The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

Aanaes K. Johansen HK. Poulsen SS. Pressler T. Buchwald C. Hoiby N. Secretory IgA as a diagnostic tool for Pseudomonas aeruginosa respiratory colonization.  J Cyst Fibros 2013; 12: 81-87. [PubMed]

Pseudomonas aeruginosa sinusitis may be the focus for intermittent lung colonization in patients with cystic fibrosis (CF). The sinusitis may induce elevated IgA levels in nasal secretion and saliva against P. aeruginosa.

120 CF patients chronically infected, intermittently colonized or without P. aeruginosa in the lungs participated in this cross-sectional study. IgA and IgG against P. aeruginosa sonicate and alginate were measured in nasal secretions, saliva, and in serum by ELISA.

RESULTS: The intermittently colonized patients had significantly higher IgA levels in nasal secretions and saliva than those without P. aeruginosa in the lungs, indicating that P. aeruginosa sinusitis may precede intermittent colonization and chronic infection of the lungs.

The authors conclude specific IgA against P. aeruginosa in nasal secretions and saliva can contribute to differentiation between patients chronically infected, intermittently colonized, and without P. aeruginosa in the lungs. The diagnostic value of the IgA ELISA awaits a prospective study.

The upper respiratory tract is receiving more attention as a source of  organisms invading the lower airways – particularly P. aeruginosa.  ELISA determined antibodies to P. aeruginosa have been used by some units for many years and found to be valuable in indicating the presence of Pseudomonas.

 

Summary of Kasper Aanaes’s (figure 1) Doctoral Thesis on this subject has been published and is fully referenced and liberally illustrated.  “Bacterial sinusitis can be a focus for initial lung colonisation and chronic lung infection in patients with cystic fibrosis. Aanaes K. J Cyst Fibros 2013; 12 (Suppl 2):S1-S20.

Fig.1: Kasper Aanaes

Adam RJ. Michalski AS. Bauer C. Abou Alaiwa MH. Gross TJ. Awadalla MS. Bouzek DC. Gansemer ND. Taft PJ. Hoegger MJ. Diwakar A. Ochs M. Reinhardt JM. Hoffman EA. Beichel RR. Meyerholz DK. Stoltz DA. Air trapping and airflow obstruction in newborn cystic fibrosis piglets. Am J Resp Crit Care 2013; 188:1434-41.[PubMed]

Air trapping and airflow obstruction are being increasingly identified in infants with cystic fibrosis. These findings are commonly attributed to airway infection, inflammation, and mucus build up. This study was to determine if air trapping and airflow obstruction are present before the onset of airway infection and inflammation in cystic fibrosis.                 

On the day they are born, piglets with CF lack airway infection and inflammation so the authors used newborn wild-type piglets and piglets with CF to assess air trapping, airway size, and lung volume with inspiratory and expiratory X-ray computed tomography scans. Micro-computed tomography scanning was used to assess more distal airway sizes. Airway resistance was determined with a mechanical ventilator. Mean linear intercept and alveolar surface area were determined using stereologic methods.

 

On the day they were born, piglets with cystic fibrosis exhibited air trapping more frequently than wild-type piglets (75% vs. 12.5%, respectively). Moreover, newborn piglets with CF had increased airway resistance that was accompanied by luminal size reduction in the trachea, mainstem bronchi, and proximal airways. In contrast, mean linear intercept length, alveolar surface area, and lung volume were similar between both genotypes.                                                                 

 The authors conclude that the presence of air trapping, airflow obstruction, and airway size reduction in newborn piglets with cystic fibrosis before the onset of airway infection, inflammation, and mucus accumulation indicates that cystic fibrosis impacts airway development. They suggest their findings suggest that early airflow obstruction and air trapping in infants with cystic fibrosis might, in part, be caused by congenital airway abnormalities.

 

This is a fascinating study showing what has been suspected previously – that the airways of the newborn with CF are anatomically abnormal. Anatomical abnormalities have already been described in airways of CF piglets (Meyerholz DK et al, 2010. [PubMed] 20622026). The trachea and mainstem bronchi had a uniformly small calibre and cross-sections of trachea were less circular than in controls, the trachealis smooth muscle had an altered bundle orientation and increased transcripts in a smooth muscle gene set, the submucosal glands were hypoplastic and had global reductions in tissue-specific transcripts. To learn whether any of these changes occurred in young patients with CF, they examined CT scans from children 2 years of age and younger, and found that CF tracheas were less circular in cross-section, but lacked differences in lumen area. However, analysis of previously published morphometric data showed reduced tracheal lumen area in neonates with CF.

Occasionally the lower airway abnormalities are such that a young infant presents a clinical picture resembling tracheomalacia with intractable expiratory wheezing which gradually improves through infancy.

 

Alicandro G, Faelli N, Gagliardini R, Santini B, Magazzu G, Biffi A, Rise P, Galli C, Tirelli AS, Loi S, Valmarana L, Cirilli N, Palmas T, Vieni G, Bianchi ML, Agostoni C, Colombo C. A randomized placebo-controlled study on high-dose oral algal docosahexaenoic acid supplementation in children with cystic fibrosis. Prostag Leukotr Ess 2013; 88:163-169. [PubMed]

Low plasma concentrations of docosahexaenoic acid (DHA) are reported in unsupplemented cystic fibrosis patients. Forty-one CF patients aged from 6 to 12 years were randomized to receive high-dose DHA (100 mg/kg/day in the first month and 1g per day thereafter through a 12-month supplementation) or placebo (germ oil). Primary outcome was percentage change in plasma AA: DHA ratio. Secondary outcomes were changes in the number of pulmonary exacerbations compared to previous year, lung function, BMI, skin fold thicknesses, and body composition assessed by DXA and in serum concentrations of C-reactive protein, cytokines and vitamin (alpha-tocopherol and retinol). Compared to the control group plasma AA: DHA ratio decreased in the intervention group after 6 months (median percentage changes: -73% in the intervention group vs. -10% in the control group, P=0.001). No differences were detected between groups for secondary outcomes.

 

Despite a decrease of the AA/DHA ratio, DHA supplementation for one year did not induce any significant biochemical and clinical improvement in CF patients. This is yet another study that failed to confirm the findings in mice of Beharry S et al. (Long-term docosahexaenoic acid therapy in a congenic murine model of cystic fibrosis. Am J Physiol – Gastr L 2007; 292:G839-48).[PubMed]. Although the DHA had a favourable effect on the liver disease.

 

Alton EW. Baker A. Baker E. Boyd AC. Cheng SH. Coles RL. Collie DD. Davidson H. Davies JC. Gill DR. Gordon C. Griesenbach U. Higgins T. Hyde SC. Innes JA. McCormick D. McGovern M. McLachlan G. Porteous DJ. Pringle I. Scheule RK. Shaw DJ. Smith S. Sumner-Jones SG. Tennant P. Vrettou C. The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep. Biomaterials 2013; 34:10267-77. [PubMed]

The UK CF Gene Therapy Consortium is currently evaluating long-term repeated delivery of pGM169 complexed with the cationic lipid GL67A in a large Multidose Trial. This regulatory-compliant evaluation of aerosol administration of nine doses of pGM169/GL67A at monthly intervals, to the sheep lung, was performed in preparation for the Multidose Trial. All sheep tolerated treatment well with no adverse effects on haematology, serum chemistry, lung function or histopathology. Acute responses were observed in relation to bronchoalveolar cellularity comprising increased neutrophils and macrophage numbers 1 day post-delivery but these increases were transient and returned to baseline.                    Importantly there was no cumulative inflammatory effect or lung remodelling with successive doses. Molecular analysis confirmed delivery of pGM169 DNA to the airways and pGM169-specific mRNA was detected in bronchial brushing samples at day 1 following doses 1, 5 and 9. In conclusion, nine doses of pGM169/GL67A were well tolerated with no significant evidence of toxicity that would preclude adoption of a similar strategy in CF patients.

This regulatory compliant evaluation preceded the multi-dose gene therapy trial which started in 2013 and was projected to finish in mid-2014.

 

Alton EW. Boyd AC. Cheng SH. Cunningham S. Davies JC. Gill DR. Griesenbach U. Higgins T. Hyde SC. Innes JA. Murray GD. Porteous DJ. A randomised, double-blind, placebo-controlled phase IIB clinical trial of repeated application of gene therapy in patients with cystic fibrosis. Thorax 2013; 68:1075-7.[PubMed]

The members of the UK Cystic Fibrosis Gene Therapy Consortium have been working towards clinical gene therapy for patients with cystic fibrosis for over 10 years.  They have recently embarked on a large, multi-dose clinical trial of a non-viral, liposome-based formulation powered for the first time to detect clinical benefit. The article describes the details of the protocol.

 

By early 2014 the gene therapy trial mentioned was well advanced and projected to end in mid 2014. The lack of serious side effects shown in the sheep study was confirmed in the subsequent trial with the CF patients who tolerated the treatment without serious side effects.

 

Anand A. Tullis E. Stephenson A. Nickel JC. Leveridge MJ. Pseudomonas aeruginosa bacteremia and prostatitis in a patient with cystic fibrosis. Canadian Urological Association Journal. 2013; 7:E1-3. [PubMed]

Patients with cystic fibrosis commonly suffer chronic respiratory infections, although systemic dissemination is relatively rare. Acute bacterial prostatitis presents dramatically and is believed to be mostly caused by local migration (with or without instrumentation) of the lower urinary tract and presents with a predictable microbial aetiology. The authors report a case of a 26-year-old man who has CF presenting with acute Pseudomonas aeruginosa bacterial prostatitis due to haematogenous propagation from a chronic pulmonary infection.

 

Ashish A. Shaw M. Winstanley C. Humphreys L. Walshaw MJ. Halting the spread of epidemic Pseudomonas aeruginosa in an adult cystic fibrosis centre: a prospective cohort study. JRSM Short Reports. 4(1):1, 2013 Jan. [PubMed]

To assess if cohort segregation policies are effective in preventing cross-infection in cystic fibrosis (CF) clinics. A prospective cohort study in a large adult CF centre in Northwest England including all CF patients cared for at the Liverpool adult CF centre 2003-2009. Regular sputum sampling with genotyping of pseudomonas aeruginosa (Psa) isolates led to a policy of inpatient and outpatient segregation by microbiological group.       MAIN OUTCOME MEASURES: Prevalence and cross-infection/super-infection rates of a transmissible Psa strain, i.e. the Liverpool epidemic strain (LES) in adult CF patients at the Liverpool adult CF centre from 2003 to 2009.

RESULTS: There was a decline in the proportion of patients with LES (71-53%) and an increase in those with unique strains (23-31%) and without Psa infection (6-17%) from 2003 to 2009. There were two cases of LES super-infection and one case of new chronic Psa infection (with a unique strain). There were no cases of transmissible strain infection in patients previously uninfected by Psa.

 

The authors concluded that their segregation policy has halted the spread of the commonest highly transmissible strain in the UK (LES) in their  clinic, without endangering patients who were not previously infected with Psa. They consider that the findings confirm that if genotypic surveillance is used, it is unnecessary to segregate patients infected with unique strains from those without Psa infection.

Not all would agree that uninfected patients be allowed to mix with those infected even by unique strains of P. aeruginosa.

 

Baxter CG, Moore CB, Jones AM, Webb AK, Denning DW. E-mediated immune responses and airway detection of Aspergillus and Candida in adult cystic fibrosis. Chest 2013; 143:1351-7. [PubMed]

A 2-year prospective observational cohort study was performed. Fifty-five adult patients with CF had sputum monitored for Aspergillus by culture and real-time polymerase chain reaction and Candida by CHROMagar and carbon assimilation profile (API/ID 32C). Skin prick tests and ImmunoCAP IgEs to a panel of common and fungal allergens were performed. Lung function and pulmonary exacerbation rates were monitored over 2 years.

Sixty-nine percent of patient sputum samples showed chronic colonization with Candida and 60% showed colonization with Aspergillus. There was no association between the recovery of either organism and the presence of specific IgE responses. There was no difference in lung function decline for patients with Aspergillus or Candida colonization compared with those without. However, there was a significantly greater decline in FEV1 and increase in IV antibiotic days for those sensitized to Aspergillus (FEV1 decline, P = .03; IV antibiotics days, P = .03).

The authors concluded allergic sensitization is not associated with recovery of Candida or Aspergillus from the sputum of patients with CF. Aspergillus but not Candida sensitization is associated with greater lung function decline and pulmonary exacerbations.

 

Bellin MD. Laguna T. Leschyshyn J. Regelmann W. Dunitz J. Billings J. Moran A. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes 2013; 14:417-421. [PubMed]

An open-label pilot study in CF patients with the G551D mutation given new prescriptions for ivacaftor. At baseline and 4wk after daily ivacaftor therapy, intravenous glucose tolerance tests (IVGTT) and oral glucose tolerance tests (OGTT) were performed.

Five patients aged 6-52 were studied. After 1month on ivacaftor, the insulin response to oral glucose improved by 66-178% in all subjects except one with long-standing diabetes. OGTT glucose levels were not lower in the two individuals with diabetes or the two with normal glucose tolerance (NGT), but the glucose tolerance category in the subject with impaired glucose tolerance (IGT) improved to NGT after treatment. In response to intravenous glucose, the only patient whose acute insulin secretion did not improve had newly diagnosed, untreated CFRD. The others improved by 51-346%. Acute insulin secretion was partially restored in two subjects with no measurable acute insulin response at baseline, including the one with IGT and the one with long-standing diabetes.

The authors concluded the results suggest there is a direct role of CFTR in human insulin secretion. Larger, long-term longitudinal studies are necessary to determine whether early initiation of CFTR correction, particularly in young children with CF who have not yet lost considerable beta-cell mass, will delay or prevent development of diabetes.

 

These are really encouraging results for the prevention of CF related diabetes would represent a major advance in improving the health and quality of life of the majority of adults with CF most of whom will eventually develop CF related diabetes mellitus.

Fig. 1a: Melena Bellin

www.diabetes.umn.edu

Dr Melena Bellin (figure 1a) is a paediatric endocrinologist at the Schulze Diabetes Institute, University of Minnesota. She completed her pediatric residency and pediatric endocrine fellowship training at the University of Minnesota, and joined the faculty as an Assistant Professor in 2009, with a joint appointment in Pediatrics and Surgery. Dr. Bellin’s research focus is islet transplantation (transplantation of the insulin producing cells of the pancreas) for patients with type 1 diabetes mellitus and for patients who have their pancreas removed to treat severe chronic pancreatitis.

 

Bridges N. Diabetes in cystic fibrosis. Paediatric Respiratory Reviews 2013; 14 Suppl 1:16-8. [PubMed]

Cystic fibrosis related diabetes (CFRD) is a common complication of cystic fibrosis, caused by a fall in insulin secretion with age in individuals with pancreatic insufficiency. CFRD is associated with worse clinical status and increased mortality. Treatment of CFRD with insulin results in sustained improvements in lung function and nutrition. While clinical experience with insulin treatment in CF has increased, the selection of who to treat and glycaemic targets remain uncle

 

Dr Nicola Bridges (figure 2) is paediatric endocrinologist and Service Director for paediatric medical specialities at the Chelsea and Westminster Hospital, London. She provides endocrinological expertise for the children attending the paediatric CF clinic at the Royal Brompton Hospital, London.

Fig. 2: Nicola Bridges

 

Byrnes CA. Vidmar S. Cheney JL. Carlin JB. Armstrong DS. Cooper PJ. Grimwood K. Moodie M. Robertson CF. Rosenfeld M. Tiddens HA. Wainwright CE. ACFBAL Study Investigators. Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age. Thorax 2013; 68:643-651. [PubMed]

The authors determined the rate, duration and clinical features of exacerbations in preschool children with CF and whether they were associated with changes in growth, lung structure and function at age 5 years.

168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year.  80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05).

 

The authors concluded respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group. It is interesting that the exacerbation rate was 26% lower in children receiving prophylactic antibiotics - lending some support to the UK recommendation of prophylactic flucloxacillin for all CF infants for the first 3 years.

 

Bilton D. Bellon G. Charlton B. Cooper P. De Boeck K. Flume PA. Fox HG. Gallagher CG. Geller DE. Haarman EG. Hebestreit HU. Kolbe J. Lapey A. Robinson P. Wu J. Zuckerman JB. Aitken ML. CF301 and CF302 Investigators. Pooled analysis of two large randomised phase III inhaled mannitol studies in cystic fibrosis. J Cyst Fibros 2013; 12:367-7. [PubMed]

To evaluate safety and efficacy of inhaled mannitol treatment in subgroups of a large global CF population. Data were pooled from two multicentre, double-blind, randomised, controlled, parallel group phase III studies in which 600 patients inhaled either mannitol (400 mg) or control (mannitol 50 mg) twice a day for 26 weeks. Both the mean absolute change in FEV(1) (mL) and relative change in FEV(1) by % predicted from baseline for mannitol (400 mg) versus control were statistically significant (73.42 mL, 3.56%, both p<0.001). Increases in FEV(1) were observed irrespective of rhDNase use. Significant improvements in FEV1 occurred in adults but not children (6-11) or adolescents (aged 12-17). Pulmonary exacerbation incidence was reduced by 29% (p=0.039) in the mannitol (400 mg) group.

 

The authors concluded there were sustained six-month improvements in lung function and decreased pulmonary exacerbation incidence indicating that inhaled mannitol is an important additional drug in the treatment of CF.

 

Berkhout MC. Rijntjes E. El Bouazzaoui LH. Fokkens WJ. Brimicombe RW. Heijerman HG. Importance of bacteriology in upper airways of patients with Cystic Fibrosis.  J Cyst Fibros 2013; 12:525-529. [PubMed]    

Recently the influence of the upper airways (UAW) on the general health of a patient with Cystic Fibrosis (CF) has been acknowledged. Surprisingly the microbiology of the upper compartment of the airways receives barely any attention in the treatment of CF. The aim of the present study was to investigate the microbiology of the upper airways in adult patients with CF, to correlate these findings with cultures from the lower airways (LAW) and with clinical characteristics. In this cross-sectional study bacteriological and clinical data were gathered from 104 adult patients with CF. UAW samples for culture were collected by nasal lavage and middle meatal swabs; LAW cultures were performed on expectorated sputum or cough swabs. Each patient performed the Rhinosinusitis Outcome Measure (RSOM-31).

In 72 patients (69.2%) UAW cultures yielded micro organisms other than normal nasal flora and in 50 patients (48.1%) Pseudomonas aeruginosa grew from the UAW cultures. Similarity between UAW and LAW cultures was determined in 50.0% of these 72 patients. In 3 patients P. aeruginosa was cultured from the UAW after successful eradication of P. aeruginosa from the LAW. P. aeruginosa in the UAW did not influence symptoms of sinonasal disease compared to other micro organisms.

 

The authors concluded comparison of UAW and LAW cultures in adult patients with CF showed one or more concordant micro organism in 50.0% of the patients. P. aeruginosa was most frequently cultured from the UAW. P. aeruginosa can be cultured from the UAW after eradication therapy which may suggest persistence of P. aeruginosa in the UAW. They feel this is may be a motive to include the UAW in eradication therapy in Cystic Fibrosis.

