Journal of Cystic Fibrosis

Osteopenia in Cftr-deltaF508 mice

Josée Paradis, Martina Wilke, Christina K. Haston — 2010-07-01

Abstract: Background: Mice with the cystic fibrosis transmembrane conductance regulator (Cftr) gene knocked out develop osteopenia. To determine whether this phenotype is present in cystic fibrosis mouse models with the ΔF508 Cftr mutation we assessed the femora of adult FVB/N Cftrtm1Eur and C57BL/6 Cftrtm1Kth mice.Methods: Bone disease, relative to littermate controls, was measured using histology, densitometry and quantitative imaging.Results: C57BL/6 Cftrtm1Kth mice had shorter femurs and bones of lower volume due to thinner trabeculae, compared to wild type littermates. FVB/N Cftrtm1Eur mice also presented a lower bone volume which was due to significantly fewer trabeculae in this strain. Osteoblast and osteoclast numbers did not differ between CF and controls, for either of FVB/N Cftrtm1Eur or C57BL/6 Cftrtm1Kth mice. The bone architecture of FVB/N Cftrtm1Eur mice did not significantly differ from that of C57BL/6 Cftrtm1Kth mice.Conclusions: An osteopenic bone disease is evident in adult ΔF508-Cftr cystic fibrosis mouse models.

Pneumothorax in cystic fibrosis: Prevalence and outcomes in Scotland

A. MacDuff, J. Tweedie, L. McIntosh, J.A. Innes — 2010-07-01

Abstract: Background: Pneumothorax is a feared complication of cystic fibrosis. With improved survival into adult life the incidence of pneumothorax is expected to increase. The optimal management of these patients is unclear.Methods: Case review of patients from the three Scottish adult CF centres.Results: A total of 22 episodes of pneumothorax occurred in 20 patients over a 12year period. 2 patients died as a result of the pneumothorax. 16 pneumothoraces were treated by insertion of an intercostal drain and 8 by observation. 8 patients suffered a prolonged air leak. 5 patients were treated with pleurodesis. Pneumothorax was associated with a small decline in lung function which persisted for at least 1year.Conclusion: Pneumothorax can present a challenge to treat in adult CF. However successful outcomes can be achieved even in cases of prolonged air leaks. Current national guidelines help in selecting optimal pleural interventions.

Year-to-year changes in lung function in individuals with cystic fibrosis

2010-07-01

Abstract: Background: We examined the year-to-year change in FEV1 for individuals and the overall cystic fibrosis population to better understand how individual trends may differ from population trends.Methods: We calculated individual yearly changes using the largest annual FEV1 percent predicted (FEV1%) measurement in 20,644 patients (6–45years old) included in the Epidemiologic Study of Cystic Fibrosis. We calculated yearly population changes using age-specific medians.Results: FEV1% predicted decreased 1–3 points per year for individuals, with maximal decreases in 14–15year olds. Population changes agreed with individual changes up to age 15; however after age 30, yearly population change approximated zero while individual FEV1% predicted decreases were 1–2 points per year.Conclusions: Adolescents have the greatest FEV1% predicted decreases; however, loss of FEV1 is a persistent risk in 6–45year old CF patients. Recognizing individual year-to-year changes may improve patient-specific care and may suggest new methods for measuring program quality.

Serum-surfactant SP-D correlates inversely to lung function in cystic fibrosis

Hanne Vebert Olesen, Uffe Holmskov, Peter Oluf Schiøtz, Grith Lykke Sørensen — 2010-07-01

Abstract: Background: Cystic fibrosis (CF) affects the lungs causing infections and inflammation. Surfactant protein D (SP-D) is an innate defense lectin primarily secreted in the lungs. We investigated the influence of the SP-D Met11Thr polymorphism on CF lung function; and serum SP-D as a marker for CF lung disease.Methods: For 107 CF patients (73 children, and 34 adults) serum SP-D and SP-D Met11Thr genotype were available. Leukocyte count was obtained for a subset of patients. Lung function was measured as forced expiratory volume in one second (FEV-1).Results: Serum SP-D was increased in CF patients compared to healthy controls, positively correlated to leukocyte count, and negatively correlated to FEV-1. We found no correlation between SP-D Met11Thr genotype and FEV-1, and we found corresponding genotype frequencies in CF patients and in healthy controls.Conclusion: Serum SP-D in CF patients was increased in parallel with leukocyte count and with reduced FEV-1 and may constitute an alternative biomarker for lung disease, in the clinical setting and in research.

