Journal of Cystic Fibrosis

Editorial

Gerd Döring — 2012-01-01

Eradication of Pseudomonas aeruginosa by early antibiotic treatment has been one of the major advances in the last decade for subjects with CF . This fantastic success has let many people to forget that this pathogen is not the only one present in CF airways. The study by Vanderhelst and colleagues puts the finger on another dangerous bacterium, methicillin-resistant Staphylococcus aureus (MRSA) which rose in prevalence in CF from 0.1% in 1995 to 22% in 2007. Using registry data from 2002 to 2010, their retrospective case–control study showed that the prevalence of MRSA in chronically S. aureus infected patients, was 15.2% from which 12.6% were chronically infected. Importantly, MRSA caused a more rapid lung function decline compared with controls.

Prevalence and impact on FEV1 decline of chronic methicillin-resistant Staphylococcus aureus (MRSA) colonization in patients with Cystic Fibrosis: A single-center, case control study of 165 patients

E. Vanderhelst, L. De Meirleir, S. Verbanck, D. Piérard, W. Vincken, A. Malfroot — 2011-09-12

Abstract: Background: Risk factors for methicillin-resistant Staphylococcus aureus (MRSA) in Cystic Fibrosis (CF) and the impact on CF disease progression are still under debate.The objectives of this study were to determine clinical variables associated with MRSA colonization and examine impact on FEV1 evolution in CF patients.Methods: A retrospective case–control study using the University Hospital of Brussels CF clinic patient registry from 2002 to 2010, comparing clinical variables and decline of FEV1 of MRSA positive patients with age and sex matched controls, chronically colonized with S. aureus.Results: Thirty of the 165 CF patients, chronically colonized with S. aureus, had cultures positive for MRSA (18.2%). Excluding patients under 4years, the prevalence became 15.2% (23/151). Chronic colonization (i.e., three or more consecutive positive cultures) was found in 19/151 (12.6%).The MRSA positive group showed a higher proportion of patients with genotype F508del, less pancreas sufficient patients, more bronchiectasis and more frequent hospitalization.The FEV1 recorded one year prior to, and at the moment of MRSA acquisition, was lower but not significantly different from that obtained in controls (72.9%±26.6 vs 84.3±21.8 and 68.2%±27.1 vs 81.4%±24.3 respectively, p>0.1). However, FEV1 decline over 2- and 6-year periods, were significantly greater in the chronic MRSA group than in the controls (−5%±5.5 vs −2.5±2.3 over 2years (p=0.043) and −1.8%±4.6 vs −1.0%±1.9 over a 6-year period (p=0.026)).Conclusion: In our center the prevalence of MRSA in CF patients, chronically colonized with S. aureus and over the age of 4years, was 15.2% (12.6% chronic infection). MRSA colonization was shown to be associated with a genotype F508del, presence of bronchiectasis and hospitalization. Our spirometric data also show that a MRSA episode entails an FEV1 decline that is almost double that predicted for CF patients who can remain unaffected by MRSA.

Chronic Stenotrophomonas maltophilia infection and exacerbation outcomes in cystic fibrosis

2011-08-22

Abstract: Background: Chronic Stenotrophomonas maltophilia infection is a risk factor for pulmonary exacerbation in cystic fibrosis (CF) but its impact on subsequent clinical outcomes is unknown. The aim of this study was to determine the effect of chronic S. maltophilia infection and associated antimicrobial therapy on the recovery of forced expiratory lung volume in 1s (FEV1) following pulmonary exacerbation.Methods: This was a retrospective cohort study of patients with CF followed at The Hospital for Sick Children and St. Michael's Hospital from 1997 to 2008. The primary outcome was the difference in FEV1 percent predicted from baseline to follow up after a pulmonary exacerbation. Secondary outcomes for the effect of antimicrobial therapy included time to subsequent exacerbation.Results: There were 1667 pulmonary exacerbations in 440 CF patients. Patients with chronic S. maltophilia infection did not recover their baseline FEV1 following 31% of exacerbations and had an overall mean FEV1 decline of 1.84% predicted after exacerbation. Older (p=0.02), female (p=0.02) patients with lower BMI z score (p=0.002) and Burkholderia cepacia complex infection (p=0.005), but not chronic S. maltophilia infection (p=0.86), had a greater decrease in follow up FEV1% pred compared to baseline. The number of days of antibiotic therapy against S. maltophilia during a pulmonary exacerbation was not associated with a significant difference in the FEV1 recovery (p=0.69) or with a longer time to subsequent pulmonary exacerbation (p=0.56).Conclusions: Although CF patients experience a significant decline in lung function following exacerbation, chronic S. maltophilia infection and associated antimicrobial therapy do not affect subsequent lung function recovery.