 

Undoubtedly the upper airways are now receiving more attention as a potential reservoir of infection. The relationship between the cultures from the upper and lower airways is not surprising but the persistence even after P. aeruginosa eradication therapy certainly suggests more active measures would be appropriate.  However, some years ago decontamination of the upper respiratory tract was attempted with regular polymyxin/tobramycin/amphotericin gel to treat patients newly colonised by P. aeruginosa infection but did not prove to be successful (Dalzell AM et al, 1990. [PubMed]).

 

Bradley JM, Blume SW, Balp MM, Honeybourne D, Elborn JS. Quality of life and healthcare utilisation in cystic fibrosis: a multicentre study. Eur Respir J 2013; 41:571-7. [PubMed]

The aim of this study was to discover the health status and healthcare utilisation associated with pulmonary exacerbations in cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection.

Patients with CF from five UK CF centres attended two visits, 8-12 weeks apart. They were classified at visit 1 as being in one of the three health states: no current pulmonary exacerbation; "mild" (no hospitalisation) pulmonary exacerbation; and "severe" (hospitalisation) pulmonary exacerbation. All patients completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and EuroQol (EQ-5D) and a clinical form, and forced expiratory volume in 1 s (FEV1) was measured at visits 1 and 2. Annual healthcare utilisation data were collected. 94 patients of mean±sd age 28.5±8.2 yrs and FEV1 58.7±26.8% were recruited.

60 patients had no pulmonary exacerbation, 15 had a mild and 19 had a severe pulmonary exacerbation at visit 1. EQ-5D and CFQ-R data showed that the worse the exacerbation, the poorer the health-related quality of life (HRQoL). There were strong relationships between the CFQ-R and EQ-5D domain scores. The mean rate of pulmonary exacerbations per patient per year was 3.6 (1.5 in hospital and 2.2 at home). The mean length of stay per hospital pulmonary exacerbation was 9 days. As exacerbation status worsens, patients experience worse HRQoL.

The authors confirmed that there is a significant healthcare burden associated with treatment of pulmonary exacerbation and long-term prophylaxis.

Fig. 3: Judy Bradley
Judy Bradley (Fig. 3) is Professor of Physiotherapy at the University of Ulster. She has had a distinguished career in respiratory diseases particularly cystic fibrosis both nationally and internationally.  She was presented with the Award of Distinguished Research Fellowship by the University in 2004 in recognition of her contribution to research in the area of respiratory physiotherapy. She was subsequently promoted to a Reader Joint Appointment at the University of Ulster/Belfast Health and Social Care Trust in 2005 and Professor in 2013.

 

Chan BK. Rupasinghe SN. Hennessey I. Peart I. Baillie CT. Retained central venous lines (CVLs) after attempted removal: an 11-year series and literature review. J Pediatr Surg 2013;  48:1887-91.  [PubMed]

This paper documents the incidence and management of retained CVLs in a tertiary pediatric surgical centre with access to interventional cardiology services. Children with retained CVLs were identified from departmental morbidity and mortality records over an 11-year period. The 11-year incidence of retained CVL was 0.3% (n=10; median duration in-situ 66.5 {range 47-146} months). The underlying pathology in 8 was cystic fibrosis. Antegrade transfemoral snare retrieval was successful in 6 of 7 attempts. In the remaining 3, a conservative approach was adopted following consultation with the family. None of the 4 with retained CVL developed complications (median follow-up 7.5 {range 1-53} months). The literature describes 38 pediatric index cases (including 10 from the current series). Seventeen (49%) were managed conservatively either intentionally or by default after failed endovascular removal attempt (n=4). No complications directly attributed to retained CVLs have been reported (median follow-up 40 {range 1-120} months). Reported morbidity associated with endovascular retrieval includes: procedural failure 30%, line embolization 8%, and intra-operative thrombo-embolism 8%.

 

The authors observed that literature regarding management of retained CVLs is anecdotal. Although uncommon, the complication should feature in consent for removal of CVLs. Conservative management carries long-term risks of infection, thrombosis, and even migration, albeit unquantified over a child's lifetime. Endovascular retrieval is feasible with appropriate expertise.

 

Chakrabarty B. Kabra SK. Gulati S. Toteja GS. Lodha R. Kabra M. Pandey RM. Srivastava A. Peripheral neuropathy in cystic fibrosis: a prevalence study. J Cyst Fibros 2013; 12:754-760.   [PubMed]                                                                                     

Information on peripheral neuropathy in children with cystic fibrosis is scanty. The aetiology can be multifactorial (micronutrient deficiency, chronic hypoxia, impaired glucose tolerance, immunological, vasculopathic, critical illness).                                                                                                            Forty five children with CF aged 1-18 years on vitamin E supplementation for at least 6 months underwent detailed neurological examination, serum vitamin E, vitamin B12, folate, copper levels and detailed nerve conduction studies.                                                                                               The mean age of the study population was 8.35 years (+4.9 years) with 62.2% being males. Overall 22 out of 45 (48.88%,CI: 33.7-64.2) had electrophysiological evidence of peripheral neuropathy which was predominantly axonal (86.4%), sensory (50%), and polyneuropathy (95.45%). There was no significant association between status of serum micronutrients and electrophysiological evidence of peripheral neuropathy.  The authors concluded that patients with CF have electrophysiological evidence of peripheral neuropathy (predominantly axonal, sensory and polyneuropathy). There is significant association of higher chronological age with occurrence of peripheral neuropathy.

It is interesting that there was no significant association with the levels of micronutrients. There is some evidence that there is an intrinsic neurological abnormality as part of the abnormality of CFTR. See also Reznikov Lr et al, 2013 re. neuropathy in CFTR deficient pigs [PubMed]) and El-Salem K et al, 2010. [PubMed].

 

Clancy JP. Szczesniak RD. Ashlock MA. Ernst SE. Fan L. Hornick DB. Karp PH. Khan U. Lymp J. Ostmann AJ. Rezayat A. Starner TD. Sugandha SP. Sun H. Quinney N. Donaldson SH. Rowe SM. Gabriel SE. Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function. PLoS ONE [Electronic Resource]. 8(9):e73905, 2013. [PubMed].                                                                                    

Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction.                                                                                                                                  Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (A/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P<0.005, CF vs non-CF for all parameters). Receiver Operating Characteristic curves indicated that each parameter discriminated CF from non-CF subjects (area under the curve of 0.94-0.98). CFTR dependent currents following 18-24 hours of cold storage for forskolin/IBMX, carbachol, and forskolin/IBMX+carbachol stimulation (n=17 non-CF subjects) were 44%, 47.5%, and 47.3%, respectively of those in fresh biopsies. CFTR-dependent currents from biopsies studied after cold storage at two sites simultaneously demonstrated moderate correlation (n=14 non-CF subjects, Pearson correlation coefficients 0.389, 0.484, and 0.533). Similar CFTR dependent currents were detected from fresh biopsies obtained by either forceps or suction (within-subject comparisons, n=22 biopsies from three non-CF subjects).

The authors concluded multicentre intestinal current measurement a feasible CFTR outcome measure that discriminates CF from non-CF ion transport, offers unique advantages over other CFTR bioassays, and warrants further development as a potential CFTR biomarker.

 

Previous studies were published as far back as 1991 – Veeze HJ, Sinaasappel M, Bijman J, Bouquet J, de Jonge HR. Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis. Gastroenterology 1991; 101:398-403. [PubMed]; Hardcastle J et al. Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis. Gut 1991; 32:1035-1039. [PubMed]; Cohen-Cymberknoh M et al, Pediatr Pulmonol 2013; 48:229-235. [PubMed].

 

Clancy JP. Dupont L. Konstan MW. Billings J. Fustik S. Goss CH. Lymp J. Minic P. Quittner AL. Rubenstein RC. Young KR. Saiman L. Burns JL. Govan JR. Ramsey B. Gupta R. Arikace Study Group. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax 2013; 68:818-825.[PubMed]     (free article available)

 Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. This study examined the safety and efficacy of 28 days of once-daily Arikace in CF patients chronically infected with P. aeruginosa.              

105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days.                

Results: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L+0.203 vs -0.032L+0.119; p=0.003) versus placebo. Sputum P. aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49).

The authors concluded that once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P. aeruginosa infection.

 

Coelho-Macias V. Fernandes S. Lamarao P. Assis-Pacheco F. Cardoso J. Aquagenic keratoderma associated with a mutation of the cystic fibrosis gene.  Rev Port Pneumol 2013; 19:125-8. [PubMed]

Reported for the first time in 1996, aquagenic keratoderma is a rare condition which is characterized by oedematous flat-topped papules appearing on palmar skin after water immersion. Multiple anecdotal associations have been described but, recently, the association with cystic fibrosis gene mutations (CFTR) has been highlighted. The authors describe an 18 year-old female, with one-month complaints of pruritus and swelling of palmar skin after water immersion. On examination, palmar skin was unremarkable but, 5 minutes after water immersion, multiple whitish papules became apparent. CFTR genotype study showed a F508del mutation in one allele. She had no other symptoms and no relevant family history. Aquagenic keratoderma is probably an under-diagnosed entity that might represent a manifestation of CFTR mutations, making carrier state identification and genetic counseling possible.

 

There has been much published on the reactions of the hands to water in CF since the first description of finger wrinkling by Prof. Bob Elliott from New Zealand in 1974 (above).

 

Cohen-Cymberknoh M. Yaakov Y. Shoseyov D. Shteyer E. Schachar E. Rivlin J. Bentur L. Picard E. Aviram M. Israeli E. Kerem E. Wilschanski M. Evaluation of the intestinal current measurement method as a diagnostic test for cystic fibrosis.Pediatr Pulmonol 2013; 48:229-235. [PubMed]

The aim of this study is to evaluate the diagnostic reliability of intestinal current measurements (ICM). Rectal biopsies were obtained from three groups: CF patients, controls, and patients who were suspected for CF. ICMs were performed by mounting the rectal biopsy in an Ussing chamber and sequentially adding secretagogues while recording current changes.

Twenty-one CF patients (aged 3.0+/-3.8 years) and 16 controls (aged 15.6+/-15.1 years) were examined and have remarkably different results (presented as A/cm(2) ): carbachol 16.3+/-6.9, histamine 13.2+/-8.9, and cAMP/forskolin 4.8+/-4.0 for control group and carbachol -1.5+/-5.3 (P<0.0001), histamine -1.5+/-3.1 (P<0.0001), and cAMP/forskolin 0.36+/-0.67 (P<0.0001) for the CF group. Our suggested reference values are: +5.40, +3.52, +2.19 for carbachol, histamine, and cAMP/forskolin, respectively. The combination parameter (the arithmetic sum of carbachol, histamine, and cAMP/forskolin) of +7.19 differentiates normal from abnormal (ROC curve analysis, area under the curve=1.00, both sensitivity and specificity are 100%). This statistical model was applied to 71 patients suspected for CF and revealed that 66 patients had normal ICM results (combination >7.19) and five patients had abnormal ICM results (combination <7.19).

The authors have shown that ICM tests may be useful to differentiate between patients suspected to have CF. They consider that these results require confirmation so that ICM may be included in diagnostic algorithms.

Further confirmation that intestinal current measurements can be used to differentiate CF and non-CF individuals.

 

Corris PA. Lung transplantation for cystic fibrosis and bronchiectasis.  Semin Resp Crit Care M 2013; 34:297-304.[PubMed]

Despite the challenges that the CF patients present, survival is more favourable than that seen in patients with chronic obstructive pulmonary disease and pulmonary fibrosis. Although those CF and bronchiectasis patients with severe respiratory disease are often infected with organisms that display in vitro resistance to the commonly used antibiotics, they usually have successful outcomes with transplantation, which are reported to be the same as in those patients with less resistant bacteria. Preoperative synergy testing has been demonstrated to reduce the presence of postoperative bacteremia and empyema in patients with CF. Newer challenges include the increasing presence of nontuberculous mycobacteria and in particular the rapid grower Mycobacterium abscessus, for which patient-to-patient spread has been recently recognized. The increased recognition of gastroesophageal reflux offers challenges regarding when and to whom one should offer fundoplication. Most potential CF recipients have metabolic bone disease warranting treatment, especially with the significant loss of bone density seen in the first year after transplantation. Diabetes mellitus, renal dysfunction, and hypertension and their consequences remain common and are of increasing importance as median survival increases in excess of 10 years. With increased experience, more programs are now transplanting patients who require membrane oxygenator support in addition to noninvasive ventilation pretransplantation and the use of a membrane device in the awake patient principally to remove excessive CO2 and reduce acidemia is worthy of note (Novalung; Novalung GmbH, Heilbronn, Federal Republic of Germany). Many centers now take the view that an awake and ambulant patient receiving such support represents a more favourable option than an intubated patient. The limiting factor in lung transplantation remains the number of organs available. Efforts to increase the donor pool, such as low tidal volume ventilation, are effective in allowing a greater percentage of offered organs to be accepted. Perhaps the most encouraging development, however, is that of ex vivo lung perfusion. This permits not only the ability to measure the function of the lungs, something of great value for lungs from donors with circulatory death (donation after cardiac death), but also the potential to introduce lung repair and convert a nonusable lung to one that can be safely used for transplantation.

 

This is a comprehensive account of the present situation regarding lung transplantation by Professor Paul Corris of the Freeman Hospital Newcastle - The UK's largest transplant unit. Both in Newcastle and in other units ex vivo lung perfusion to extend the life of the donor organs has permitted the use of lungs which previously would have been rejected. 

 

Dahabreh MM, Najada AS. Pseudo-Bartter syndrome, pattern and correlation with other cystic fibrosis feature. Saudi J Kidney Dis Transpl 2013; 24:292-29. [PubMed]

All patients with CF who attended the respiratory clinic at Queen Rania Al-Abdallah Hospital from January 2000 to April 2010 were included in this retrospective case-control study. Eighteen of 110 (16.3%) patients had one or more episodes of Pseudo-Bartter syndrome (PBS). The median follow-up period was 6.2 years. All the episodes occurred during summer and in infancy. Median age of the initial episode of PBS was three months. One-third of them were initially followed at the nephrology clinic. Three patterns of PBS were identified: single episode in three (16.6%) patients, recurrent in 12 (66.6%) patients and chronic in three (16.6%) patients. Early colonization of Pseudomonas spp before 1st birthday was seen in 44% patients with PBS compared with 12% in other CF patients (P-value = 0.0075) and their mean clinical score lower in those with recurrent PBS. Gene mutation was identified in only 30% of the entire cohort.

The authors concluded that PBS is common in patients with CF, and it should be kept in mind in any patient with hypotonic dehydration and metabolic alkalosis.

 

In hot climates PBS is obviously more likely to occur as in this instance. As we have mentioned previously, this syndrome will be identified if the precaution is taken to perform serum electrolytes on any infant, CF or non-CF, who has a significant degree of “failure to thrive” (see 'Topics - Electrolytes' for more on PBS).

 

Dalbøge CS, Pressler T, Høiby N, Nielsen KG, Johansen HK. A cohort study of the Copenhagen CF Centre eradication strategy against Staphylococcus aureus in patients with CF. J Cyst Fibros. 2013; 12:42-48. [PubMed]

All airway cultures from 300 patients at the Copenhagen CF centre in a 2-year period were retrieved and all anti-S. aureus antibiotic treatments were evaluated for treatment success. Chronic infection was defined as a positive culture of S. aureus in 50% or more of the months each year. Change in FEV(1) following 2 weeks of treatment of S. aureus was assessed in clinically stable patients. Primary outcome was S. aureus eradication at next clinical visit (visits are every month) and number of patients chronically infected.

The yearly prevalence of S. aureus intermittent and chronic infection was 47% and 14%, respectively. Eradication was successful at the next clinical visit in 61% of the standard treatment and 53% of the prolonged treatments, respectively. FEV(1) improved significantly following anti-S. aureus treatment (3.3%, p<0.0001).

The authors conclude that their anti-S. aureus eradication strategy in CF patients resulted in a low prevalence of chronic infections and high treatment efficacy. Furthermore, anti-staphylococcal treatment may be associated with a short-term improvement in lung function.

The authors state that “Antibiotic treatment of any relevant micro organisms, ignoring the presence or absence of respiratory symptoms has been our policy since the establishment of our centre in 1968”. They observe that “use of a stepwise two-drug antibiotic combination therapy strategy results in a high level of eradication with a prevalence of chronic S. aureus infection of less than 15% which ahs been unchanged for decades”.  This prevelance is much lower than the 50% reported in some patient registries.

 

Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG, Rodriguez S, Li H, Yen K, Ordonez CL, Ahrens R. VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Resp Crit Care 2013; 187:1219-1225. [PubMed]

This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in young patients with cystic fibrosis aged 6-11 years with at least one G551D-CFTR mutation. Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies.

Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was -53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups.

The authors concluded that in patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo.

These trials reporting the effects of ivacaftor must surely be the most sensational and important publications that have appeared to date relating to the treatment of CF.

 

Dhooghe B. Noel S. Bouzin C. Behets-Wydemans G. Leal T. Correction of Chloride Transport and Mislocalization of CFTR Protein by Vardenafil in the Gastrointestinal Tract of Cystic Fibrosis Mice. PLoS ONE [Electronic Resource]. 8(10):e77314.  [PubMed]                   These authors have previously shown that cGMP-dependent phosphodiesterase type 5 (PDE5) inhibitors rescue defective CF Transmembrane conductance Regulator (CFTR)-dependent chloride transport across the mouse CF nasal mucosa. Using F508del-CF mice, they examined the transrectal potential difference 1 hour after intraperitoneal injection of the PDE5 inhibitor vardenafil or saline to assess the amiloride-sensitive sodium transport and the chloride gradient and forskolin-dependent chloride transport across the GI tract. In the same conditions, we performed immunohistostaining studies in distal colon to investigate CFTR expression and localization.                                                                          F508del-CF mice displayed increased sodium transport and reduced chloride transport compared to their wild-type littermates. Vardenafil, applied at a human therapeutic dose (0.14 mg/kg) used to treat erectile dysfunction, increased chloride transport in F508del-CF mice. No effect on sodium transport was detected. In crypt colonocytes of wild-type mice, the immunofluorescence CFTR signal was mostly detected in the apical cell compartment. In F508del-CF mice, a 25% reduced signal was observed, located mostly in the subapical region. Vardenafil increased the peak of intensity of the fluorescence CFTR signal in F508del-CF mice and displaced it towards the apical cell compartment.

The authors consider the intestinal mucosa as a valuable tissue to study CFTR transport function and localization and to evaluate efficacy of therapeutic strategies in CF. They conclude that vardenafil mediates potentiation of the CFTR chloride channel and corrects mislocalization of the mutant protein. The study provides compelling support for targeting the cGMP signalling pathway in CF pharmacotherapy.

 

Over the past decade there has been a considerable amount of work on the effects of various phosphodiesterase inhibitors in reducing the effects of CFTR mutations which has not, as yet, been subjected to extensive clinical trials.