Renal impairment in children with cystic fibrosis

2010-07-01

Abstract: Background: Due to the improvement in life expectancy in cystic fibrosis (CF), co-morbidities such as renal function impairment may be more frequent.Aim: To determine the prevalence of renal disease in children with CF and to identify associated risk factors.Methods: A single-center retrospective study analyzing the genetic, clinical and therapeutic characteristics of 112 children. The estimated glomerular filtration rate (GFR), microalbuminuria and lithiasic risk factors were assessed.Results: The median calculated GFR (Schwartz) was 123, 161 and 155ml/min/1.73m2 in children aged 1, 6 and 15years, respectively. The cumulative dose of aminoglycosides was not correlated to GFR. Microalbuminuria was present in 22/38 patients. Hyperoxaluria was observed in 58/83 patients and was associated with a severe genotype, pancreas insufficiency and liver disease. Hypercalciuria, hyperuricuria and hypocitraturia were identified in 16/87, 15/83 and 57/76 patients, respectively.Conclusion: Renal impairment in CF has various presentations. There appears to be low levels of renal impairment in children with CF. However, the risk of oxalocalcic urolithiasis is enhanced, and GFR may be underestimated by the Schwartz formula. Further studies using measured GFR techniques are thus warranted.

Report of two patients with associated conditions in addition to cystic fibrosis

Supriya K. Jambhekar, John L. Carroll, Steven Keiles — 2010-07-01

Abstract: Purpose: To report two patients with associated conditions in addition to cystic fibrosis.Methods: We reviewed our database and report two patients with cystic fibrosis who had associated conditions. These patients also had novel disease causing CFTR mutations on full gene sequence analysis.Results: We identified 2 patients with novel disease causing cystic fibrosis transmembrane conductance regulator mutations that we report here. A 12-year-old female with cystic fibrosis, diagnosed at 18months, had normal pulmonary function tests and chest X-ray. Her main cystic fibrosis-related health issue was poor growth. Results of cystic fibrosis transmembrane conductance regulator DNA analysis showed deltaF508; L467P; and 7T/9T. She was later diagnosed with Crohn's disease. An 11-year-old male with Rubinstein–Taybi syndrome, diagnosed with cystic fibrosis at 2years of age, had minimal findings on chest X-ray and pancreatic insufficiency. Results of his cystic fibrosis transmembrane conductance regulator DNA analysis showed deltaF508; 4329delCT; and 7T/9T.Conclusion: We report 2 patients with CF who had associated conditions and also had novel disease causing CFTR mutations. Associated conditions may worsen the clinical manifestations of CF and complicate medical management.

Lung transplantation in patients with cystic fibrosis and Mycobacterium abscessus infection

2010-07-01

Abstract: Mycobacterium abscessus lung disease is difficult to treat and has been considered a strong relative contraindication to lung transplantation. We performed double lung transplantation in three cystic fibrosis patients with ongoing, and a fourth with recent treatment for Mycobacterium abscessus lung infection. Despite prolonged antibiotic courses and adjustment of immunosuppressive therapy the first three patients developed skin infection and abscesses. At follow-up after 1, 3, 5 and 7years respectively no patient had evidence of M abscessus infection and all had stable lung function. Lung transplantation in patients with M abscessus lung infection is feasible but may involve severe complications.

Effect of Th2 type cytokines on hCLCA1 and mucus expression in cystic fibrosis airways

2010-07-01

Abstract: Correlations between expression of interleukin (IL)-9, the calcium-activated chloride channel hCLCA1 and mucus expression in cystic fibrosis (CF) airways have suggested a causal relationship. To verify this hypothesis mucosal tissue from upper airways of CF patients (N=5) was stimulated with the Th2 type cytokines IL-4, IL-9, or IL-13. Expression of hCLCA1 mRNA and protein as well as mucus and mucin (MUC5AC) gene expression was quantified using real time PCR, immunohistochemistry (hCLCA1) and PAS staining (mucus). Th2 type cytokines significantly increased hCLCA1 protein expression (P<0.05) whereas increase in hCLCA1 mRNA expression failed to reach statistical significance (P>0.05). Mucin protein and MUC5AC mRNA expression were not significantly changed (P>0.05). These data suggest that Th2 type cytokines may increase hCLCA1 expression in CF but may not have a significant effect on mucus expression. Therefore the role of hCLCA1 as a mediator of mucus overexpression in CF has to be questioned.