Delayed publication of clinical trials in cystic fibrosis

M.N. Hurley, A.P. Prayle, A.R. Smyth — 2011-09-05

Abstract: Background: When the publication of important trial data is delayed, or data are never published, this will prevent the proper practice of evidence based medicine through robust systematic reviews. Clinical trial registries allow researchers to interrogate the trial protocol and afford the opportunity to identify studies that have been completed and so determine the time lag between completion and publication.Methods: We searched ClinicalTrials.gov with the keywords ‘cystic fibrosis’. Intervention trials which had completed 1st Jan 1998–31st Dec 2010 were selected. Time to publication in a peer-reviewed journal was calculated. Survival analyses using the log rank test were undertaken.Results: We identified 142 records. Of these, 62 had full paper publications. The median time to publication was 3.25years. Phase of study (phase one studies more delayed, p=0.024) but not source of funding (p=0.34) was associated with time to publication.Conclusions: Clinical trials in cystic fibrosis take a considerable amount of time to report their findings. More importantly, a large number of trials fail to report at all.

Exercise improves lung function and habitual activity in children with cystic fibrosis

2011-09-07

Abstract: Background: Cystic fibrosis (CF) lung disease leads to progressive deterioration in exercise capacity. Because physical activity has been shown to improve lung function and quality of life (QoL), developing routine exercise programs can benefit this patient population.Methods: Lung function, nutritional status, and exercise capacity and assessments of habitual activity and QoL were measured before and after a two-month, subject-designed exercise regimen based on self-reported activity assessment. Statistical analysis included Wilcoxon signed-rank, Wilcoxon rank sum, and Fisher's exact tests.Results: Subjects completing the study demonstrated significant improvement in exercise capacity and body image perception, a CF-specific QoL measure (p<0.001). In secondary analyses, subjects improving exercise capacity showed significant increases in lung function and self-reported habitual activity.Conclusions: Increases in exercise capacity over a two-month period resulted in significantly improved lung function and self-reported habitual activity. Longer, controlled trials are needed to develop individualized exercise recommendations.

Validation of a predictive survival model in Italian patients with cystic fibrosis

2011-09-26

Abstract: Background: In 2001 Liou published a 5-year survival model using CFF Registry data.Aims: To evaluate its validity in predicting survival in Italian CF patients.Methods: In a retrospective study on 945 patients, the 9 variables selected by Liou were analyzed, vital status on December 2008 recorded and observed and expected deaths compared. To develop a new model, patients were randomly divided into a derivation (n=475) and a validation sample (n=470).Results: A significant difference was found between observed and expected deaths based on Liou's model (62 vs 94), with a 34% reduction in mortality (p<0.05). A new model (based on FEV1, Staphylococcus aureus and Burkholderia cepacia complex infection, number of pulmonary exacerbations/year) was generated, that correctly predicted survival in the validation sample (31 observed vs 29 expected deaths, p=0.660).Conclusions: The Liou model did not adequately predict 5-year survival in our CF population that, compared to the one in which it was originally tested, could benefit from 10years of improvement in treatments and practice patterns. A new generated model, based on only four variables, was more accurate in predicting 5-year survival in Italian CF patients.

Mild cystic fibrosis in patients with the rare P5L CFTR mutation

2011-10-10

Abstract: Over 1800 Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) mutations have been identified so far, determining different degrees of CFTR dysfunction and a range of different cystic fibrosis phenotypes. The P5L CFTR mutation is a recently described N-terminus missense variant which may cause defect of protein folding and processing/trafficking, but the functional classification is still unclear. Given the rarity of the mutation, the associated clinical phenotype is still unknown. The aim of our study was to describe the clinical phenotypes in a group of 7 patients with the P5L mutation including 2 adults, 2 adolescents and 3 children. The P5L variant was associated with ΔF508 in 5 patients and with W1282X in two patients.All patients had positive or borderline sweat test values. All had pancreatic sufficiency, no hepatobiliary disease, no or mild respiratory symptoms and normal lung function. The two adult males were fertile. Most of the patients presented recurrent episodes of dehydration and hypochloronatremia.We conclude that, although it has been speculated that the N-terminus CFTR missense variants may severely affect the behaviour of the CFTR chloride channel, patients with the P5L CFTR mutation, in association with a severe class II mutation, may be asymptomatic or may be affected by mild disease.