 

de Lima Marson FA, Bertuzzo CS, Secolin R, Ribeiro AF, Ribeiro JD. Genetic interaction of GSH metabolic pathway genes in cystic fibrosis. BMC Med Genet 2013; 14:60.

[PubMed]

Among the possible modifier genes of CF, those associated to metabolic pathways of glutathione (GSH) have been considered as potential modulators of CF clinical severity and thus of pivotal importance to investigate gene polymorphisms at Glutamate-Cysteine Ligase, Catalytic Subunit (GCLC), Glutathione S-transferase Mu 1 (GSTM1), Glutathione S-transferase Theta 1 (GSTT1), and Glutathione S-transferase P1 (GSTP1), which have been associated to the GSH metabolic pathway and CF clinical severity.

In this study a total of 180 CF patients were included, which investigated polymorphisms in GCLC and GST genes (GCLC -129C>T and -3506A>G; GSTM1 and GSTT1 genes deletion, and GSTP1*+313A>G) by PCR and PCR-RFLP associating to clinical variables of CF severity, including variables of sex, clinical scores [Shwachman-Kulczycki, Kanga e Bhalla (BS)], body mass index, patient age, age for diagnosis, first clinical symptoms, first colonization by Pseudomonas aeruginosa, sputum's micro organisms, haemoglobin oxygen saturation in the blood, spirometry and co morbidities. The CFTR genotype was investigated in all patients, and the genetic interaction was performed using MDR2.0 and MDRPT0.4.7 software.

The analysis of multiple genes in metabolic pathways in diseases with variable clinical expression, as CF disease, enables understanding of phenotypic diversity. This data shows evidence of interaction between the GSTM1 and GSTT1 genes deletion, and GSTP1*+313A>G polymorphism with CFTR gene mutation classes, and BS (Balance testing accuracy=0.6824, p=0.008), which measures the commitment of bronchopulmonary segments by tomography.

The authors conclude polymorphisms in genes associated with metabolism of GSH act on the CF's severity.

 

These findings are interesting in view of other work suggesting the importance of glutathione (see Topics - Drug modulation, New drugs).

 

Desai CS, Gruessner A, Habib S, Gruessner R, Khan KM. Survival of cystic fibrosis patients undergoing liver and liver-lung transplantations. Transplant Proc 2013; 45:290-292.

[PubMed]

The authors evaluated the outcome of combined liver-lung transplantation (L-LTx) in cystic fibrosis (CF) patients with liver transplantation (LTx) for CF liver disease. The United Network for Organ Sharing (UNOS) data were analyzed from October 1987 to August 2009.

Of 294 patients (210 children), 265 (90.1%) received an LTx and 29, an L-LTx. Patient survival was: adult LTx, 80%, 74%, and 67% at 1, 3, and 5 years, and L-LTx, 72%, 61.4%, and 61.4% (P = .7); pediatric LTx, 85%, 82%, and 74% at 1, 3, and 5 years, and L-LTx, 83%, 83%, and 83% (P = .4). Pediatric patients had a slight survival advantage over adults for LTx (P = .08). Graft survival, not affected by immunosuppression regimens, was similar to patient survival.

 

The authors concluded the outcome of liver lung transplantation appears similar to liver transplantation in CF providing support for the prospect of a combined transplant.

 

Drzymala-Czyz S. Kwiecien J. Pogorzelski A. Rachel M. Banasiewicz T. Plawski A. Szczawinska-Poplonyk A. Herzig KH. Walkowiak J. Prevalence of Helicobacter pylori infection in patients with cystic fibrosis. J Cyst Fibros 2013; 12:761-765.  [PubMed]                   

Helicobacter pylori (H. pylori) is one of the most common bacterial infections worldwide. The prevalence of Hp infection in cystic fibrosis (CF) is unclear – although there have been a number of previous studies. The aim of this study was to determine the prevalence of H. pylori infection in CF patients and to correlate H. pylori presence with CF expression.    The presence of H. pylori infection was assessed using a breath test with isotope-labelled urea in CF 79 patients compared to 302 healthy control subjects (HS).                                                                                      

Fifteen (19.0%) the CF patients were H. pylori positive. No statistical differences in the basic clinical parameters or in their distribution were documented. No clinical factor was an independent risk factor of H. pylori infection. The corrected prevalence of H. pylori infection in pediatric CF patients and HS was 14.4% and 9.8%, respectively.

The authors concluded that the prevalence of H. pylori infection in CF patients is not different from that in healthy subjects.

 

This confirms previous work that H. pylori does not seem to be a significant problem for people with cystic fibrosis. (See Topics -> Gastroenterology -> Helicobacter pylori).

 

Dugueperoux I. Audrezet MP. Parent P. Audebert-Bellanger S. Roussey M. Ferec C. Scotet V. Cascade testing in families of carriers identified through newborn screening in Western Brittany (France). J Cyst Fibros 2013; 12:338-44. [PubMed

An assessment of family testing following the identification of carriers by newborn screening for over 20 years, in an area where CF is frequent. The authors reviewed all of the carriers identified by NBS between 1991 and 2010 and registered the tests done in those families.

NBS identified 0.1% of the newborns as carriers, which correspond only to 2.6% of the expected carriers born within the period, and 1/3 of those with an increased IRT level. Of the 195 families, 75.9% requested testing (2.5 tests per family). We identified 183 carriers and five 1-in-4 risk couples. Reassurance about genetic status was provided to 96% of the couples.

The authors concluded that carriers detected by newborn screening appeared to be well managed in their area, and cascade testing that informs on genetic status seems relatively active.

 

The late Maurice Super successfully pioneered the use of "cascade screening" of relatives in the UK during the Nineties (Super M, Schwarz MJ, Malone G, Roberts T, Haworth A, Dermody G. Active cascade screening for carriers of cystic fibrosis gene. BMJ 1994; 308:1462-1467. [PubMed]). Identification of carriers is a major additional advantage of newborn CF screening; it difficult to understand those who initially opposed the disclosure of an infant’s carrier status.

 

Durmowicz AG. Witzmann KA. Rosebraugh CJ. Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest 2013; 143:14-18. [PubMed]

Ivacaftor is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV(1) and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV(1) and sweat chloride would facilitate development of new drugs that target the defective CFTR.

Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV(1) (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV(1), nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV(1) was apparent.

The lack of correlation of sweat chloride with improvement in FEV(1) speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points.

 

Ivacaftor is the first drug to alter the abnormal sweat electrolytes in people with CF. However, the numerous variables which influence the FEV make it unlikely that this single measure will be an accurate reflection of the effect of ivacaftor.

 

Eaden J. Peckham D. Myocardial infarction in an adult with cystic fibrosis and heart and lung transplant. Multidiscip Respir M 2013; 8:37. [PubMed]

 A myocardial infarction in a 19 year old female with cystic fibrosis who had a heart and lung transplant performed at the age of four years old. She presented atypically with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. A coronary angiogram showed proximal stenosis of the left anterior descending artery and right coronary artery. She was treated with percutaneous coronary intervention, involving drug eluting stents to the left anterior descending artery (LAD) and the right coronary artery (RCA).

 

In this study the authors discuss the pathophysiology, investigations and treatment of cardiac transplant vasculopathy. Although complete reversal of LAD and RCA stenosis was achieved, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events.

 

Farinha CM. King-Underwood J. Sousa M. Correia AR. Henriques BJ. Roxo-Rosa M. Da Paula AC. Williams J. Hirst S. Gomes CM. Amaral MD. Revertants, Low Temperature, and Correctors Reveal the Mechanism of F508del-CFTR Rescue by VX-809 and Suggest Multiple Agents for Full Correction. Chem Biol 2013; 20:943-55. [PubMed]

Cystic fibrosis is mostly caused by the F508del mutation, which impairs CFTR protein from exiting the endoplasmic reticulum due to misfolding. VX-809 is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA).

In this study the authors assessed if VX-809 is additive or synergistic with genetic revertants of F508del-CFTR, other correctors, and low temperature to determine its mode of action. They explored and integrated those various agents in combined treatments, showing how they add to each other to identify their complementary MoA upon correction of F508del-CFTR. Their experimental and modelling data, while compatible with putative binding of VX-809 to NBD1:ICL4 interface, also indicate scope for further synergistic F508del-CFTR correction by other compounds at distinct conformational sites/cellular checkpoints, thus suggesting requirement of combined therapies to fully rescue F508del-CFTR.

Trials are in progress of VX-809 combined with ivacaftor for patients with the F508del mutation.

 

Fainardi V. Koo SD. Padley SP. Lam SH. Bush A. Prevalence of scoliosis in cystic fibrosis. Pediatr Pulmonol 2013; 48:553-5. [PubMed]

The prevalence of idiopathic scoliosis in the general pediatric population is reported to be between 0.5% and 3.2%. Previous studies have reported an increased prevalence of scoliosis in children with cystic fibrosis. Chest X-rays of 319 patients attending the Royal Brompton CF Centre were reviewed. CF patients showed a similar prevalence of scoliosis as in the normal population (2.2% vs. 0.5-3.2%). There was the same gender (female) and side (right-sided) predilection as in normal population.

Also a recent comment – Acquisition bias may have led to acceptance of the false null hypothesis that prevalence off scoliosis is the same in cystic fibrosis as the general population (Hathorn C, et al. 2014 Pediatr Pulmonol 2014; 49:201.[PubMed]).

 

In a previous Leeds study (Kumar N et al, 2004) the incidence of scoliosis in the 132 CF children in the study was 15.6% - 20 times the prevalence in local non-CF children. However, these were children referred to Leeds since 1982 when chest involvement in many children was severe which presumably was a major contributory factor.

 

Fleet JE, Guha K, Piper S, Banya W, Bilton D, Hodson ME. Retrospective analysis of the impact of azithromycin maintenance therapy on adults attending a UK cystic Fibrosis clinic. J Cyst Fibros 2013; 12:49-53, [PubMed]

A retrospective study of 81 adult patients with CF taking continuous azithromycin from the Brompton clinic. Percentage predicted FEV1 and courses of intravenous antibiotics were examined at yearly intervals two years prior to and two years after azithromycin initiation. The FEV1 deteriorated in the two years before starting azithromycin by a mean of 2.02% per year and in the year after increased by 1.15% (P=0.01) but a mean 2.58% reduction was observed in year two. There was no statistically significant effect on courses of intravenous antibiotics in these older patients.

The authors concluded azithromycin resulted in an improved FEV1 at year one but this effect was not sustained beyond the first year of treatment. The CF Foundation guidelines recommend long term azithromycin for all patients of 6 years and older chronically infected with P. aeruginosa. In contrast, in the UK the CF Trust Antibiotic Working Group recommends azithromycin only if the patient is "deteriorating on conventional therapy"; the UK group considers there is insufficient evidence to recommend all patients with chronic P. aeruginosa should receive long term azithromycin. This present study from London would lend support to this UK view which.

 

Gelfond D. Ma C. Semler J. Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule.  Dig Dis Sci 2013; 58:2275-81.[PubMed]                                                                                                                                The authors utilized a wireless motility capsule (WMC) to study intestinal pH profile and gastrointestinal transit profile in CF subjects. The studies were done on ten adult CF patients with pancreatic insufficiency (PI) while off acid suppression medication and ten age, gender and BMI matched healthy controls.

A statistically significant difference was observed between mean pH values during the first 23 min of small bowel transit (p < 0.05). In CF subjects, there was a significant delay in time interval required to reach and sustain pH 5.5 and pH 6.0 (p < 0.001), which is required for PERT dissolution. Only small bowel transit in CF subjects was noted to be significantly delayed (p = 0.004) without a compensatory increase in whole gut transit time.

 

The authors confirmed the findings in a number of previous studies that there is significant delay in the small intestinal transit and a deficient buffering capacity required to neutralize gastric acid in the proximal small bowel of patients with CF. See also two studies from Leeds. One with a pH-sensitive radio telemetry capsule - Gilbert J et al. Ileal pH in cystic fibrosis. Scand J Gastroenterol 1988; 23(Suppl 143):132-134. [PubMed]; this confirmed the acid conditions detrimental to lipid digestion .are confined to the upper small bowel.  The length of time that small bowel pH exceeds 6.0 is adequate for dissolution of microencapsulated enzymes and lipid absorption. Also Seal S et al. Stable isotope studies on pancreatic enzyme release in vivo. Postgrad Med J 1996; 72 (Suppl 2):S37-S38. [PubMed]. As part of this investigation the oro-caecal transit time was found to be prolonged (6hrs Range 4.0-7.5 hrs) compared with the normal 1.0-2.0 hrs. Also Bali A et al. Prolonged intestinal transit time in cystic fibrosis. BMJ 1983; 287:1011-1013. [PubMed] was the first documentation of prolonged small bowel transit in CF (see entry in Eighties Clinical above).

 

Griese M. Kappler M. Eismann C. Ballmann M. Junge S. Rietschel E. van Koningsbruggen-Rietschel S. Staab D. Rolinck-Werninghaus C. Mellies U. Kohnlein T. Wagner T. Konig S. Teschler H. Heuer HE. Kopp M. Heyder S. Hammermann J. Kuster P. Honer M. Mansmann U. Beck-Speier I. Hartl D. Fuchs C. Glutathione Study Group. Hector A. Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial.  Am J Resp Crit Care 2013; 188:83-89. [PubMed] 

Glutathione is the major antioxidant in the extracellular lining fluid of the lungs and depleted in patients with cystic fibrosis (CF). This study aimed to assess glutathione delivered by inhalation as a potential treatment for CF lung disease. This randomized, double-blind, placebo-controlled trial evaluated inhaled glutathione in subjects with CF 8 years of age and older and FEV1 of 40-90% of predicted. Subjects were randomized to receive 646 mg glutathione in 4 ml (n = 73) or placebo (n = 80) via an investigational eFlow nebulizer every 12 hours for 6 months.

FEV1 (absolute values), both as pre-post differences (P = 0.180) and as area under the curves (P = 0.205), were the primary efficacy endpoints, and were not different between the glutathione group and the placebo group over the 6-month treatment period. Exploratory analysis showed an increase of FEV1 from baseline over placebo of 100 ml or 2.2% predicted; this was significant at 3 months, but not later. Subjects receiving glutathione had neither fewer pulmonary exacerbations, nor better scores for quality of life. Whereas increased glutathione and metabolites in sputum demonstrated significant delivery to the lungs, there was no indication of diminished oxidative stress to proteins or lipids, and no evidence for anti-inflammatory or antiproteolytic actions of glutathione supplemented to the airways. The adverse event incidence was similar between glutathione and placebo.

So the authors concluded that inhaled glutathione, in the dose administered, did not demonstrate clinically relevant improvements in lung function, pulmonary exacerbation frequency, or patient-reported outcomes. Glutathione delivery to the airways was not associated with changes in markers of oxidation, proteolysis, or inflammation.

 

Since 1974 there has been considerable interest in the use of inhaled glutathione - a prodrug of acetyl cysteine. The main facts are that glutathione is transported via CFTR and also much of the published work concerns the antioxidant properties.

 

Dr David Sheppard of Bristol summarised the situation in reply to a question put to the UK CF Trust. The main points of his reply were as follows – "In 1993 Dr Ron Crystal reported reduced levels of glutathione in the airway surface liquid of people with CF. In 1998 Drs Paul Linsell and John Hanrahan showed CFTR transports glutathione from inside to outside the cell but several less fold that chloride; Christine Bear suggests that CFTR may transport chloride and glutathione by different mechanisms. So glutathione transport is a normal function of CFTR suggesting that loss of CFTR contributes to the development and progression of CF. Dr Valerie Hudson of Brigham Young University has argued forcefully this point and in collaboration with Dr Clark Bishop has tested the effect on a small number of patients".

For more information visit "Topics - New Drugs - Glutathione. N-acetyl cysteine"

 

Gilchrist FJ. Cox KJ. Rowe R. Horsley A. Webb AK. Jones AM. Bright-Thomas RJ. Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis. J Cyst Fibros 2013; 12:399-402.[PubMed]                           

Although there have been case reports of hypothalamic-pituitary-adrenal (HPA) axis suppression in patients with cystic fibrosis (CF) caused by the combination of oral itraconazole and inhaled fluticasone, to date no study has assessed the incidence of this potentially serious side effect. Synacthen tests were conducted on all patients with CF receiving itraconazole and inhaled fluticasone and an equal number of patients with CF receiving inhaled fluticasone but not itraconazole. Itraconazole levels were measured in patients receiving the therapy. RESULTS: Twelve patients receiving itraconazole and fluticasone underwent synacthen tests. All 12 had abnormal synacthen test results and 10/12 (83%) had HPA axis suppression. Two patients had severe HPA axis suppression with a peak cortisol <75 nmol/L and further 3 patients had moderately severe suppression with a peak cortisol <250 nmol/L. In contrast, only 2/12 on fluticasone alone had HPA axis suppression (both mild). The median (range) basal cortisol levels were significantly lower in those patients receiving itraconazole and inhaled fluticasone compared to those on fluticasone alone (219(22-508) nmol/L v 348(41-738) nmol/L, p=0.02), similar results were seen for peak cortisol levels (404(59-706)nmol/L v 672(432-1178)nmol/L, p<0.001) and cortisol rise (179(37-240)nmol/L v 368(210-539)nmol/L, p<0.001). The median (range) itraconazole level was 5.5(1.7-14.7)mg/L. Neither itraconazole levels nor fluticasone dose correlated with the degree of adrenal suppression.

 

In this study, all patients receiving itraconazole and inhaled fluticasone had abnormal synacthen test results. The incidence of HPA axis suppression with this treatment combination appears to be higher than that previously reported with itraconazole and inhaled budesonide.

Important information for those treating patients with allergic pulmonary aspergillosis.

 

Goralski JL, Lercher DM, Davis SD, Dellon ES. Eosinophilic esophagitis in cystic fibrosis: a case series and review of the literature. [Review] J Cyst Fibros 2013; 12:9-14. [PubMed]

Three patients with eosinophilic esophagitis (EoE) are reported. EoE is a TH-2 driven, allergen-mediated disease which is diagnosed by esophageal biopsies.

There have been no prior cases documenting the co-existence of EoE an CF although oesophageal reflux in people with CF and its potential consequences has received much attention over many years.

 

Grassme H, Riethmuller J, Gulbins E. Ceramide in cystic fibrosis. [Review]  Handbook of Experimental Pharmacology 2013; 216:265-274, 2013. [PubMed]

Recent studies have shown that sphingolipids, especially ceramide, play a crucial role in the pathogenesis of cystic fibrosis. These studies have demonstrated that ceramide accumulates in the lungs of cystic fibrosis patients and mice, causing inflammation and high susceptibility to bacterial infections.

The results of initial clinical studies suggest that interfering with sphingolipids may be a novel treatment strategy for cystic fibrosis.

