee a une hyperhydratation intracellulaire avec hypokaliemie et hypochloremie. Les mesures de rehydratation ont permis la normalisation du ionogramme sanguin en 48 heures, sauf chez une patiente decedee d’hyperthermie maligne. Conclusion En cas de forte chaleur, la prevention (hydratation, apport sales) du risque de deshydratation severe chez les patients atteints de mucoviscidose est essentielle.

Mediastinal Tuberculosis in an Adult Patient with Cystic Fibrosis

ABSTRACT Tuberculosis (TB) is rarely observed in cystic fibrosis (CF) patients. We report the first case of mediastinal TB, associated with leg pain and skin rash, in an adult patient with CF, and discuss factors suggestive of TB in the course of CF.