Smoking prevention and cessation programme in cystic fibrosis: Integrating an environmental health approach

2011-10-14

Abstract: Background: There have been several studies assessing the epidemiology and effects of tobacco smoke in the cystic fibrosis (CF) population, but few address the efforts of smoking cessation interventions. Our objective is to present one tobacco prevention and cessation programme targeting patients with CF in the Mediterranean region of Murcia (Spain).Methods: All registered patients in the Regional CF unit (n=105) in 2008 were included in a cross-sectional and prospective uncontrolled study of tobacco use and exposure in CF patients using a baseline and 1-year follow-up. Target population includes both patients and other family members living at home. The study included an initial telephone questionnaire, measurement of lung function, urinary cotinine levels, and several telephone counselling calls and/or personalised smoking cessation services.Results: Of the 97 contacted patients, 59.8% (n=58) were exposed to environmental tobacco smoke (ETS), 12.4% (n=12) had smoked at one time, and 14.3% (n=8) of patients over the age of 15 actively smoked. The mean age was 31.13 (range: 19–45). Of the non-smokers (n=89), 56.2% reported ETS and 26.9% live with at least one smoker at home. 49.2% had urinary cotinine levels >10ng/ml. The correlation found between patients' cotinine levels and their reported tobacco exposure was (0.77, p<0.0001). Active smoking by mothers during pregnancy was associated with significantly lower lung function in young CF patients (−0.385, p=0.04). At the 1-year follow-up, 13 individuals made attempts to stop smoking, 6 of which are now ex-smokers (12.5% of all smokers).Conclusions: Smoking during pregnancy adversely affects lung function in individuals with CF. Tobacco prevention and cessation programmes are an effective and vital component for CF disease management. The trained professionals in prevention and smoking cessation services could provide patients with adequate follow-up, integrating an environmental health approach into CF patients' healthcare.

Ambulatory venovenous extracorporeal respiratory support as a bridge for cystic fibrosis patients to emergent lung transplantation

2011-10-31

Abstract: Venovenous extracorporeal membrane oxygenation (VV ECMO) is a therapeutic option to bridge patients with advanced lung disease to lung transplantation. The use of VV ECMO avoids the use of mechanical ventilation while allowing patients to participate in physical therapy and to eat normally while receiving respiratory support. We describe the successful use of ambulatory single-venous VV ECMO as a bridge to bilateral lung transplantation in 4 patients with end-stage lung disease due to cystic fibrosis who developed acute hypercapnic respiratory failure. The use of ambulatory single-venous VV ECMO was safe and effective in this small cohort of CF patients. Based on our experiences, our belief is that a key step in the treatment course was early application of VV ECMO soon after development of acute respiratory failure requiring mechanical ventilation.

Recurrent abdominal pain in children with cystic fibrosis: A pilot prospective longitudinal evaluation of characteristics and management

2011-09-12

Abstract: Children with cystic fibrosis commonly experience abdominal pain; however this remains poorly characterised. This prospective cross-sectional study with a longitudinal design, examined the prevalence, causes and effect of pain management via daily diaries, validated questionnaires for pain characteristics, anxiety status and quality of life. One hundred and thirty CF patients aged 8 to 18years, regularly followed at our centre, were questioned on recurrent abdominal pain. Eight patients fulfilled the criteria; all wished to enter the study. Pain management included behavioural intervention with effective pain relief, and had a positive impact on anxiety and quality of life. This study is the first one to prospectively assess recurrent abdominal pain in CF. We documented a very low prevalence of 6%. We suggest that, ruling out abdominal discomfort, only a minority of CF children presented recurrent abdominal pain with a true negative impact on daily life. We emphasise the need for further studies including larger cohorts.