 

Goncalves AC. Marson FA. Mendonca RM. Ribeiro JD. Ribeiro AF. Paschoal IA. Levy CE. Saliva as a potential tool for cystic fibrosis diagnosis. Diagn Pathol 2013; 46:2014. [PubMed]

 The aim of this study was to compare the concentrations of sodium and chloride ions in saliva samples taken from CF patients and healthy subjects. The chloride and sodium concentrations in the saliva samples were higher for CF patients in comparison with healthy subjects.

 

Although the authors considered the use of saliva as a tool for CF diagnosis could be considered a new challenge and recommended a population study including patients in all age classes be performed in different countries over the world, the subject has been explored on a number of occasions in the past and the degree of separation between normal and CF individuals considered to preclude the use of saliva for diagnosis. (See Electrolytes in the Topics section: Johnson WH. Salivary electrolytes in fibrocystic disease of the pancreas. Arch Dis Child 1956; 31:477-480. [PubMed]; Lawson D. Use of a micro-sodium electrode in the diagnosis of cystic fibrosis. Bibl Paediatr 1967; 86:273-278. [PubMed]). So it would be difficult to support their suggestions.

 

Goss CH. Ratjen F. Update in cystic fibrosis 2012.[Review]. Am J Resp Crit Care. 187(9):915-9, 2013 May 1. [PubMed]

A brief review of the progress in cystic fibrosis research and management during 2012. In summary the authors note that there have benn major advances in in care and clinical outcome of persons with cystic fibrosis. To quote from the introduction 1."Animal models are shaping our understanding of the early physiological changes in CF airways. 2. but persistent challenges persist in understanding key componenents of airway infection, airway inflammation, as well as how to translate this knowledge into treatment of persons with the lung disease. We highlight some of the important scientific developments in CF during 2012, focusing on infection, airway inflammation, novel treatments, and issues surrounding lung transplantation."

 

Gunduz O, Ozsarac KC, Ercin ME. Aquagenic palmar wrinkling induced by combined use of salazopyrin and indomethacin. Case Reports Dermatology 2013; 5:21-26. [PubMed]

Despite some studies implying a relationship between cystic fibrosis and aquagenic palmar wrinkling (APW), there are also reports of APW cases without an accompanying CF. In this report the authors describe a 19-year-old ankylosing spondylitis patient, who developed APW lesions after the start of combined salazopyrin and indomethacin treatment. His palmar lesions were resistant to topical corticosteroid and aluminium hydroxide therapy and disappeared only after stopping the anti-inflammatory drugs.

 

Hansen CR, Pressler T, Ridderberg W, Johansen HK, Skov M. Achromobacter species in cystic fibrosis: cross-infection caused by indirect patient-to-patient contact.  J Cyst Fibros. 2013; 12:609-15.  [PubMed]                                                                                                        A report of cases of Achromobacter ruhlandii cross-infection between patients after well-described indirect contact.  Both cases were young, stable, CF patients without chronic infections and with normal FEV1, but experienced clinical deterioration after visits to the home of a CF patient with A. ruhlandii infection and after sharing facilities with an A. ruhlandii infected CF patient on a skiing vacation, respectively. Both cases became positive for A. ruhlandii in airway secretions and were colonized with A. ruhlandii in their sinuses. Aggressive, long-term antibiotic treatment led to clinical stability. One of the cases developed chronic A. ruhlandii infection.

Achromobacter species can cause cross-infection even after a short period of indirect contact between infected and non-infected CF patients. The authors suggest the patients should be followed closely for several months before the possibility of cross-infection is ruled out.

 

Harrison MJ, Murphy DM, Plant BJ.
Ivacaftor in a G551D Homozygote with Cystic Fibrosis
N Eng J Med 2013; 369: 1280 - 1282.  [PubMed] No abstract but free article via PubMed.

An interesting report of the use of ivacaftor in a 19-year-old woman who was homozygous for the G551D mutation. After a period of progressive deterioration with recurrent infective exacerbations (seven separate courses of intravenous antibiotics in the previous 12 months), the baseline FEV1 had decreased to 24% of the predicted value, she had become dependent on oxygen, and she was referred for assessment for lung transplantation. Simultaneously, ivacaftor therapy was initiated. Within 8 weeks, the FEV1 had increased to 35% of the predicted value, continuous oxygen was discontinued with a resting oxygen saturation of 95% (it was previously 85%) while the patient was breathing ambient air, and assessment for transplantation was deferred. Prospectively, over the subsequent 12 months of therapy, she required one course of intravenous antibiotics, the FEV1 increased by 16 percentage points (from 24 to 40% of the predicted value), the sweat chloride level decreased from 92 mmol per liter to 18 mmol per liter, the 6-minute walk distance increased by 410 m (from 140 to 550 m), and the weight increased by 8.4 kg (from 42.0 to 50.4 kg In addition, the serum albumin level increased from 3.3 g per deciliter to 4.5 g per deciliter, and the daily consumption of pancreatic-enzyme supplements decreased by approximately 60%.

 

In the VX08-770 clinical-trial cohort of patients who were heterozygous for the G551D mutation, the improvements in sweat chloride levels and the FEV1 reached a plateau after 2 weeks. To date, we have not found a plateau effect with ivacaftor therapy in our G551D homozygous patient. The progressive reduction and normalization of the sweat chloride level (a marker of CFTR dysfunction), coupled with the continued clinical improvements in lung function, weight, and walk distance throughout the 12-month follow-up period provide support for the increased efficacy of ivacaftor in homozygous versus heterozygous patients.

Ireland has the highest reported frequency of the G551D mutation worldwide, at 12% (as compared with 4.4% in the United States), and eight persons with cystic fibrosis in Ireland are known to be homozygous for the G551D mutation. Prospective analysis involving this cohort may confirm our observation.

 

Dr Barry Plant (figure 3a) of the College of Medicine and Health, Alimentary Pharmabiotic Centre and the HRB - Clinical Research Facility, University College Cork/Cork University Hospital, Ireland. He is Director of the Adult CF Unit there and heads a recently formed international consortium of Cystic Fibrosis clinicians and scientists, in a major EU-funded collaboration project focused on the development and trial of personalized antibiotic treatment for patients with CF during respiratory infections. CFMATTERS an acronym for ‘Cystic Fibrosis Microbiome-determined Antibiotic Therapy Trial in Exacerbations: Results Stratified’ will receive approximately €6 million in funding from the European Union's Seventh Framework Programme.

Fig. 3a: Barry Plant

Dr Desmond Murphy has been consultant Respiratory Physician at Cork University Hospital since 2009 having worked at both the Freeman Hospital Newcastle and McMaster University, Canada

 

Hubert D. Reglier-Poupet H. Smet-Gaudelus I. Ferroni A. Le Bourgeois M. Burgel PR. Serreau R. Dusser D. Poyart C. Coste J. Association between Staphylococcus aureus alone or combined with Pseudomonas aeruginosa and the clinical condition of patients with cystic fibrosis. J Cyst Fibros 2013; 12:497-503. [PubMed]

In a retrospective study on 419 sputum producer CF patients (293 adults and 126 children >7years of age), S. aureus was found in 72% of the patients: MSSA in 68.2% of children and 48.8% of adults; MRSA in 17.5% of children and 17.8% of adults. Sixty percent of MRSA patie and 60.4% of MSSA patients also harboured PA. The rate of deterioration of clinical status of the various groups, as assessed from respiratory function, IV antibiotic courses and hospitalisations, increased in the order: no SA/no PA, MSSA alone, MRSA alone, MSSA/PA, MRSA/PA, and PA alone. Nutritional status did not differ between groups. Results were roughly similar for children and adults.

The yearly FEV1 decline was significantly higher only for MRSA/PA patients (p=0.03) compared to no SA/no PA patients.

Clinical condition of CF patients with MSSA only or MRSA only appeared similar, whereas MRSA/PA patients had more severe respiratory function than MSSA/PA patients. In CF patients, MRSA might be more deleterious than MSSA only when associated with PA.

 

It is surprising that so many patients in this series (68.2% of the children) are allowed to become chronically infected with a known pathogen such as MSSA when in the majority chronic infection can be avoided by eradication therapy. We surely do not require a controlled trial to know that S. aureus is a damaging pathogen that used to kill children with CF and one which should always be eradicated when cultured!! 

 

Horsley AR. Davies JC. Gray RD. Macleod KA. Donovan J. Aziz ZA. Bell NJ. Rainer M. Mt-Isa S. Voase N. Dewar MH. Saunders C. Gibson JS. Parra-Leiton J. Larsen MD. Jeswiet S. Soussi S. Bakar Y. Meister MG. Tyler P. Doherty A. Hansell DM. Ashby D. Hyde SC. Gill DR. Greening AP. Porteous DJ. Innes JA. Boyd AC. Griesenbach U. Cunningham S. Alton EW. Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation. Thorax 2013; 68:532-9. [PubMed]

A study by members of the UK Gene Therapy Consortium to evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for their 2013-2014 clinical trial of CFTR gene therapy. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers.

Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31).

The authors identified the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with their study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.

The UK Gene Therapy Consortium commenced their multi-dose major gene therapy trial in June 2012 (Alton EW et al. Pediatr Pulmonol 2013; Suppl 36: Poster 245). This study helped to determine the parameters which would be used in the trial. The primary outcome chosen was the FEV1 and secondary outcomes the lung clearance index, CT changes and CFQ questionnaire. The trial will be completed around June 2014.

 

The Cystic Fibrosis Trust provided substantial funding for these studies and many other studies during the decade leading up to the 2013/14 gene therapy trial but the charity was unable to fund the trial itself. However, the GTC, due to the excellence of their work, were successful in achieving funding from the Medical Research Council  Efficacy and Mechanism Evaluation (EME) funding.

 

Inci I. Benden C. Kestenholz P. Hillinger S. Schneiter D. Ganter M. Bechir M. Grunenfelder J. Weder W. Simultaneous bilateral lobar lung transplantation: one donor serves two recipients. Ann Thorac Surg 2013; 96:e69-71.  [PubMed]                                              

There is a shortage of suitable donor organs, in particular for small or pediatric patients. Simultaneous bilateral lobar lung transplantation derived from one large donor into two small recipients is reported. The upper lobes were transplanted into the smaller female recipient, and the middle and right lower lobe and left lower lobe were transplanted into the male recipient.

 

Inci I. Schuurmans MM. Kestenholz P. Schneiter D. Hillinger S. Opitz I. Boehler A. Weder W. Long-term outcomes of bilateral lobar lung transplantation. Eur J Cardio-Thorac 2013; 43:1220-5. [PubMed]

Lobar lung transplantation is an option that provides the possibility of transplanting an urgent listed recipient of small size with a size-mismatched donor lung by surgically reducing the size of the donor lung. The authors report their short- and long-term results with bilateral lobar lung transplantation (BLLT) and compare it with the long-term outcomes of our cohort.

Retrospective analyses of 75 lung transplant recipients who received downsized lungs with a special focus on 23 recipients with BLLT performed since January 2000. Postoperative surgical complications, lung function tests, late complications and survival were analyzed. The decision to perform lobar transplantation was considered during allocation and finally decided prior to implantation.

Cystic fibrosis was the most common indication (43.5%) followed by pulmonary fibrosis (35%). Median age at transplantation was 41 (range 13-66) years. Fifteen were females. Nineteen of the transplantations (83%) were done with extracorporeal membrane oxygenation (ECMO) support; 3 of them were already on ECMO prior to transplantation. There was no 30-day or in-hospital mortality. No bronchial complications occurred. The most common early complication was haematothorax (39%), which required surgical intervention. The rate of postoperative atrial arrhythmias was 30%. Forced expiratory volumes in 1 s (% predicted) at 1 and 2 years were 76 +/- 23 and 76 +/- 22, respectively (mean +/- standard deviation). By 2-year follow-up, bronchiolitis obliterans syndrome was documented in 3 patients with a median follow-up of 1457 days. Overall survivals at 1 and 5 years were 82 +/- 8 and 64 +/- 11%, respectively and were comparable with those of 219 other recipients who received bilateral lung transplantation during the same period (log rank test, P = 0.56).

 

This study demonstrates that BLLT has short- and long-term outcomes comparable with those of standard bilateral lung transplantation. The limitation of lung transplantation due to size-mismatch, particularly in smaller recipients, could be overcome by utilizing lobar lung transplantation.

 

Jagannath VA. Fedorowicz Z. Thaker V. Chang AB. Vitamin K supplementation for cystic fibrosis. [Update of Cochrane Database Syst Rev. 2011;(1):CD008482; PMID: 21249710]

Cochrane Database of Systematic Reviews. 4:CD008482, 2013. [PubMed]

To assess the effects of vitamin K supplementation in people with cystic fibrosis and to determine the optimal dose and route of administration of vitamin K for both routine and therapeutic use. Two trials (total of 32 participants) were included in the review and were assessed as having a moderate risk of bias.

The authors concluded that evidence from randomised controlled trials on the benefits of routine vitamin K supplementation for people with CF is currently weak and limited to two small trials of short duration. However, no harm was found and until further evidence is available, the present recommendations of 1 mg daily should be adhered to.

 

Jones A. Bilton D. Evans TW. Finney SJ. Predictors of outcome in patients with cystic fibrosis requiring endotracheal intubation. Respirology 2013; 18:630-636. [PubMed]

Thirty patients required intubation on 34 occasions. Eleven patients died in ICU and 7 after ICU but not hospital discharge. Fifty-nine per cent of 22 patients intubated for pneumothorax and/or haemoptysis survived to hospital discharge. Of the twelve intubated for infective exacerbations, 33% survived to hospital discharge. Those who died after hospital discharge survived 447 days. Osteoporosis and a greater fall in body mass index over the 24 months prior were more frequent in non-survivors.

 

So experience at the Royal Brompton Hospital, London indicated patients with CF developing haemoptysis and/or pneumothorax should be admitted to ICU and intubated promptly, should this be required. Chronic disease markers may be more relevant prognostically than rates of hospitalization or forced expiratory volume in 1s decline which the authors suggest should not be bars to invasive ventilation.

 

Jih KY. Hwang TC. Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Proc Nat Acad Sci 2013; 110:4404-9[PubMed]

The underlying mechanism for the action of Vx-770 remains elusive partly because this compound not only increases the activity of wild-type (WT) channels whose gating is primarily controlled by ATP binding/hydrolysis, but also improves the function of G551D-CFTR, a disease-associated mutation that abolishes CFTR's responsiveness to ATP. Their data (see summary) corroborate that Vx-770 increases the open time of WT-CFTR by stabilizing a post hydrolytic open state and thereby fosters decoupling between the gating cycle and ATP hydrolysis cycle. The current study also suggests that this unique mechanism of drug action can be further exploited to develop strategies that enhance the function of CFTR.

 

Kidd TJ, Ramsay KA, Hu H, Marks GB, Wainwright CE, Bye PT, Elkins MR, Robinson PJ, Rose BR, Wilson JW, Grimwood K, Bell SC. ACPinCF Investigator Group. Shared Pseudomonas aeruginosa genotypes are common in Australian cystic fibrosis centres. Eur Resp J 2013; 41:1091-100. [PubMed]

Recent molecular-typing studies suggest cross-infection as one of the potential acquisition pathways for Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In Australia, there is only limited evidence of unrelated patients sharing indistinguishable P. aeruginosa strains. The authors therefore examined the point-prevalence, distribution, diversity and clinical impact of P. aeruginosa strains in Australian CF patients nationally.

983 patients attending 18 Australian CF centres provided 2887 sputum P. aeruginosa isolates for genotyping by enterobacterial repetitive intergenic consensus-PCR assays with confirmation by multilocus sequence typing. Demographic and clinical details were recorded for each participant.

Overall, 610 (62%) patients harboured at least one of 38 shared genotypes. Most shared strains were in small patient clusters from a limited number of centres. However, the two predominant genotypes, AUST-01 and AUST-02, were widely dispersed, being detected in 220 (22%) and 173 (18%) patients attending 17 and 16 centres, respectively. AUST-01 was associated with significantly greater treatment requirements than unique P. aeruginosa strains.

 

Thus multiple clusters of shared P. aeruginosa strains are common in Australian CF centres. At least one of the predominant and widespread genotypes is associated with increased healthcare utilisation.

Although the authors conclude that longitudinal studies are now needed to determine the infection control implications of these findings, experience from elsewhere, such as the UK, indicates that strict patient segregation is required. A similar survey was carried out in the UK in 2003/4 (Scott FW et al. 2004. J Med Microbiol 2004; 53:609-615.) the results of which had a major influence on the national introduction of infection control measures.

 

Kelly A. Moran A. Update on cystic fibrosis-related diabetes. J Cyst Fibros 2013; 12:318-31. [PubMed]

This paper reviews the 2010 U.S. and other international guidelines for screening and treating CFRD. It highlights newer data regarding early glucose and insulin secretion defects, mechanisms linking CFRD to worse outcomes, and recent advances in T2DM that may provide insights for CFRD; insulin secretion is be reviewed as background for these recent developments.

A detailed review of the present situation regarding the recognition and management of CFRD by recognised experts in the condition.

 

Karanth L. Barua A. Kanagasabai S. Nair NS. Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders. Cochrane Database of Systematic Reviews. 4:CD009824, 2013.

[PubMed]

The authors reviewed randomised and quasi-randomised controlled trials investigating the efficacy of desmopressin acetate versus tranexamic acid or factor VIII or rFactor VII or fresh frozen plasma in preventing and treating congenital bleeding disorders during pregnancy were eligible. The review did not identify any randomised controlled trials investigating the relative effectiveness of desmopressin acetate for bleeding during pregnancy in women with congenital bleeding disorders. In the absence of high quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials) to decide whether or not to treat women with congenital bleeding disorders with desmopressin acetate.

 

Our experience in Leeds suggests that desmopressin should be used with extreme caution in people with cystic fibrosis. (Simmonds EJ, Mahony MJ, Littlewood JM. Convulsion and coma after intranasal desmopressin in cystic fibrosis. BMJ 1988; 297:1614.[PubMed]).

A 13 yr old girl with CF was given 10ug, 20ug, 20 ug, and 10ug on consecutive mornings for nocturnal enuresis. On the morning after her fourth dose of desmopressin the patient developed headache, nausea, and vomiting. She had remained dry for the first time the previous night. Review of her weight chart showed a sharp weight gain since treatment started: 41.35 kg to 43.15 kg. On the third day of treatment serum sodium concentration had been 125 mmol/l and on the fourth day this had fallen to 114 mmol/l. Later that day she had a convulsion lasting about five minutes and subsequently remained comatose. Her desmopressin was discontinued and she was managed with fluid restriction alone to prevent possible pontine myelinolysis. Twenty eight hours after her last dose of desmopressin she passed urine again and continued to pass good quantities of dilute urine. Forty hours after fluid restriction was started intravenous fluids with her normal daily sodium requirements were started. Her serum sodium concentration rose and five days later was normal (135 mmol/l). Forty eight hours after her convulsion she was still deeply comatose.. Physical examination showed response only to deep pain, poor corneal reflexes, absent cough reflex, and absent peripheral reflexes. Computed tomography of her head and lumbar puncture showed nothing abnormal. Fortunately she gradually regained consciousness and over two weeks returned to normal with no neurological sequelae.
This patient with cystic fibrosis had a very severe adverse reaction to intranasal desmopressin.