High dose intermittent ticarcillin–clavulanate administration in pediatric cystic fibrosis patients

Jeffery T. Zobell, Krow Ampofo, Jared Cash, Kent Korgenski, Barbara A. Chatfield — 2010-07-01

Abstract: Background: The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin–clavulanate 400mg/kg/day divided every 6h, (maximum 24g/day). This dosing strategy is higher than the Cystic Fibrosis Foundation (CFF) recommendations and the Food and Drug Administration (FDA) approved package labeling. The purpose is to determine the safety of this dosing regimen.Methods: A retrospective study of pediatric cystic fibrosis (CF) patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7days. Baseline and follow-up laboratory parameters were recorded. Statistical analysis was performed.Results: 127 patients met inclusion criteria. The mean (±SD) ticarcillin dose was 3.5g (±2.16) every 6h; while the mean (±SD) total ticarcillin dose was 13.5g (±6.5) per day. No significant differences occurred in liver function tests, white blood count, and platelet count from baseline. Serum creatinine showed a statistically significant decrease from baseline.Conclusions: Higher than FDA approved doses of ticarcillin–clavulanate may be safely used in the treatment of exacerbations in pediatric cystic fibrosis patients.

Opportunities for quality improvement in cystic fibrosis newborn screening

Molly K. Groose, Richard Reynolds, Zhanhai Li, Philip M. Farrell — 2010-07-01

Abstract: Background: With the rapid implementation of cystic fibrosis (CF) newborn screening (NBS), quality improvement (QI) has become essential to identify and prevent errors. Using Process Failure Modes and Effects Analysis (PFMEA), we adapted this method to determine if it could be applied to discover and rank high priority QI opportunities.Methods: Site visits to three programmes were conducted, and PFMEA exercises were accomplished in Colorado, Massachusetts and Wisconsin with 23 experienced professionals. During each of these comprehensive sessions, participants identified and ranked potential failures based on severity, occurrence and detection to calculate risk priority number (RPN) values.Results: A total of 96 failure modes were generated and ranked in a list of the 20 riskiest problems that show no significant discordances by site, although there were differences by profession of the rater, particularly nurses.Conclusions: Our results illustrate that the PFMEA method applies well to CF NBS and that steps requiring communication and information transfer are perceived to be the highest risks. The number of identified failures makes and their potential impact demonstrate considerable overall risk and a need for ongoing QI.

Cystic fibrosis gene mutations and gastrointestinal diseases

2010-07-01

Abstract: Background: This study examined if CF mutation heterozygosity is associated with diseases of gastrointestinal epithelial barrier function.Design and methods: Swedish registers identified 865 patients with a diagnosis of CF between 1968 and 2003 and matched with 8101 individuals without CF. Gastrointestinal disease risk was examined among 1534 biological parents and 1396 siblings of CF patients, compared with 15,526 parents and 15,542 siblings of individuals without CF.Results: First-degree relatives of CF patients were not at lower risk of the gastrointestinal diseases, in contrast with a raised risk among CF patients.Conclusion: Heterozygosity for CF gene mutations does not protect against gastrointestinal diseases where impaired barrier function may be relevant.

Serum tobramycin levels following delivery of tobramycin (Tobi®) via eFlow® advanced nebuliser in children with cystic fibrosis

E.L. Guy, M. Bosomworth, M. Denton, S.P. Conway, K.G. Brownlee, T.W.R. Lee — 2010-07-01

Abstract: Background: Safety and toxicity data for nebulised tobramycin are mainly derived from use of the Pari LC® Plus nebuliser, yet many centres are now using advanced nebulisers, such as the eFlow®.Methods: Ten children (ages 2–16years) receiving 300mg TOBI® via eFlow® for clinical reasons participated. Serum tobramycin levels were obtained 1h post nebulisation. Nine provided samples for urinary NAG, and 10 underwent audiology.Results: Tobramycin levels were >1mg/L in 3 children (maximum 3.8, 2 children aged 2years). Urine NAG/creatinine levels were raised (>0.94μmol/min/mmol) in 5 children, 1 of these had a tobramycin level of >1mg/L. One patient had high frequency hearing loss.Conclusion: Serum tobramycin levels over 1mg/L can occur 1h post 300mg TOBI® delivered by eFlow®. Raised urinary NAG levels suggest that some children may have some associated early renal toxicity.

Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: Three areas for future research: Which areas to target? Which particle size to deliver? Which device to use?

Bart L. Rottier, Anne H. de Boer, Eric J. Duiverman — 2010-07-01

We have read the European consensus article about inhaled medication and inhalation devices in CF therapy with great interest and would like to congratulate the authors on a great achievement . The aim of inhaled antibiotic therapy in CF is to reach the best clinical response with a minimum of side effects. On three important topics regarding inhaled antibiotics no recommendations were made. With this letter we would like to put these issues forward as areas for future research, both bench- and bed-side, as well as to hypothesize on the answers.