Australian epidemic strain pseudomonas (AES-1) declines further in a cohort segregated cystic fibrosis clinic

2011-09-12

Abstract: Aim: To evaluate changes in prevalence of an epidemic strain of Pseudomonas aeruginosa (AES-1, Australian epidemic strain, type 1) in a paediatric cystic fibrosis (CF) centre practising cohort segregation, to describe the patients' clinical characteristics at acquisition and observe mortality rates.Methods: Cohort segregation was introduced in our paediatric CF clinic January 2000. The prevalence of AES-1 was analysed in 1999, 2002 and 2007. Age at acquisition, lung function, presence of bronchiectasis, hospitalisations, prior P. aeruginosa infection and mortality rates were collected. AES-1 infection was determined by pulse-field-gel-electrophoresis (PFGE) on airway specimen cultures taken three monthly.Results: The prevalence of AES-1 declined from 21% in 1999 to 14% in 2002 (risk difference 7% (95% CI 1,13) p=0.0256) and to 6% in 2007 (risk difference 8% (95% CI 3,13) p=0.0018). New acquisitions after the introduction of cohort segregation were uncommon (10 by 2002 and another 7 by 2007) with a declining incidence of 3.3cases/year (1999 to 2002) compared to 1.4cases/year (2002 to 2007). Twenty-two of 32 (69%) deaths between 1999 and 2007 occurred in patients infected with AES-1.Conclusion: Cohort segregation has been associated with reductions in the prevalence of AES-1 in our CF clinic. Mortality was higher in patients infected with AES-1 than other organisms.

Frequency of the hyperactive W493R ENaC variant in carriers of a CFTR mutation

Melanie Handschick, Silke Hedtfeld, Burkhard Tümmler — 2011-09-14

Abstract: Background: The basic defect of the autosomal recessive disorder cystic fibrosis (CF) manifests in chloride hyposecretion and sodium hyperabsorption. CF-like disease has been reported in a heterozygous carrier of F508del CFTR and the hyperactive variant p.W493R-SCNN1A of the epithelial sodium channel (ENaC).Methods: The hypothesis that heterozygosity for p.W493R-SCNN1A and one loss-of-function CFTR mutation causes or predisposes to CF or CF-like disease was tested in 441 parents of a child with CF.Results: p.W493R-SCNN1A was detected in three female carriers of F508del CFTR who did not show any symptoms of respiratory or intestinal disease that could be interpreted as the manifestation of CF or CFTR-related disorder. Frequency of p.W493R was lower in CF parents than in Caucasian control subjects.Conclusions: A hyperactive ENaC does not necessarily cause CF-like disease in a CF gene carrier, but its low frequency in CF parents suggests that it is a risk factor.

The prevalence of “risky behaviour” in adults with cystic fibrosis

Felicity A. Mc Ewan, Margaret E. Hodson, Nicholas J. Simmonds — 2011-10-04

Abstract: Background: The prevalence of “risky-behaviour” including alcohol and illicit drug use, smoking and unprotected sexual intercourse, of adults with cystic fibrosis (CF) is unknown. We conducted this prospective questionnaire-based study to further explore this issue.Methods: An anonymous 71-point questionnaire was sent to all adult patients aged ≥18years attending the Royal Brompton CF Unit. Results were compared to national (non-CF) data.Results: 83% (n=151) drink alcohol and 13% (n=23) drink more than recommended by national guidelines. 46% (n=84) have tried smoking and 3% (n=5) continue to smoke regularly. 35% (n=64) have tried illicit drugs and 3% (n=6) continue to use them. 86% (n=154) are sexually active; 60% use contraception (males 46%, females 62%). Compared with the general (non-CF) UK population, less CF patients drink heavily (13 vs. 23%; p<0.001), smoke (3 vs. 21%; p<0.001), have tried illicit drugs (35 vs. 37%; p<0.001) and are sexually active (86 vs. 97%; p<0.001).The same proportion use contraception (60 vs. 61%; p=0.8).Conclusion: Participation in risky behaviour was modest. With improved life expectancy this may increase. Awareness of this is important so that health promotion measures can be introduced early.

MALDI-TOF MS improves routine identification of non-fermenting Gram negative isolates from cystic fibrosis patients

2011-10-04

Abstract: Identification of non-fermenting Gram-negative bacteria (NFGNB) from cystic fibrosis (CF) patients is often limited. A collection of stored NFGNB isolates (n=182) recovered from CF patients over a 15year period was examined. The routinely reported identification during this period was compared with that obtained by MALDI-TOF MS. Isolates giving discrepant identification at the genus level were further analyzed by 16S rDNA sequencing. The MALDI-TOF MS system identified 94% of the isolates, including Burkholderia cepacia and Pandoraea spp. isolates, the latter previously misidentified as other NFGNB by conventional microbiological methods. Lack of identification by MALDI-TOF MS was associated with the absence of entries in the database.