 

Kernan NG, Alton EW, Cullinan P, Griesenbach U, Bilton D. Oral contraceptives do not appear to affect cystic fibrosis disease severity. Eur Resp J 2013; 41:67-73. [PubMed]

A retrospective study of the effects of oral contraceptive (OCs) on clinical outcomes in females with CF. Data from 681 females were available, of whom 42% had taken OCs for varying periods of time. There were no differences between the two groups. Nor did an an intra-patient analysis of the same outcomes over a 3-yr period. The authors concluded that the use of OCs does not affect CF disease severity.

A reassuring report for women with CF of experience from a major adult CF Centre.

 

Kriemler S. Kieser S. Junge S. Ballmann M. Hebestreit A. Schindler C. Stussi C. Hebestreit H. Effect of supervised training on FEV1 in cystic fibrosis: a randomised controlled trial. J Cyst Fibros 2013; 12:714-720. [PubMed]                                                                                            A study to determine the positive effects of long-term exercise training on FEV1. 39 Swiss patients with CF were randomly divided into strength training (ST, n=12), endurance training (AT, n=17) and controls (CON(CH), n=10), and also compared with age-matched Swiss (n=35) and German (n=701) CF registry data. A partially supervised training of 3x30 min/week for 6 months took place with measurements at baseline and after 3, 6, 12 and 24 months. Primary outcome was FEV1 at 6 months.                                                                                            

The FEV1 increased significantly in both training groups compared with the controls (AT:+5.8+0.95, ST:+7.4+2.5, CON(CH):-11.5+2.7% predicted, p<0.001) and both registry groups at 6 months. At 24 months, changes in favour of the training groups persisted marginally compared with controls, but not compared with registry data.

The authors concluded partially supervised training over 6 months improved FEV1 but effects were basically gone 18 months off training. Regular long-term training should be promoted as essential part of treatment in CF.

 

Kopp BT. Kirkby S. Hayes D Jr. Flanigan KM. Diabetic myonecrosis in a cystic fibrosis patient.  Resp Care 2013; 58:e123-5.  [PubMed]                                                                       The authors report the case of a 32-year-old with poorly controlled diabetes presenting with sub-acute leg pain and focal quadriceps tenderness. Neuromuscular testing and extensive workup revealed diabetic myonecrosis. To the authors’ knowledge, this is the first reported case of diabetic myonecrosis in a patient with CF, and highlights the need for pulmonary physicians to recognize this diabetic complication in CF patients, which is associated with a poor long-term prognosis and existing microvascular complications.

 

Lavin J. Bhushan B. Schroeder JW Jr. Correlation between respiratory cultures and sinus cultures in children with cystic fibrosis. Int J Pediatr Otorhi 2013; 77:686-9.[PubMed]     Previous studies have had varying results on the correlation between respiratory and sinus cultures so further investigation is warranted.   Bacterial growth from preoperative sputum, bronchoalveolar lavage, and oropharyngeal cultures were compared to the bacterial growth from intraoperative sinus cultures in patients with cystic fibrosis undergoing endoscopic sinus surgery.

In the patients over eight years of age, 16 of 26 sputum cultures matched sinus cultures (p=0.4). When sputum cultures with normal flora and no growth were eliminated, 16 of 21 matched sinus cultures (p=0.02). No statistically significant associations were found for sputum cultures in patients under eight years of age. No statistically significant associations were found between oropharyngeal or bronchoalveolar lavage cultures and intraoperative sinus cultures from patients of any age. When Staphylococcus aureus was cultured from sputum in patients over eight years of age the positive and negative predictive values that S. aureus would be cultured from the sinuses were 100% and 75% respectively. The positive and negative predictive values for Pseudomonas aeruginosa were 73% and 86% respectively.  

            

The authors concluded that in children with CF who are over eight years of age, organisms grown from sputum cultures are similar to organisms grown from sinus cultures when bacterial growth is present.

 

Ledger SJ. Owen E. Prasad SA. Goldman A. Willams J. Aurora P. A pilot outreach physiotherapy and dietetic quality improvement initiative reduces IV antibiotic requirements in children with moderate-severe cystic fibrosis. J Cyst Fibros 2013; 12:766-772.[PubMed]        The current model of care for children with moderate-severe CF is focused on intensive inpatient intervention, regular outpatient clinic review and specialist outreach care as required. An alternative model providing more regular physiotherapy and dietetic outreach support, in addition to these specialist services, may be more effective.  Introduction of such a policy             resulted in a 23% reduction in inpatient IV antibiotic requirement and 20% reduction in home IV antibiotic requirement during the intervention year. The authors concluded that this pilot programme demonstrated a reduction in IV and admission requirements with a cost benefit in a small group of children with moderate-severe CF.

The confirmation of benefit from this more intensive approach is to be expected and welcome. It is doubtful if such a finding would warrant a full scale trial however.

 

Leonard A, Lebecque P, Dingemanse J, Leal T, Miglustat effects on the basal nasal potential differences in cystic fibrosis. J Cyst Fibros 2013; 12:89. [PubMed]

Confirmation of their previous work, in reply to a letter questioning their findings, that in a model of respiratory CF cells chronically treated with low-concentration miglustat, rescue of F508delCFTR function was maximal and then stable after 4 days treatment while disappearing within 4 days of washing out the drug.

 

Lindig J. Steger C. Beiersdorf N. Michl R. Beck JF. Hummel T. Mainz JG. Smell in cystic fibrosis. Eur Arch Oto-Rhino-L 2013; 270:915-921. [PubMed]

Thirty-five CF patients of different ages were compared to 35 age-matched healthy controls. Olfactory function was assessed by 'Sniffin'Sticks', gustatory qualities by "Taste-strips", and symptoms by sino-nasal outcome test 20 (SNOT-20).

Normosmia was found in 62.8 % of healthy controls but only in 28.6 % of CF patients. In contrast the majority of CF patients exhibited a smell loss; almost 62.9 % of them were hyposmic, and 8.6 % functionally anosmic. Importantly, reduced olfactory function only affected odour thresholds, which were significantly increased in CF, not odour identification. This suggests that the olfactory dysfunction in CF results from the olfactory periphery due to either problems in conduction and/or a functional lesion due to the inflammatory process. SNOT-20 scores increased continuously from normosmic to hyposmic and anosmic CF patients (means 7.2/11.1/28.3 points). Neither sinonasal pathogen colonization, gender, pulmonary function, nor allergy or sinonasal surgery appeared to have significant effects on olfactory function and taste.

The authors conclude olfactory disorders are considerably more frequent in CF patients than in age-matched healthy controls. Assessing these parameters within CF-routine care should be considered because of their importance to nutrition and, thus, overall therapy outcome.

 

Certainly this problem is very relevant in people with CF and likely to be a contributory factor to poor appetite and inadequate dietary intake. As the condition in the upper respiratory tract nor treatment had a significant effect it is difficult to see how the situation could be improved. As more CF patients had reduced rather than absent sense of smell, which affected only 8.6%, increasing the olfactory stimuli from food etc would presumably be a first step in improving the situation. However, a previous study found that nutritional status was unrelated to the sensation of smell (Aitken ML et al. Sensation of smell does not determine nutritional status in patients with cystic ifbrosis. Pediatr Pulmonol 1997; 24:52-56. [PubMed])

 

Leung JM. Olivier KN. Nontuberculous mycobacteria: the changing epidemiology and treatment challenges in cystic fibrosis. Curr Opin Pulmon Med 2013; 19:662-9.   [PubMed]

Although overall rates of NTM isolation appear to be increasing, particular concern has focused on the emerging predominance of Mycobacterium abscessus. New data suggest that chronic macrolide therapy now part of routine CF care has contributed to this rise; however, these have yet to be confirmed prospectively. Transmission of M. abscessus between CF patients has also now been described through the use of genome sequencing. Although the greater virulence of M. abscessus makes it a challenging species to treat, identification of the subspecies type can now determine the presence of inducible macrolide resistance, thereby helping to guide treatment.

 

Given increasing prevalence rates, the authors suggest clinicians should maintain a high level of suspicion for NTM as disease-causing organisms in CF, particularly for M. abscessus. New knowledge regarding this species, however, can help to tailor appropriate therapy.

 

Mayer-Hamblett N. Rosenfeld M. Treggiari MM. Konstan MW. Retsch-Bogart G. Morgan W. Wagener J. Gibson RL. Khan U. Emerson J. Thompson V. Elkin EP. Ramsey BW. EPIC. ESCF Investigators.  Standard care versus protocol based therapy for new onset Pseudomonas aeruginosa in cystic fibrosis.   Pediatr Pulmonol 2013; 48:943-953[PubMed]                        The Early Pseudomonal Infection Control (EPIC) randomized trial rigorously evaluated the efficacy of different antibiotic regimens for eradication of newly identified Pseudomonas (Pa) in children with cystic fibrosis (CF). Protocol based therapy in the trial was provided based on culture positivity independent of symptoms. It is unclear whether outcomes observed in the clinical trial were different than those that would have been observed with historical standard of care driven more heavily by respiratory symptoms than culture positivity alone. We hypothesized that the incidence of Pa recurrence and hospitalizations would be significantly reduced among trial participants as compared to historical controls whose standard of care preceded the widespread adoption of tobramycin inhalation solution (TIS) as initial eradication therapy at the time of new isolation of Pa.

Eligibility criteria from the trial were used to derive historical controls from the Epidemiologic Study of CF (ESCF) who received standard of care treatment from 1995 to 1998, before widespread availability of TIS. Pa recurrence and hospitalization outcomes were assessed over a 15-month time period.

As compared to 100% of the 304 trial participants, only 296/608 (49%) historical controls received antibiotics within an average of 20 weeks after new onset Pa. Pa recurrence occurred among 104/298 (35%) of the trial participants as compared to 295/549 (54%) of historical controls (19% difference, 95% CI: 12%, 26%, P<0.001). No significant differences in the incidence of hospitalization were observed between cohorts.

The authors concluded protocol based antimicrobial therapy for newly acquired Pa resulted in a lower rate of Pa recurrence but comparable hospitalization rates as compared to a historical control cohort less aggressively treated with antibiotics for new onset Pa.

 

A nice study, but it must be said, confirming what was common knowledge in Europe for over 20 years. Failing to treat a new growth of P. aeruginosa must now be regarded as suboptimal treatment adversely affecting the long term prognosis.

 

Mohite PN, Popov AF, Yacoub MH, Simon AR. Live related donor lobar lung transplantation recipients surviving well over a decade: still an option in times of advanced donor management. J Cardiothorac Surg 2013; 8:37. [PubMed]

As waiting lists for lung transplantation are ever increasing, the number of organ donors is not able to keep pace with it. Living donor lobar lung transplantation is a source of organs which could be lifesaving in end-stage lung disease patients who cannot wait for cadaveric organs due to deteriorating lung function and clinical condition. Two young women with end stage cystic fibrosis received lobes from their relatives and an altruistic friend. They are surviving for more than 12 and 14 years with good lung function.

 

Fig. 4: Andre R Simon

www.rbhh-specialistcare.co.uk

Mr André R Simon (figure 4) is director of heart and lung transplantation and ventricular assist devices and consultant cardiac surgeon at Royal Brompton & Harefield NHS Foundation Trust. He holds a position as an honorary senior lecturer at Imperial College. He trained at the Christian Albrechts University in Kiel, Germany, the Harvard Medical School, USA and the Hannover Medical School, Germany, where he qualified as a cardiac and thoracic surgeon. Dr Simon worked as an attending cardiac surgeon at Hannover Medical School from 2003 to 2010 and was the director of the Hannover Thoracic Transplant Program in 2007-2010, where he was instrumental in the clinical development of minimally invasive lung transplantation, the development of new ex vivo lung perfusion techniques and the concept of partial circulatory support.

 

Maisonneuve P, Marshall BC, Knapp EA. Lowenfels AB. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J Nat Cancer Inst 2013; 105:122-9. [PubMed]

From 1990 to 2009, 41,188 patients received care at one of the 250 US CF care centers. Observed number of cancers in nontransplanted and transplanted patients were compared with that expected in the general population. The overall burden of cancer in CF patients remained low in all groups; however they do have an increased risk of digestive tract cancer, particularly following transplantation. They also have increased risk of lymphoid leukaemia and testicular cancer, and decreased risk of melanoma.

 

McGarry ME. Nielson DW. Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest 2013; 144:1376-8.  [PubMed]

There are 10 known class 3 gating mutations, the most common of which is G551D. Ivacaftor is a drug that in vitro increases open time and transepithelial chloride transport in all 10 gating mutations, but it is approved for use only in patients with the G551D mutation.  The authors  report complete normalization of sweat chloride concentration and rapid clinical improvement over 6 weeks of treatment with ivacaftor in a patient with CF with the gating mutation S549N.

They suggest that ivacaftor should be considered for use in patients with any of the known gating mutations.

 

McIlwaine MP. Alarie N. Davidson GF. Lands LC. Ratjen F. Milner R. Owen B. Agnew JL. Long-term multicentre randomised controlled study of high frequency chest wall oscillation versus positive expiratory pressure mask in cystic fibrosis. Thorax 2013; 68:746-751. [PubMed]

Positive expiratory pressure (PEP) is the most commonly used method of airway clearance (AC) in Canada for patients with cystic fibrosis (CF) whereas, in some countries, high frequency chest wall oscillation (HFCWO) is the preferred form of airway clearance. There have been no long-term studies comparing the efficacy of HFCWO and PEP in the CF population. This study was to determine the long-term efficacy of HFCWO compared with PEP mask therapy in the treatment of CF as measured by the number of pulmonary exacerbations (PEs). A randomised controlled study was performed in 12 CF centres in Canada. After a 2-month washout period, subjects were randomised to perform either HFCWO or PEP mask therapy for 1 year.                                                            

RESULTS: 107 subjects were enrolled in the study; 51 were randomised to PEP and 56 to HFCWO. There were 19 dropouts within the study period, of which 16 occurred prior to or at the time of randomisation.   There were significant differences between the groups in the mean number of PEs (1.14 for PEP vs 2.0 for HFCWO) and time to first PE (220 days for PEP vs 115 days for HFCWO, p=0.02). There was no significant difference in lung function, health-related quality of life scores or patient satisfaction scores between the two groups. PEP mask therapy required a shorter treatment time.

 

The results of this study favour PEP and do not support the use of HFCWO as the primary form of AC in patients with CF. Apparently the previous study on PEP from Vancouver by Maggie McIlwaine and her colleagues had a major influence on the introduction of the PEP mask into N. America (McIlwaine PM et al. J Pediatr 2001; 138:845-850. [PubMed]).

 

Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B. Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. [Review] Am J Resp Crit Care 2013; 187:680-9[PubMed]

A new review of the literature to update the 2007 recommendations, including consideration of new medications and additional evidence on previously reviewed therapies. Published evidence for chronic lung therapies was systematically reviewed and resulting treatment recommendations were graded based on the United States Preventive Services Task Force scheme. These guidelines provide up-to-date evidence of safety and efficacy of chronic treatments of CF lung disease, including the use of novel therapies that have not previously been included in CF pulmonary guidelines.

These recommendations are intended for the USA, and although useful some are not entirely relevant for the UK where recommendations differ in certain respects. For example, in the use of prophylactic anti-staphylococcal antibiotics in infants and long term anti-staphylococcal treatment in older patient confirmed as having chronic infection with that organism. The group were unable to recommend inhaled antibiotics other than aztreonam and tobramycin whereas in Europe inhaled colistin is widely used and was recently shown to be effective in powder from for patients with chronic P. aeruginosa infection. Many outstanding questions are mentioned and some are discussed such as - prioritization of therapies, interactions between medications, effect of bacterial resistance; the optimal use of medications under 6 years (who have not been included in most trials up to present). Also they mention the sequence of administration.

Peter Mogayzel

Fig. 5: Peter Mogayzel

from www.hopkinscf.org

Dr. Peter Mogayzel (figure 5) has been the Director of the Cystic Fibrosis Center since 2002. His research interests include the regulatory properties of the CFTR gene, mucociliary clearance and development of new therapeutics for cystic fibrosis

 

Naehrlich L, Dorr HG, Bagheri-Behrouzi A, Rauh M. Iodine deficiency and subclinical hypothyroidism are common in cystic fibrosis patients. J Trace Elem Med Bio 2013; 27:122-125.[PubMed]

Disorders of thyroid function have been inconsistently described in cystic fibrosis patients and in CF animals but the literature lacks reports on iodine status of CF individuals. The authors hypothesized that iodine deficiency is common in CF and accounts for abnormal thyroid function in CF patients. So they investigated 129 children, adolescents, and adults with CF, who were living in the northern part of Bavaria/Germany. Malnutrition and lung function were analyzed. Urinary iodine excretion, TSH (thyroid-stimulating hormone), and ft4 (free thyroxine) were measured and set in relation to population-based, age-adjusted reference ranges.

Subclinical hypothyroidism (normal fT4, elevated TSH) was found in 11.6% of subjects, and iodine deficiency in 83.7%. No correlations were found with age, BMI, status of malnutrition, or lung function.

The authors concluded that there was dramatic iodine deficiency in their cohort of CF patients and this condition can cause subclinical hypothyroidism; they therefore advise an individual iodine supplementation program is necessary and should be started immediately.

Fig. 6: Large goitre due to iodide therapy. From Cystic Fibrosis. Ed. Lynn M Taussig, 1984.

Thyroid function and iodine status in CF have been the subject of many publications over the years. Some have failed to detect any abnormality of thyroid function (Volta C et al. Horm Res 2005: 63:206-210.[PubMed]) attributing previous findings possibly to the presence of associated selenium deficiency or iodine overload in the CF patients. Over 50 years ago hypothyroidism was described in two patients as a complication of iodide therapy, used to treat the respiratory condition in CF (Ruben BL et al. Am J Dis Child 1960; 100:721-722. See details in “Topics- Endocrine”). Later Dolan TF & Gibson LE (J Pediatr 1971; 79:684-687. Details in Topics - Endocrine) reported 55 patients on long-term iodide therapy of whom a remarkable 85% developed goitres and also 24% had evidence of hypothyroidism. Their thyroid glands were enlarged, sometimes markedly so, usually after three years or so of iodide therapy (figure 6). There was discussion as to the possibility of an intrinsic defect of thyroid function but people with CF not taking iodides were all euthyroid. Also the findings of Volta et al, 2005 (above) are reassuring suggesting perhaps the recent advice of Naerhrlich et al. 2013 is not generally applicable.

 

Nazareth D. Walshaw M. A review of renal disease in cystic fibrosis. J Cyst Fibros 2013; 12:309-17. [PubMed]

Kidney disease is becoming increasingly common in CF. This review looks at the effect of CFTR on the kidney, the problems with measuring renal function effectively in CF, the causes and incidence of renal dysfunction, and its pathophysiology. Strategies to reduce aminoglycoside toxicity are discussed.

This is a fully referenced detailed review of an increasing problem in older people with CF.

 

Nahrlich L. Mainz JG. Adams C. Engel C. Herrmann G. Icheva V. Lauer J. Deppisch C. Wirth A. Unger K. Graepler-Mainka U. Hector A. Heyder S. Stern M. Doring G. Gulbins E. Riethmuller J. Therapy of CF-patients with amitriptyline and placebo - a randomised, double-blind, placebo-controlled phase IIb multicenter, cohort-study. Cell Physiol Biochem 2013; 31:505-12. [PubMed]

Several recent studies revealed an accumulation of ceramide in bronchial, tracheal and intestinal epithelial cells of mice and patients with cystic fibrosis (CF). Normalization of ceramide concentrations in lungs of CF mice employing the functional acid sphingomyelinase inhibitor amitriptyline also normalized mucociliary clearance, chronic inflammation and infection susceptibility to pulmonary P. aeruginosa in these mice.

To test for a beneficial effect of amitriptyline in vivo, we performed a phase IIb randomised, double-blind, placebo-controlled study. Twenty-one CF patients were treated with 25 mg/d amitriptyline twice daily for 28 days. The placebo consisted of 19 patients and was also treated twice per day. The primary endpoint was the change in lung function in the intention-to-treat (ITT) population. Secondary endpoints were ceramide levels in epithelial cells and safety.

After treatment, forced expiratory volume in 1 sec predicted (FEV1) increased 6.3 +/- 11.5% (p=0.08) in the ITT population (36 of 40 CF patients) and 8.5 +/- 10% (p=0.013) in the per protocol (PP) population (29 of 40 patients). Ceramide levels decreased in nasal epithelial cells after amitriptyline treatment. Amitriptyline had no severe and only mild and mostly transient adverse effects, i.e. xerostomia and tiredness.

The authors concluded amitriptyline is safe in CF-patients, increases FEV1 and reduces ceramide in lung cells of CF patients.

 

These results confirm the earlier proof of principle study (Riethmuller J et al. Cell Physiol Biochem 2009; 24:65-72.[PubMed]). In commenting on this earlier study, Ian Balfour-Lynn expressed interest but was concerned that amitryptyline may suppress the acute rise in ceramide that is seen with Pseudomonas aeruginosa infectons, which presumably is part of the host defence response. However, future developments will be awaited with interest.

 

O'Sullivan BP, Baker D, Leung KG, Reed G, Baker SS, Borowitz D. Evolution of pancreatic function during the first year in infants with cystic fibrosis. J Pediatr 2013; 162:808-812. [PubMed]

Monthly fecal elastase were estimated in 82 infants diagnosed after newborn CF screening. A total of 61 infants had an initial stool sample obtained at age <3.5 months and a final stool sample obtained at age >9 months. Twenty-six of 29 infants with a fecal elastase value <50 ug/g at study entry had a fecal elastase value <200 ug/g (the accepted cut off value for pancreatic insufficiency) on all measurements during the year; all 29 had a value <200 ug/g at the end of the study.

Of the 48 infants with initial fecal elastase value <200ug/g, 13 had at least 1 fecal elastase value >200 ug/g but had a final stool fecal elastase value <200 ug/g; however, 4 infants with an initial fecal elastase value <200 ug/g ended the year with a value >200 ug/g. Eleven of 13 infants with an initial fecal elastase value of >200 ug/g still had a value >200 ug/g at the end of the first year.

The authors concluded that infants with CF exhibit variability in fecal elastase values during the first year. Infants with a fecal elastase level of 50-200 ug/g at diagnosis should be treated with pancreatic enzyme replacement therapy, but fecal elastase should be re-measured at age 1 year to ensure that those with an initial falsely low value do not continue to receive pancreatic enzyme replacement therapy unnecessarily. Those with a fecal elastase value >200 ug/g initially can become pancreatic insufficient with time.

 

This is useful practical data to help with the early management of pancreatic replacement therapy and further confirms the fecal elastase as an excellent investigation. The test is particularly useful as the patient does not have to stop taking exogenous enzymes before the test is valid - as was the case with faecal chymotrypsin. So evaluation of a new patient referred to the clinic or a test to ensure a patient is still requiring pancreatic enzymes can be arranged without interfering with the treatment.

 

Peckham D, Whitaker P. Drug induced complications; can we do more?  J Cyst Fibros 2013; 12:547-58.[PubMed] 

Drug induced complication are becoming increasingly common in CF. In this detailed, extensively referenced and illustrated review the authors discuss some of the key issues relating to drug side effects in an ageing population of patients with CF. Strategies to reduce drug complications are also discussed.  Subjects covered include in relation to pancreatic enzymes, abnormalities of glucose metabolism, corticosteroids, nutrition therapy, intravenous antibiotics, choice of antibiotics and dose and duration for an exacerbation, nebulised antibiotics, aminoglycosides and ototoxicity, other complications of IV antibiotics and microbial resistance. Finally, future perspectives are discussed.

 

Polenakovik HM. Sanville B. The use of ivacaftor in an adult with severe lung disease due to cystic fibrosis (F508/G551D)J Cyst Fibros 2013; 12:530-1.  [PubMed]                      

An adult with cystic fibrosis (F508/G551D) with severe lung disease (forced expiratory volume (FEV1) in one second 24% predicted) was admitted for a pulmonary exacerbation. He was managed with maximal medical therapy, but did not have significant improvement until after he was started on ivacaftor on hospital day 15. He subsequently had significant improvement in lung function with normalization of hypercarbia, oxygen saturation on room air, and increase in FEV1 to 36% predicted. Prior to use of ivacaftor he was being assessed for a lung transplant. However, after ivacaftor therapy for 6 months, he is no longer considering this treatment modality due to his improvement of lung function and functional status.

 

Proesmans M, Vermeulen F, Boulanger L, Verhaegen J, De Boeck K. Comparison of two treatment regimens for eradication of Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros 2013; 12:29-34. [PubMed]

Two eradication regimens in children with new Pseudomonas (Pa) infection were compared - tobramycin inhalation solution for 28 days (TIS) or inhaled sodium colistimethate (2x2millU/day) plus oral ciprofloxacin (30 mg/kg/day) for 3 months (CC). The primary outcome was Pa eradication at the end of treatment.

Eradication at end of treatment was similar for both treatments. After 2 years, 10% of patients had chronic Pa infection. The authors concluded inhalation of TIS (28 days) or CC (3 months) resulted in similar eradication success at the end of treatment (80 and 90% respectively) and similar clinical evolution during the first 2 years of follow-up.

 

These results confirm the usually reported results of early eradication therapy for which a number of regimes are effective.

The published work on eradication therapy for early Pa infection has been reviewed in detail recently (Schelstraete et al 2013. below).

 

Reznikov LR, Dong Q, Chen JH, Moninger TO, Park JM, Zhang Y, Du J, Hildebrand MS, Smith RJ, Randak CO, Stoltz DA, Welsh MJ. CFTR-deficient pigs display peripheral nervous system defects at birth. Proc Nat Acad Sci USA 2013; 110:3083-8. Free text available [PubMed]

The authors tested the hypothesis that disruption of the cystic fibrosis transmembrane conductance regulator (CFTR) gene directly influences nervous system function by studying newborn CFTR(-/-) pigs. They showed CFTR expression and activity in Schwann cells, and loss of CFTR caused ultra structural myelin sheath abnormalities similar to those in known neuropathies.

The authors concluded that loss of CFTR directly alters Schwann cell function suggesting that some nervous system defects in people with cystic fibrosis are likely primary rather than secondary.

There is an extensive review of the neurological problems that have been reported as affecting people with CF.

 

Ren HY. Grove DE. De La Rosa O. Houck SA. Sopha P. Van Goor F. Hoffman BJ. Cyr DM. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.  Mol Biol Cell 2013; 24:3016-24.[PubMed]CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, the authors explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR

 

Rosenfeld MJ et al. American Thoracic Society Assembly on Pediatrics Working Group on Infant and Preschool Lung Function Testing. An official American Thoracic Society workshop report: optimal lung function tests for monitoring cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheezing in children less than 6 years of age. Annals of the American Thoracic Society 2013; 10:S1-S11. [PubMed]

Official American Thoracic Society workshops were convened in 2009 and 2010 to review six lung function tests based on a comprehensive review of the literature (infant raised-volume rapid thoracic compression and plethysmography, preschool spirometry, specific airway resistance, forced oscillation, the interrupter technique, and multiple-breath washout). In these proceedings, the current state of the art for each of these tests is reviewed as it applies to the clinical management of infants and children under 6 years of age with cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheeze, using a standardized format that allows easy comparison between the measures. Although insufficient evidence exists to recommend incorporation of these tests into the routine diagnostic evaluation and clinical monitoring of infants and young children with cystic fibrosis, bronchopulmonary dysplasia, or recurrent wheeze, they may be valuable tools with which to address specific concerns, such as ongoing symptoms or monitoring response to treatment, and as outcome measures in clinical research studies.

 

As it is realised that very early treatment and monitoring are of crucial importance to identify infection and reduce early lung damage this review is timely. Previously unavailable to many infants, it appears feasible to use the newer techniques such as multiple breath washouts even infants.

 

Reynolds L. Latchford G. Duff AJ. Denton M. Lee T. Peckham D. Decision Making about Risk of Infection by Young Adults with CF. Pulmonary Medicine 2013:658638. [PubMed]

Young people with cystic fibrosis (CF) are asked to avoid a number of environments associated with increased infection risk, but in practice they need to balance this with competing priorities such as building and sustaining relationships with friends and family. This study explored the process by which young people make these decisions. Mixed methods were used: a vignette study presenting choices around engaging in activities involving a degree of infection risk and a thematic analysis of participant's accounts of their decision making.

The eight participants chose to engage in high risk behaviours in 59% of the choices. All participants chose to engage in at least one risky behaviour, though this was less likely when the risk was significant. Thematic analysis revealed large areas of misunderstanding and lack of knowledge, leading to some potentially worrying misconceptions about the nature of infections and risk.

The authors concluded that young people with CF are not currently making informed decisions around activities that involve increased risk of infection, and there is an urgent need for CF teams to address this in information provision.

 

Ruddy J. Emerson J. Moss R. Genatossio A. McNamara S. Burns JL. Anderson G. Rosenfeld M. Sputum tobramycin concentrations in cystic fibrosis patients with repeated administration of inhaled tobramycin. J Aerosol Med Pulm D 2013; 26:69-75. [PubMed]
This investigation was prompted by evidence of possible antibiotic accumulation in respiratory secretions with repeated dosing. There was no evidence of significant drug accumulation in respiratory secretions with repeat dosing of TSI. Peak bioactive concentrations, although lower than peak total concentrations, were still generally well within the bactericidal range. Sputum induction as a method for determining airway drug concentrations appears safe and feasible.

 

Rundfeldt C. Steckel H. Scherliess H. Wyska E. Wlaz P. Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis.

Eur J Pharm Biopharm 2013; 83:44-53.[PubMed]                                                                   57% of CF patients are colonized by Aspergillus species and 10-20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA).

The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation. Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA. The suspension was stable if stored at 8C for 3 months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulisers. A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7 days at a predicted dose of 45mg/kg in rats. A single dose inhalation at a predicted dose of 22.5mg/kg resulted in maximum lung tissue concentration of 21.4mug/g tissue with a terminal half-life of 25.4h. Serum concentrations were lower, with a maximum concentration of 104ng/ml at 4h after dosing and a terminal half-life of 10.5h.

 

The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA. High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily treatment.

 

Sander-Struckmeier S. Beckmann K. Janssen-van Solingen G. Pollack P. Retrospective analysis to investigate the effect of concomitant use of gastric acid-suppressing drugs on the efficacy and safety of pancrelipase/pancreatin (CREON) in patients with pancreatic exocrine insufficiency. Pancreas 2013; 42:983-989.  [PubMed]                                                              This study aimed to determine whether the efficacy of pancrelipase/pancreatin (CREON) may be affected by the concomitant use of proton pump inhibitors (PPIs)/histamine-2 receptor antagonists (H2RAs).  An analysis of integrated data from all clinical trials of pancrelipase/pancreatin supported by Abbott (34 trials, 1142 unique subjects) was conducted. All trials included patients with pancreatic exocrine insufficiency, and most cases were associated with cystic fibrosis, chronic pancreatitis, or pancreatic surgery. Study designs included single and double blind, open label, parallel group, and crossover, and most were randomized. The primary end point for this analysis was on-treatment coefficient of fat absorption (CFA) according to concomitant PPI/H2RA use(yes/no).                                                                       

There were no meaningful differences in mean CFA values at the end of pancrelipase/pancreatin treatment by concomitant PPI/H2RA use: yes (n = 254), 82.7% versus no (n = 449), 84.2%. No meaningful differences were observed when the same analysis was carried out by disease type (cystic fibrosis, chronic pancreatitis, and pancreatic surgery).

 The authors concluded this analysis of data from clinical trials enrolling patients with pancreatic exocrine insufficiency suggests that the efficacy of pancrelipase/pancreatin is not affected by concomitant PPI/H2RA use, as determined by end-of-treatment CFA values, and supports the treatment guidelines' recommendation that acid suppression is not routinely required with pancreatic enzyme replacement therapy.

 

This is useful practical information relevant to the use of Creon which is composed of acid resistant microspheres. However, before the availability of such efficient preparations acid suppression did improve the fat absorption of some patients with cystic fibrosis taking he older unprotected pancreatic preparations and in the individual patient there is still a place for the use of acid suppression if malabsorption is difficult to control even with substantial doses of PERT.

 

Fig. 6a: Suntje Sander-Struckmeier

Dr Suntje Sander-Struckmeier (figure 6a) is Director of Clinical Development at Abbott Products GmbH.

 

Shah N1, Tan HL, Sebire N, Suri R, Leuven K.The role of endoscopy and biopsy in the management of severe gastrointestinal disease in cystic fibrosis patients.Pediatr Pulmonol 2013; 48:1181-9.[PubMed]
Nine of the 12 CF patients seen at the the GOS combined paediaitric GI clinic had evidence of mucosal inflammation in their biopsies, including duodenitis with eosinophilic infiltrate, chronic non-specific inactive gastritis, enteropathy with partial villous atrophy, and non-specific colitis. Immunosuppressive and anti-inflammatory therapies were commenced in these nine patients, including prednisolone, azathioprine, methotrexate, ketotifen, mesalazine, and sulfasalazine as well as the use of parenteral nutrition and elemental feeds. All the patients clinically responded to therapy. Five of the patients commenced on anti-inflammatory therapy had repeat biopsies 1-5 years following commencement of treatment and all showed histological improvement of the mucosal inflammation. GI endoscopy with mucosal biopsy has a significant role to play in the management of CF children with severe GI disease. In these patients the findings influenced the management in the majority of patients with severe GI symptoms. Furthermore, if GI mucosal inflammation is identified on biopsy, management with immunomodulatory agents may be clinically beneficial

 

Schuster A, Haliburn C, Döring G, Goldman MH: for Freedom Study Group. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients wit cystic fibrosis: a randomised study. Thorax 2013;68:344-350.[Epub ahead of print][PubMed]

To assess efficacy and safety of a new dry powder formulation of inhaled colistimethate sodium in patients with cystic fibrosis (CF) aged ≥6 years with chronic Pseudomonas aeruginosa lung infn. A prospective, centrally randomised, phase III, open-label study in patients with stable CF aged ≥6 years with chronic P aeruginosa lung infection. Patients were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). Study duration was 24 weeks.

380 patients were randomised. After logarithmic transformation of data due to a non-normal distribution, adjusted mean difference between treatment groups (CDPI vs TIS) in change in forced expiratory volume in 1 s (FEV(1)% predicted) at week 24 was -0.97% (95% CI -2.74% to 0.86%) in the intention-to-treat population (n=374) and -0.56% (95% CI -2.71% to 1.70%) in the per protocol population (n=261). The proportion of colistin-resistant isolates in both groups was ≤1.1%. The number of adverse events was similar in both groups. Significantly more patients receiving CDPI rated their device as 'very easy or easy to use' (90.7% vs 53.9% respectively; p<0.001).

Colobreathe demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment. There was no emergence of resistance of P. aeruginosa to colistin. Overall, CDPI was well tolerated.

 

It has been suggested that it would have been preferable to compare Colobreathe powder and colomycin inhalation solution. Unfortunately when the trial was started some years ago tobramycin was the only liquid antibiotic preparation for inhalation that was licensed in Europe. Early in 2013 Colobreathe was approved for use in the UK.

 

Singer F. Kieninger E. Abbas C. Yammine S. Fuchs O. Proietti E. Regamey N. Casaulta C. Frey U. Latzin P. Practicability of nitrogen multiple-breath washout measurements in a pediatric cystic fibrosis outpatient setting. Pediat Pulmonol 2013; 48:739-46. [PubMed]

Although lung clearance index (LCI) is a sensitive indicator of mild cystic fibrosis (CF) lung disease, it is rarely measured due to lengthy protocols and the commercial unavailability of multiple-breath washout (MBW) setups and tracer gases. We used a newly validated, commercially available nitrogen (N2) MBW setup to assess success rate, duration, and variability of LCI within a 20min timeframe, during clinical routine. We also evaluated the relationship between LCI and other clinical markers of CF lung disease.

At least one LCI was feasible in 123 (90%) children, with a mean (range) of 3.3 (1.2-6.4) min per test. Two or more measurements were feasible in 56 (41%) children. Comparing LCI in CF versus controls, LCI mean (SD) was 12.0 (3.9) versus 6.1 (0.9), and the intra- and inter-test coefficient of repeatability was 1.00 versus 0.81 and 0.96 versus 0.62, respectively. LCI was correlated with spirometry, blood gases, and Pseudomonas aeruginosa infection.

The authors concluded that using available N2 MBW equipment; LCI measurements are practical and fast in children. LCI is correlated with markers of CF lung disease.

 

Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, Murray CP, Stick SM; AREST CF Investigators. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med. 2013; 23; 368:1963-70. 23692169 [PubMed]
Bronchiectasis develops early in the course of cystic fibrosis, being detectable in infants as young as 10 weeks of age, and is persistent and progressive. The authors sought to determine risk factors for the onset of bronchiectasis, using data collected by the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) intensive surveillance program.
They examined data from 127 consecutive infants who received a diagnosis of cystic fibrosis after newborn screening. Chest computed tomography (CT) and bronchoalveolar lavage (BAL) were performed, while the children were in stable clinical condition, at 3 months and 1, 2, and 3 years of age. Longitudinal data were used to determine risk factors associated with the detection of bronchiectasis from 3 months to 3 years of age.
The point prevalence of bronchiectasis at each visit increased from 29.3% at 3 months of age to 61.5% at 3 years of age. In multivariate analyses, risk factors for bronchiectasis were presentation with meconium ileus (P=0.002), respiratory symptoms at the time of CT and BAL (P=0.008), free neutrophil elastase activity in BAL fluid (P<0.001), and gas trapping on expiratory CT (P=0.01). Free neutrophil elastase activity in BAL fluid at 3 months of age was associated with persistent bronchiectasis (present on two or more sequential scans), with the odds seven times as high at 12 months of age and four times as high at 3 years of age.