Ancestral haplotype 8.1 and lung disease severity in European cystic fibrosis patients

2011-10-12

Abstract: Background: The clinical course of cystic fibrosis (CF) lung disease varies between patients bearing identical CFTR mutations. This suggests that additional genetic modifiers may contribute to the pulmonary phenotype. The highly conserved ancestral haplotype 8.1 (8.1AH), carried by up to one quarter of Caucasians, comprises linked gene polymorphisms on chromosome 6 that play a key role in the inflammatory response: LTA +252A/G; TNF −308G/A, HSP70-2 +1267A/G and RAGE −429T/C. As inflammation is a key component inducing CF lung damage, we investigated whether the 8.1AH represents a lung function modifier in CF.Methods: We analyzed the lung function of 404 European CF patients from France (n=230), Germany (n=95) and UK (n=79). FEV1 differences between 8.1AH carriers and non-carriers were calculated in each country and pooled using a random effects model.Results: The frequency of 8.1AH carriers was similar between French (22%), German (29%) and UK (27%) patients. We found that 8.1AH carriers had significantly lower FEV1, adjusted for age classes and countries (P<0.04, mean FEV1 difference −6.4% CI95% [−12.4%, −0.5%]). No difference was observed with respect to BMI Z-scores and chronic colonization with P. aeruginosa.Conclusions: These findings support the concept that 8.1AH is an important genetic modifier of lung disease in CF. To conclude, multiple linked genes outside the CF locus might explain some of the variability in lung phenotype.

Hypothesis: Cystic fibrosis carrier geography reflects interactions of tuberculosis and hypertension with vitamin D deficiency, altitude and temperature. Vitamin D deficiency effects and cf carrier advantage

Mark Lubinsky — 2011-10-04

Abstract: Interactions between selective factors (hypertension and tuberculosis) and environmental effects (vitamin D deficiency [VDD], temperature, and altitude) largely explain cystic fibrosis (CF) carrier geography. For VDD sequelae such as hypertension and tuberculosis vulnerability, clinical evidence of carrier protection is supported by indications that decreased CF arylsulfatase B activity suppresses tuberculosis, and that excess CF salt loss decreases blood pressure. A need for salt retention in the tropics selected against CF carriers despite possible advantages against cholera, typhoid, and other factors, but salt retention was less important elsewhere. Increased hypertension with cold selected for carriers with increasing latitude, and with altitude, where hypertensive complications of pregnancy also rise. ΔF508 rates especially seem to follow these parameters, and may be particularly protective against hypertension, while lower rates in Ashkenazi Jews are consistent with a greater role for tuberculosis in this group. This scenario suggests geographical correlations of CF with other genes affecting blood pressure, and significant carrier levels, especially of ΔF508, in mountainous areas of Asia with VDD.

Staphylococcus aureus and cystic fibrosis

Marcelo J. Mimica — 2011-08-24

I read with great interest the review entitled “Staphylococcus aureus and MRSA in cystic fibrosis” by Goss and Muhlebach . They included important information regarding the current knowledge on the circulation of new methicillin-resistant Staphylococcus aureus (MRSA) clones, usually carrying SCCmec type IV, in cystic fibrosis patients throughout the world. I would like to take this opportunity to put it in parallel with recent data from Brazil.

Ursodeoxycholic acid in cystic fibrosis-associated liver disease

Chee Y. Ooi, Scott Nightingale, Peter R. Durie, Steven D. Freedman — 2011-08-24

Sir, We read with interest the recent guidelines for the management of cystic fibrosis-associated liver disease (CFLD), particularly the section addressing indications and dosing of ursodeoxycholic acid (UDCA) . The guidelines recommended the use of UDCA, at an initial dose of 20mg/kg/day and as soon as the diagnosis of CFLD is made, in order to delay disease progression. However, the use of UDCA in all cholestatic diseases, including CFLD, is controversial and not as clear-cut as the recommendations suggest.

Response to the letter by Ooi et al.

2011-10-19

We read with interest the letter from Dr. CY Ooi and Coll. pointing out that more clinical and experimental evidence is needed before firm recommendations concerning long-term use of UDCA in CFLD are issued.