The main conclusion was that neutrophil elastase activity in BAL fluid in early life was associated with early bronchiectasis in children with cystic fibrosis. The authors regarded this observation sets the stage for future trials of treatment that targets neutrophils or inhibit neutrophil elastase activity.

 

This is an interesting study but it is unfortunate that there is no mention of the treatment the infants were receiving. As 22.2% of the children were growing S. aureus at 3 years presumably there was not a policy of SA prophylaxis and eradication in operation.

 

Subbarao P. Stanojevic S. Brown M. Jensen R. Rosenfeld M. Davis S. Brumback L. Gustafsson P. Ratjen F. Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. Am J Respir Crit Care 2013; 188:456-60. [PubMed]

To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers. The Infant Study of Inhaled Saline trial was a multicenter, randomized, controlled trial of hypertonic (7%) versus isotonic (0.9%) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age.

LCI measurements were performed in a single-center pilot sub study at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas. LCI measurements were standardized using published normative data (zLCI) to account for height-related changes in LCI during early childhood. A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect.

A total of 27 participants were randomized; 25 participants, aged (median [range]) 2.6 (0.34-4.95) years, had acceptable baseline and follow-up LCI measures. On average, LCI decreased in the hypertonic saline group (n = 12) by 1.19 z-scores units (95% confidence interval [CI] = -2.46 to 0.06), and remained stable in the isotonic saline group (n = 13) at 0.81 (95% CI = -0.40 to 2.02).

A significant treatment effect was observed for zLCI (2.01; 95% CI = 0.26 to 3.76; P = 0.025)

The authors concluded that multiple breath washout (MBW) testing is feasible in an interventional study in infants and preschool children with CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies.

 

The lung clearance index appears to be deservedly gaining general acceptance as a measure of respiratory function in pre-school children - such an important age group as the need for early intervention and its effects become increasingly apparent.

 

Fig. 6b: Dr Padmaja Subbarao

www.sickkids.ca

Dr Padmaja Subbarao (figure 6b) is Staff Respirologist at the Hospital for Sick Children, Scientist at the Research Institute and Assistant Professor in Paediatrics at the University of Toronto.

 

Stenbit AE. Bullington WM. Heh JL. Flume PA. Timing of inhaled tobramycin affects assessment of intravenous tobramycin pharmacokinetic monitoring. J Cyst Fibros 2013; 12:403-406.-U.S. [PubMed]

Aerosolized tobramycin inhalation solution (TIS) may be absorbed and result in measurable serum concentrations. We assessed the significance of TIS dosing in the latter portion of the IV dosing interval on the calculation of pharmacokinetic (PK) parameters and dosing. Twenty adult CF patients admitted to the hospital for treatment of a pulmonary exacerbation were enrolled. PK parameters of tobramycin were calculated before and after introduction of TIS, which was given 5-9 h after the IV dose.

Nine patients had a clinically significant change in tobramycin trough concentration. Fourteen patients had a reduced calculated elimination rate constant after TIS administration, which may be misinterpreted as a decreased clearance of IV tobramycin.

So trough tobramycin concentrations were significantly influenced in some CF patients (45%), suggesting that timing of the inhaled dose should be considered when interpreting PK measures of IV tobramycin dosing.

The absorption of inhaled tobramycin, particularly with the more efficient nebulisers, is of some concern in view of the prolonged periods that the drugs are administered to people with CF.

 

Schelstraete P, Haerynck S, Van Deal S, Deseyne S, De Baets F. Eradication therapy for Pseudomonas aeruginosa colonization episodes in cystic fibrosis patients. J Cyst Fibros 2013; 12:1-8.[PubMed]

A detailed review of previous work relating to the different eradication trials over the past 28 years. The authors conclude that all the different studies on first eradication treatment of P. aeruginosa agree on the favourable effect of antibiotics on eradication, on the recurrence frequency and on the delay in onset of chronic P. aeruginosa infection. Such early treatment is now standard care and even mucoid Pseudomonas can be eliminated. No one regimen has been shown to be superior to others.

The authors call for larger studies and also that the genotype data is included in any future trials.

 

Further trials in this instance may not be a high priority when it is now obvious that a number of eradication regimens are very effective in the short and medium term and also as there is a world wide shortage of CF patients to include in trials.

 

Schuster A, Haliburn C, Doring G, Goldman MH. Freedom Study Group. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax 2013; 68:344-50. [PubMed]

To assess efficacy and safety of a new dry powder formulation of inhaled colistimethate sodium in patients with cystic fibrosis (CF) aged >=6 years with chronic Pseudomonas aeruginosa lung infection. A prospective, centrally randomised, phase III, open-label study in patients with stable CF aged >=6 years with chronic P aeruginosa lung infection. Patients were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). Study duration was 24 weeks. 380 patients were randomised. After logarithmic transformation of data due to a non-normal distribution, adjusted mean difference between treatment groups (CDPI vs TIS) in change in forced expiratory volume in 1 s (FEV1% predicted) at week 24 was -0.98% (95% CI -2.74% to 0.86%) in the intention-to-treat population (n=373) and -0.56% (95% CI -2.71% to 1.70%) in the per protocol population (n=261). The proportion of colistin-resistant isolates in both groups was <=1.1%. The number of adverse events was similar in both groups. Significantly more patients receiving CDPI rated their device as 'very easy or easy to use' (90.7% vs 53.9% respectively; p<0.001).

Colobreathe demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment. There was no emergence of resistance of P. aeruginosa to colistin. Overall, CDPI was well tolerated.

 

On the basis of this trial the Colobreathe was approved for use in the NHS. Apparently the trial design was required by the regulatory authorities.

 

Schechter MS. Quittner AL. Konstan MW. Millar SJ. Pasta DJ. McMullen A. Scientific Advisory Group. Investigators and Coordinators of Epidemiologic Study of Cystic Fibrosis.  Long-term effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis. Ann Amer Thorac Soc 2013; 10:213-219.  [PubMed]                                             

In recent years studies of pregnancy in cystic fibrosis (CF) have shown no short-term harmful effects, but there are no long-term studies on the impact of motherhood. This study sought to evaluate longer-term physiologic and functional outcomes in women with CF reporting a pregnancy, with the intent of assessing how the demands of parenting impacted on disease course.

Using 1994 to 2005 Epidemiologic Study of Cystic Fibrosis data, the authors developed a propensity score to match women reporting a pregnancy at a 1:10 ratio with never-pregnant control subjects and compared clinical outcomes, health-related quality of life, and health care use.

One hundred nineteen pregnant women presumed to have become mothers were matched with 1,190 control subjects, a median of 6.0 years (range 1.8-11.1 yr) from the pregnancy. No differences were found in annualized change from baseline FEV1 and body mass index, in respiratory signs and symptoms, or in prescribed chronic therapies. Women who had been pregnant were treated for more pulmonary exacerbations and had more illness-related clinic visits but showed no increase in prescribed chronic therapies. They also reported lower health-related quality-of-life scores for Respiratory Symptoms, Physical Functioning, Vitality, and Health Perceptions.

The authors concluded that pregnancy and motherhood do not appear to accelerate disease progression but lead to more illness-related visits, pulmonary exacerbations, and a decrease in some domains of quality of life. These differences presumably reflect the impact of the physical and emotional challenges of early motherhood on disease self-management.

 

One of two recent publications reviewing the impact of a pregnancy on the mother's health – this from the Epidemiologic Study of Cystic Fibrosis Data and the study from the Brompton Clinic in London where the experience of one large unit was analysed in the relatively short term. In both instances there is a negative effect on the mother’s health.

 

Stass H. Weimann B. Nagelschmitz J. Rolinck-Werninghaus C. Staab D. Tolerability and pharmacokinetic properties of ciprofloxacin dry powder for inhalation in patients with cystic fibrosis: a phase I, randomized, dose-escalation study.

Clin Ther 2013; 35:1571-81.[PubMed]

A dry powder formulation of ciprofloxacin for inhalation (ciprofloxacin DPI) has been developed using PulmoSphere (Novartis, Pharma AG, Basel, Switzerland) technology (administered using a T-326 inhaler) to maximize antibacterial activity and convenience.  This study investigated the tolerability and pharmacokinetic properties of multiple-dose once-daily and twice-daily ciprofloxacin DPI in adults with CF. A Phase I, randomized, single-blind, placebo-controlled, dose-escalation study in patients with CF (median age 29.0 years [19-40]), stable pulmonary status, and chronic Pseudomonas aeruginosa infection. Sequential cohorts received ciprofloxacin DPI 32.5 mg qd (1 capsule for inhalation; n = 6), 65 mg qd (2 capsules for inhalation; n = 6), or 32.5 mg (n = 6) bid for 7 days. Each group was placebo controlled.

Twenty-five patients were enrolled (12 men; median age, 29.0 years [range, 19-40 years]; 6, 6, 6, and 7 patients in the ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid and placebo groups, respectively). No serious treatment-emergent adverse events or clinically relevant changes in tolerability parameters, including lung function measurements, were reported. Twenty-one patients (ciprofloxacin, n = 17; placebo, n = 4) experienced 29 mild drug-related treatment-emergent adverse events, including bitter taste (ciprofloxacin, 17 patients; placebo, 2) and bronchospasm (ciprofloxacin, 3; placebo, 2). Ciprofloxacin DPI was absorbed rapidly after inhalation. Systemic exposure to ciprofloxacin was low and comparable between single and multiple dosing in all 3 dose groups, suggesting an absence of substantial drug accumulation. The geometric mean AUCs after the last dose were 0.383, 1.472, and 0.781 mg h/L with ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. The range of geometric mean t(1/2) in plasma was 3.4 to 9.5 hours. Sputum concentrations of ciprofloxacin were high, with substantial variability. Geometric mean ciprofloxacin concentrations (%CV) in induced sputum were 57.7 (118.2), 177.5 (53.4), and 149.7 (249.7) mg/L 0.75 hours after the last dose of ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively.

Ciprofloxacin DPI was well tolerated, especially with respect to lung function, with minimal systemic exposure compared with data from previous studies of oral and intravenous administration, and with no apparent accumulation at steady state. Sputum ciprofloxacin concentrations above 100-times the minimum inhibitory concentration for P aeruginosa were detected. Ciprofloxacin DPI may be effectively delivered to the lungs at microbiologically active concentrations while minimizing the risk for systemic intolerabilities.

 

Stoltz DA. Rokhlina T. Ernst SE. Pezzulo AA. Ostedgaard LS. Karp PH. Samuel MS. Reznikov LR. Rector MV. Gansemer ND. Bouzek DC. Alaiwa MH. Hoegger MJ. Ludwig PS. Taft PJ. Wallen TJ. Wohlford-Lenane C. McMenimen JD. Chen JH. Bogan KL. Adam RJ. Hornick EE. Nelson GA 4th. Hoffman EA. Chang EH. Zabner J. McCray PB Jr. Prather RS. Meyerholz DK. Welsh MJ. Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs. J Clin Invest 2013; 123:2685-2693. [PubMed]

Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. The authors hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. They produced 5 CFTR-/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time.

These data indicate that expressing CFTR in intestine, without pancreatic or hepatic correction, is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies.

 

Stockmann C. Sherwin CM. Zobell JT. Young DC. Waters CD. Spigarelli MG. Ampofo K. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: III. fluoroquinolones. [Review]. Pediatr Pulmonol 2013; 48:211-220. [PubMed]

This review is the third instalment in a comprehensive State of the Art series and aims to evaluate the use of fluoroquinolones in the management of P. aeruginosa infection in both children and adults with cystic fibrosis (CF). Oral and intravenous ciprofloxacin have been shown to be well-tolerated in the treatment of acute pulmonary exacerbations (APE) secondary to P. aeruginosa. Older literature supports an oral dosing regimen of 40mg/kg/day divided every 12hr, up to 2g/day, and intravenous (IV) ciprofloxacin 30mg/kg/day divided every 8hr, maximum 1.2g/day in children, and 750mg administered orally twice a day or 400mg IV every 8hr in adults. However, a recent pharmacodynamic (PD) modeling study shows that the literature, U.S. Food and Drug Administration (FDA)-approved, and Cystic Fibrosis Foundation (CFF) guideline dosing regimens may be suboptimal for the treatment of P. aeruginosa in APE. Further study is warranted to determine if higher doses of ciprofloxacin are needed. Limited pharmacokinetic (PK), PK/PD, and efficacy studies involving levofloxacin exist in adult patients with CF. No pediatric data exists for levofloxacin in CF patients. Further study is needed to determine the tolerability and efficacy of levofloxacin in APE.

 The authors state that at this time, the routine use of levofloxacin in the treatment of acute pulmonary exacerbations in paediatric and adult patients cannot be recommended.

 

Thorpe-Beeston JG, Madge S, Gyi K, Hodson M, Bilton D. The outcome of pregnancies in women with cystic fibrosis-single centre experience 1998-2011. BJOG: An International Journal of Obstetrics & Gynaecology. 2013; 120:354-61. [PubMed]

Forty one women with CF had 48 pregnancies - two miscarriages, 44 singleton pregnancies and two sets of twins. All babies were live born and survived, mean gestational age was 35.9 +/- 3.3 weeks. There were no fetal abnormalities or terminations of pregnancy. The median birth weight centile was 31.9. Twenty-five (52.1%) of the women had pancreatic insufficiency and 17 (35.4%) required insulin. Women with FEV (1) <=60% were more likely to deliver earlier and by caesarean section compared with women with FEV(1) >60%. Three of the seven women with an FEV(1) <40% died within 18 months of delivery. Four of the eight women with FEV(1) 40-50% died between 2 and 8 years after delivery.

The authors confirmed previous experience that pregnancy for women with cystic fibrosis usually results in favourable maternal and fetal outcomes, but the incidence of preterm delivery and caesarean section is increased. However, women with pre-existing poor lung function should be counselled antenatally to ensure that they understand the implications of their shortened life-expectancy and parenthood.

 

Here is further data from the world’s largest adult CF unit, at the Royal Brompton in London, that although the immediate outcome is satisfactory, pregnancy becomes increasingly risky for the mother as the respiratory involvement becomes more severe.

 

Toyoda Y, Bhama JK, Shigemura N, Zaldonis D, Pilewski J, Crespo M, Bermudez C. Efficacy of extracorporeal membrane oxygenation as a bridge to lung transplantation. J Thorac Cardiov Surg 2013; 145:1065-70. [PubMed]

A retrospective review of 715 consecutive lung transplants performed between May 2005 and September 2011. Twenty-four lung transplants (3.4%) were performed in the 31 patients with attempted pre-transplant ECMO; another 7 patients who received ECMO did not survive or were deemed unfit for transplantation.

The 24 transplanted ECMO patients were compared with a control group of 691 patients who did not receive pre-transplant ECMO. The actuarial survivals after lung transplants at 1, 3, 6, 12, and 24 months were 96%, 88%, 83%, 74%, and 74%, respectively, in the pre-transplant ECMO group, and 97%, 94%, 90%, 83%, and 74%, respectively, in the control group (P = .787).

Although the incidence of primary graft dysfunction requiring post-transplant ECMO is higher and the hospital stay is longer in patients receiving pre-transplant ECMO, the graft survival was good (2-year survival, 74%). (There much detail in the PubMed abstract)

 

The authors considered that ECMO is efficacious as a bridge to lung transplantation with good post-lung transplant outcomes. This seems to be used more frequently and successfully in recent years when the supply of donor organs remains a problem.

 

Tsui LC. Dorfman R. The cystic fibrosis gene: a molecular genetic perspective. [Review]  Cold Spring Harbor Perspectives in Medicine 2013; 3(2):a009472. Free Download available [PubMed]

The positional cloning of the gene responsible for cystic fibrosis (CF) was the important first step in understanding the basic defect and pathophysiology of the disease. This study aims to provide a historical account of key developments as well as factors that contributed to the cystic fibrosis transmembrane conductance regulator (CFTR) gene identification work.

A redefined gene structure based on the full sequence of the gene derived from the Human Genome Project is presented, along with brief reviews of the transcription regulatory sequences for the CFTR gene, the role of mRNA splicing in gene regulation and CF disease, and, various related sequences in the human genome and other species. Because CF mutations and genotype-phenotype correlations are covered by our colleagues (Ferec C, Cutting GR. 2012. Assessing the disease-liability of mutations in CFTR. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a009480), we only attempt to provide an introduction of the CF mutation database here for reference purposes

 

van Doorn CS. De Boo DW. Weersink EJ. van Delden OM. Reekers JA. van Lienden KP. Permanent cortical blindness after bronchial artery embolization. Cardiovasc Intervent Radiol 2013;  36:1686-9. [PubMed]

 A 35-year-old female with a known medical history of cystic fibrosis had a massive haemoptysis. CTA depicted a hypertrophied bronchial artery to the right upper lobe and showed signs of recent bleeding at that location. Bronchial artery embolization (BAE) was performed with gelfoam slurry, because pronounced shunting to the pulmonary artery was present. Immediately after BAE, the patient developed bilateral cortical blindness. Control angiography showed an initially not opacified anastomosis between the embolized bronchial artery and the right subclavian artery, near to the origin of the right vertebral artery. Cessation of outflow in the bronchial circulation reversed the flow through the anastomosis and allowed for spill of embolization material into the posterior circulation. Unfortunately the cortical blindness presented was permanent.

 

Vanderhelst E. De Wachter E. Willekens J. Pierard D. Vincken W. Malfroot A. Eradication of chronic methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients. An observational prospective cohort study of 11 patients. J Cyst Fibros 2013; 12:662-666.  [PubMed]

Chronic airway infection with methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) is an increasing clinical problem, and therapeutic options are limited. Because chronic infection with MRSA can be associated with accelerated decline in lung function, eradication of MRSA is attempted in most CF centres today. The aim of this observational prospective cohort study was to determine whether it is possible to eradicate MRSA from airways of CF patients using prolonged oral antibiotic combination therapy together with topical decolonization measures. RESULTS: Eleven CF patients, (median age: 9 years (range 1-43); median FEV1: 91%pred (95%CI 74%-100%pred)) who were chronically infected with MRSA, were treated daily for six months with rifampicin and fusidic acid orally. This study did not include a patient control group. Two patients had to switch to an alternative schedule, using rifampicin and clindamycin, due to the resistance pattern of MRSA. Topical decolonization measures were applied to all patients and included mupirocin-containing nasal ointment in both nostrils three times daily for five days and chlorhexidine hair and body wash once daily for five days.               Microbiological eradication was achieved in all patients at the end of the six-month eradication protocol, even when significant time (range 18 months to 9 years) had elapsed since initial isolation. In only one patient MRSA reappeared in the six-month follow-up period after the initial study period. Side-effects, like nausea, vomiting and diarrhoea were seen in five out of eleven patients, but did not lead to therapy cessation.                                                                      

The authors concluded that chronic MRSA infection can be eradicated from respiratory tract samples using a six month dual antibiotic regimen and topical MRSA decolonization measures.

 

The high prevalence of chronic S. aureus infection in many CF centres, as judged by patient registries, suggests that active eradication is not the policy adopted in many either for MSSA or MRSA. This study confirms the feasibility of eradicating S. aureus of both types which, on the information available seems to be the correct policy.

 

VanDyke RD. McPhail GL. Huang B. Fenchel MC. Amin RS. Carle AC. Chini BA. Seid M. Inhaled tobramycin effectively reduces FEV1 decline in cystic fibrosis. An instrumental variables analysis. Ann Amer Thorac Soc 2013; 10:205-212.  23802816   [PubMed]

To determine effectiveness of inhaled tobramycin on FEV1 decline in patients with chronic P. aeruginosa infections using observational data from the Cystic Fibrosis Foundation Patient Registry.  Using center-level prescribing rates, instrumental variables analysis showed less FEV1 decline for patients who received tobramycin when first eligible compared with those who did not receive tobramycin (difference, 2.55% predicted; 95% confidence interval, 0.16-4.94; P = 0.0366).                                                     Inhaled tobramycin is effective in reducing lung function decline among patients 6 to 21 years of age with CF. Because CF care is organized by center, using center-specific prescription rates as an instrumental variable is a feasible approach to using the Cystic Fibrosis Foundation Patient Registry to determine treatment effectiveness. More generally, this approach can correct for treatment-by-condition bias arising from observational studies.

 

The excellent US database (Cystic Fibrosis Foundation Patient Registry) is being increasingly used for answering clinical questions - in this instance demonstrating the long term benefits of inhaled tobramycin.  Although the statistical aspects may be a little confusing to some of us it is reassuring to know there is long term benefit from nebulised tobramycin.

 

Wang M, Ridderberg W, Hansen CR, Høiby N, Jensen-Fangel S, Olesen HV, Skov M, Lemming LE, Pressler T, Johansen HK, Nørskov-Lauritsen N. Early treatment with inhaled antibiotics postpones next occurrence of Achromobacter in cystic fibrosis.

J Cyst Fibros 2013; 12:638-43. [PubMed] 

The authors analysed species distribution, antimicrobial susceptibility and time to next occurrence of Achromobacter in Danish cystic fibrosis (CF) patients from 2000 to 2011Thirty-four primary isolates were identified to species level and subjected to antimicrobial susceptibility testing. Effectiveness of early antimicrobial treatment was assessed by a Kaplan-Meier estimation of time to recurrence.  Achromobacter xylosoxidans accounted for 13 (38%) of the isolates, and an unnamed species accounted for 11 (32%) of the isolates. Meropenem, piperacillin-tazobactam and trimethoprim-sulfamethoxazole were highly active against chemotherapy-naïve Achromobacter, while ceftazidime, colistin and tobramycin were judged adequate for inhalation therapy. Fifty-five percent of 25 patients treated with inhaled ceftazidime, colistin, or tobramycin remained free of Achromobacter three years after acquisition, in contrast to 17% of 22 patients who did not receive inhaled antibiotics (P<0.01).

 

The authors concluded that early treatment with inhaled antibiotics may prevent or postpone chronic infection with Achromobacter in CF patients.

 

White H. Morton AM. Conway SP. Peckham DG. Enteral tube feeding in adults with cystic fibrosis; patient choice and impact on long term outcomes. J Cyst Fibros 2013; 12(6):616-622.  [PubMed]

 There are no previous studies of the longer term nutritional and clinical outcomes in an exclusively adult population with cystic fibrosis or compared the outcomes for those who meet standard criteria and opt to undertake or decline enteral tube feeding (ETF). Twenty three out of 380 patients attending the Leeds Regional Adult CF unit fulfilled the standard criteria for commencing ETF (CF Trust, 2002) between 2004 and 2008.  Seventeen of the 23 patients agreed to accept a programme of ETF, two of whom died within the first year of ETF.

In the remaining patients (n=15), weight increased by 19.5% from baseline (p<0.001), BMI increased to within the normal range and lung function stabilised. There was no reduction in the requirement for intravenous antibiotic treatment. The six patients who declined ETF had a decline in lung function and no weight gain. The authors concluded supplemental enteral tube feeding improves clinical outcomes when administered over 3 years, resulting in significant weight gain, a normal BMI and stabilisation of lung function. It does not reduce intravenous antibiotic treatment days. In contrast those patients eligible for, but who declined ETF, showed deterioration in lung function and a failure to gain weight and to achieve normal BMI status.

 

This is useful medium term data from one of the UK’s major adult CF units. The experience confirms the value of enteral tube feeding in the majority of adults who fulfil the CF Trust’s criteria for starting this treatment. The CF Trust’s criteria when to initiate enteral tube feeding in adults are as follows – a Body Mass Index of less than 19; more than 5% weight loss over more than 2 months; failure to gain weight during pregnancy (Nutritional Management of Cystic Fibrosis. April 2002. CF Trust).

 

Wilschanski M. Novak I. The cystic fibrosis of exocrine pancreas. Cold Spring Harbor Perspectives in Medicine2013; 3(5):a009746. [PubMed] (Free download available from Cold Spring Harbour Perspectives in Medicine website)

This impressive work discusses the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. Also discussed are the relationship between cystic fibrosis and pancreatitis, and the present and potential therapeutic approaches in CF treatment relevant to the pancreas.

 

This is an excellent clear review of the present state of knowledge regarding the pancreas in CF. One of the most disappointing complications for the person with CF is to be told they have now developed another major complication - diabetes mellitus. It is to be hoped that the newer more specific molecular therapies will arrest the almost inevitable pancreatic destruction and decline in B-cell function to maintain sufficient insulin production to prevent this complication. Early evidence from the ivacaftor trials suggests that this may be definite possibility.

 

Wilson K, Jamersom PA. Comparison of central venous catheter and peripheral vein samples of antibiotics in children with cystic fibrosis. J Spec Pediatr Nurs 2013; 18:33-41. [PubMed]

A trial to determine if accurate serum antibiotic levels can be obtained from central venous catheters (CVCs) in pediatric patients with cystic fibrosis. Fifty paired CVC-peripheral vancomycin or tobramycin specimens were collected within 5 min of each other following a 5-ml flush and discard. Specimen samples were randomized by first site drawn.

Central venous catheter and peripheral antibiotic levels were highly correlated (r =.97, p <.001), with no statistically significant difference (t = 1.18, p=25).  Bland-Altman plot analysis revealed a bias of.47, with limits of agreement ranging from -4.20 to 6.87.

 

So accurate antibiotic concentrations can be obtained from central venous catheters, reducing paediatric patient trauma and stress.  This is a very important paper both for the children and also for the staff who have to take the blood specimens which can be a very stressful experience for both parties even though local anaesthetic cream (EMLA) introduced in the Eighties and inhaled nitrous oxide (Entonox) introduced in 2001 were major advances in care.

 

Witters P. Dupont L. Vermeulen F. Proesmans M. Cassiman D. Wallemacq P. De Boeck K. Lung transplantation in cystic fibrosis normalizes essential fatty acid profiles. J Cyst Fibros 2013; 12:222-228. [PubMed]

 Disorders in essential fatty acid state are increasingly reported and various supplementation trials have been performed in an attempt to improve outcomes. However, the mechanisms leading to these disturbances remain elusive. The authors investigated the role of the diseased CF lung on fatty acid profiles.

They compared fatty acid profiles in patients with CF after lung transplantation (n=11) to age-matched healthy controls and homozygous F508del patients (n=22 each). RESULTS: Compared to healthy controls, in patients with CF, there are decreased levels of docosahexaenoic, linoleic and arachidonic acid and increased levels of mead acid. In patients that underwent lung transplantation, levels of docosahexaenoic, linoleic and arachidonic acid were normal. Mead acid did not decrease significantly. The diseased CFTR deficient lung is a major determinant in the disturbed fatty acid profile in CF.

 

This is new and interesting data as abnormal fatty acid profiles have been reported in CF since the first paper by Kuo et al in 1962. 

 

Wong JK, Ranganathan SC, Hart E, on behalf of the Australian Respiratory Early Surveillance Team for Cystic Fibrosis. (AREST CF). Staphylococcus aureus in early cystic fibrosis lung disease. Pediatr Pulmonol. 2013 Aug 22. doi: 10.1002/ppul.22863. [Epub ahead of print] [PubMed]

Staphylococcus aureus: is a common bacterial organism infecting children with cystic fibrosis (CF). Emerging evidence suggests early lower airway infection with this organism in young children with CF results in the deterioration of lung function, poorer nutrition parameters and heightens the airway inflammatory response. Despite contributing significantly to the burden of early lung disease among this group, there are ongoing controversies in the management of S. aureus infection, and gaps in our understanding of exactly how this organism causes lung disease. To reduce the morbidity and mortality of early infection ongoing research is needed to: (i) understand the early host immune response that enables this pathogen to reside within the CF lung; (ii) determine if there are organism specific factors that are associated with CF lung disease; and (iii) clarify the utility of anti-staphylococcal antibiotic prophylaxis and/or eradication in the treatment of this patient population.

 

This is a detailed and timely review of the significance and management of S. aureus infection in young children with CF.  Even though all endoscopy studies show the presence of S. aureus in the airways is usually associated with evidence of significant (and presumably damaging) inflammation and even though in the past the majority of CF children died from S. aureus infection, it is difficult to understand why such a high incidence of chronic infection is allowed to occur particularly in N. America. The incidence of chronic SA infection varies greatly between centres and countries depending on their policy of prophylaxis and eradication e.g. from CFF Patient Registry 29.1% in 1992 and 69% in 2012 in a country where prophylaxis and eradication are not recommended, compared with  the 10% in mid-childhood to 30% by mid-Twenties falling to 20% in older adults in the UK in 2012.  Although the present authors state that “to ensure the most suitable practices are used, research in assessing the efficacy of anti-staphylococcal prophylaxis and eradication therapies in improving patient outcomes is urgently needed”, it seems to this reviewer that prevention of and if necessary eradication of a damaging pathogen such as S. aureus would be sensible optimal therapy now.

 

There have a number of instances over the years where waiting for the results of randomised controlled trials to provide evidence of long term benefit has denied many people with CF valuable interventions that would have favourably influenced their long term health e.g. early eradication therapy of P. aeruginosa is a prime example, also early diagnosis and treatment interventions after neonatal CF screening.  It is important for the CF clinician to use all available evidence past and present.

 

Wu K, Yau YC, Matukas L, Waters V. Biofilm compared to conventional antimicrobial susceptibility of Stenotrophomonas maltophilia isolates from cystic fibrosis patients. Antimicrob Agents Ch 2013; 7:1546-8. [PubMed]

One hundred twenty-five S. maltophilia isolates from 85 CF patients underwent planktonic and biofilm susceptibility testing against 9 different antibiotics, alone and in double antibiotic combinations. When S. maltophilia isolates were grown as a biofilm, 4 of the 10 most effective antibiotic combinations included high-dose levofloxacin and 7 of the 10 combinations included colistin at doses achievable by aerosolisation.

S. maltophilia is an increasing problem and this information will be helpful to those dealing it.

 

Yang N. Garcia MA. Quinton PM. Normal mucus formation requires cAMP-dependent HCO3- secretion and Ca2+-mediated mucin exocytosis. J Physiol 2013; 591:4[PubMed]

Evidence from the pathology in cystic fibrosis (CF) and recent results in vitro indicate that HCO3- is required for gel-forming mucins to form the mucus that protects epithelial surfaces. Mucus formation and release is a complex process that begins with an initial intracellular phase of synthesis, packaging and apical granule exocytosis that is followed by an extracellular phase of mucin swelling, transport and discharge into a lumen.

Exactly where HCO3- becomes crucial in these processes is unknown, but we observed that in the presence of HCO3-, stimulating dissected segments of native mouse intestine with 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) induced goblet cell exocytosis followed by normal mucin discharge in wild-type (WT) intestines. CF intestines that inherently lack cystic fibrosis transmembrane conductance regulator (CFTR)-dependent HCO3- secretion also demonstrated apparently normal goblet cell exocytosis, but in contrast, this was not followed by similar mucin discharge. Moreover, we found that even in the presence of HCO3-, when WT intestines were stimulated only with a Ca2+-mediated agonist (carbachol), exocytosis was followed by poor discharge as with CF intestines. However, when the Ca2+-mediated agonist was combined with a cAMP-mediated agonist (isoproterenol (isoprenaline) or vasoactive intestinal peptide) in the presence of HCO3- both normal exocytosis and normal discharge was observed.

These results indicate that normal mucus formation requires concurrent activation of a Ca2+-mediated exocytosis of mucin granules and an independent cAMP-mediated, CFTR-dependent, HCO3- secretion that appears to mainly enhance the extracellular phases of mucus excretion.

 

Further evidence supporting the important role of bicarbonate which has been emphasised for a considerable time by Paul Quinton.

 

Yen EH, Quinton H, Borowitz D. Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis. J Pediatr 2013; 162:530-535. [PubMed]

To evaluate the relationship between nutritional status early in life and the timing and velocity of height growth, lung function, complications of cystic fibrosis, and survival using data from the Cystic Fibrosis Foundation Registry (US) for patients born between 1989 and 1992 (n=3142).

For the population studied, greater weight at age 4 years is associated with greater height, better pulmonary function, fewer complications of cystic fibrosis, and better survival through age 18 years. Furthermore, greater weight-for-age in the peripubertal period is associated on average with improved tempo and timing of pubertal height growth.

 

This data confirms, yet again, the now well established observation that improved survival correlates with a better nutritional state, first clearly shown by Richard Kraemer and colleagues in 1978 (above) [PubMed] and later by Mary Corey and colleagues from Toronto in 1988 above [PubMed].

 

Fig. 6c: Elizabeth Yen

www.ucsfbenioffchildrens.org

Dr Elizabeth Yen (figure 6c) is a pediatric gastroenterologist at University of California San Fransico Benioff Children's Hospital She is an expert in treating eosinophilic gastrointenstinal disorders, and also specializes in caring for children with cystic fibrosis.

 

Young DC, Zobell JT, Waters CD, Ampofo K, Stockmann C, Sherwin CM,, Spigarelli MG. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: IV. colistimethate sodium. Pediatr Pulmonol 2013; 48:1-7. [PubMed]

The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing the intravenous (IV) polymixin antibiotic colistimethate sodium (CMS) in the treatment of APE and to identify areas where further study is warranted. Currently, there is not an international standard on the labeling of CMS products. As a result, this has lead to confusion in the interpretation of the literature with respect to efficacy, tolerance, and optimal dosing strategy. The dosing ranges of IV CMS from the literature are 5.3-12.9 mg/kg/day, maximum 480 mg per day for 60 kg patient (Colomycin injection-European product) and 8-21.3 mg/kg/day, maximum 800 mg per day for 60 kg patient (Coly-Mycin M parenteral-US product).The literature supports a CMS dose of 8 mg/kg/day divided every 8 hr (maximum 480 mg/day) for the treatment of APE secondary to Pseudomonas aeruginosa. The maximum recommended CMS dose of 480 mg/day is less than is recommended by the FDA-approved and CFF dosing guidelines but in agreement with UK CF Trust Antibiotic Working Group recommendations.

This is helpful as there has been confusion over the dosing and designation of the various preparations over the years.

 

Ziobro R, Henry B, Edwards MJ, Lentsch AB, Gulbins E. Ceramide mediates lung fibrosis in cystic fibrosis. Biochem Biophys Res Co 2013; 434:705-709. [PubMed]

The authors demonstrate that chronic accumulation of ceramide in the lung contributes to the development of fibrosis in aged cystic fibrosis mice. Genetic or pharmacological normalization of ceramide in cystic fibrosis mice, which was achieved by heterozygosity of acid sphingomyelinase or chronic (6.5 month long) treatment of mice with pharmacological inhibitors of acid sphingomyelinase significantly decreased the development of lung fibrosis. Moreover, long-term treatment of cystic fibrosis mice with pharmacological inhibitors of acid sphingomyelinase or genetic heterozygosity of the enzyme also minimizes pulmonary inflammatory cytokines in cystic fibrosis mice.

The authors suggest this data identifies ceramide as a key molecule associated with pulmonary fibrosis in cystic fibrosis mice and demonstrate for the first time that prolonged inhibition of acid sphingomyelinase is able to attenuate fibrosis and inflammation in this animal model. The clinical trials of amitriptyline are showing positive results (Nahrlich L et al, 2013. [PubMed]; see also Grassme H et al. 2013).

 

Zobell JT. Waters CD. Young DC. Stockmann C. Ampofo K. Sherwin CM. Spigarelli MG. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. cephalosporins and penicillins. [Review] Pediatr Pulmonol 2013; 48:107-22. [PubMed]

Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin-tazobactam and ticarcillin-clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200-400mg/kg/day divided every 6-8hr, maximum 8-12g/day, and 150-200mg/kg/day divided every 6-8hr, up to 6-8g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350-600mg/kg/day divided every 4hr, maximum 18-24g/day of piperacillin component, and 400-750mg/kg/day divided every 6hr, up to 24-30g/day of ticarcillin component, respectively.

 

As a large portion of CF patients will not regain their lung function following an APE, the authors suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA-approved doses of ceftazidime, cefepime, and ticarcillin-clavulanate in APE. The usefulness of high dose piperacillin (>600mg/kg/day) may be limited due to treatment-related adverse effects. Further understanding of these adverse effects in CF patients is needed.

 

Zobell JT. Young DC. Waters CD. Ampofo K. Stockmann C. Sherwin CM. Spigarelli MG. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: VI. Executive summary. Pediatr Pulmonol 2013; 48:525-37.[PubMed]

The aim of this review is to provide an overview of the classes of intravenous anti-pseudomonal antibiotics, the findings of anti-pseudomonal antibiotic utilization surveys, the current antibiotic dosing recommendations from the U.S. and Europe, and the pharmacokinetic (PK) and pharmacodynamic (PD) differences between CF and non-CF individuals. Anti-pseudomonal antibiotic classes include beta-lactams, aminoglycosides, fluoroquinolones, and colistimethate sodium.

Recent surveys of antibiotic utilization in CF Foundation-accredited care centers have shown that a large number of centers are not following recommended dosing strategies despite published recommendations in the U.S. and Europe. The recommended doses for anti-pseudomonal antibiotics may be higher than FDA-approved doses due to PK and PD differences.

As a large portion of CF patients will not regain their lung function following an APE, it seems possible that currently available anti-pseudomonal agents are being used sub-optimally. As new anti-pseudomonal agents are not currently available, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat pulmonary exacerbations in an effort to improve outcomes for CF patients infected with Pseudomonas aeruginosa.

This summary contains a very important message – that many improvements in CF outlook have been achieved by making minor adjustments to already used therapy; in so doing optimal treatment has replaced suboptimal treatment.  The increasing use of the intravenous route rather than the oral route for antibiotic administration in the Eighties represents such an advance.