Adrienne P SavantSusanna A McColley.  2014 year in review: Cystic fibrosis.  Pediatr Pulmonol 2015 Nov;50(11):1147-56. doi: 10.1002/ppul.23309.Epub 2015 Sep 7. [PubMed]

Susanna McColley

Adrienne Savant

In this article, the authors highlight cystic fibrosis (CF) research published in Pediatric Pulmonology during 2014, as well as related articles published in other journals.

 Drs Adrienne P SavantSusanna A McColley are in the Division of Pulmonary Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Illinois.Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.   Susanna McColley also at the Stanley Manne Children’s Research Institute, Illinois.

Nicholas J Simmonds Cystic Fibrosis Papers of the Year, 2013-2014 Paediatr Respir Rev. 2015 Oct;16 Suppl 1:9-11.doi: 10.1016/j.prrv.2015.07.008.Epub 2015 Sep 26. Abstract only  [PubMed]

Nicholas Simmonds cfcare.net

Studies published in the last year in the field of cystic fibrosis have provided more data on the safety and efficacy of a number of therapies, including mutation-specific drugs. There have also been a number of publications on monitoring of early lung disease including the use of lung clearance index and magnetic resonance scanning. Evidence suggests early lung changes may remain relatively static over the first year of life. There are important outcome differences across national patient registries and there is also the increasing recognition of psychological illnesses and possible drug interactions as treatment becomes more complicated and survival improves.

Dr Nicholas Simmonds is Consultant Respiratory Physician/Honorary Senior Clinical Lecturer, Department of Cystic Fibrosis, Royal Brompton Hospital and Imperial College, Sydney Street, London, United Kingdom, SW3 6NP


Accurso FJ. Van Goor F. Zha J. Stone AJ. Dong Q. Ordonez CL. Rowe SM. Clancy JP. Konstan MW. Hoch HE. Heltshe SL. Ramsey BW. Campbell PW. Ashlock MA. Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data. J Cyst Fibros 2014; 13(2):139-47. [PubMed]
The authors examined data from a Phase 2 trial {NCT00457821} of ivacaftor, a CFTR potentiator, in cystic fibrosis (CF) patients with a G551D mutation to evaluate standardised approaches to sweat chloride measurement and to explore the use of sweat chloride and nasal potential difference (NPD) to estimate CFTR activity. The authors found that within-patient sweat chloride determinations showed sufficient precision to detect differences between dose-groups and assess ivacaftor treatment effects. Analysis of changes in sweat chloride and NPD demonstrated that patients treated with ivacaftor achieved CFTR activity equivalent to approximately 35%-40% of normal.

— These authors find sweat chloride is useful in multicenter trials as a biomarker of CFTR activity and to test the effect of CFTR potentiators. However, in Manchester UK sweat chloride was not regarded as useful clinical marker of response to ivacaftor (see below – Barry PJ et al. 2014.[PubMed]

Al-Aloul M. Nazareth D. Walshaw M. Nebulized tobramycin in the treatment of adult cystic fibrosis pulmonary exacerbations. J Aerosol Med Pulm Drug Deliv 2014; 27(4):299-305. [PubMed]


Fig 1. Mohamed Al-Aloul MeditSimple

Repeated courses of intravenous (IV) aminoglycosides in cystic fibrosis (CF) patients are associated with cumulative nephrotoxicity. Targeting their delivery through the inhaled route during acute pulmonary exacerbations may also be effective, but without systemic side effects.
Using a randomized crossover trial design, in a pilot study the authors compared 14 days of IV tobramycin with nebulized tobramycin 300mg twice a day (TNS) in acute respiratory exacerbations in 20 CF adults chronically infected with Pseudomonas aeruginosa (Psa). Patients also received IV colistin in both arms. Improvement in spirometry was similar between the two groups [mean change in FEV1 % predicted: IV group 16.4 (standard deviation 8.5) versus TNS group 19.9 (11.3), p=0.26], but there was more suppression of sputum Psa in the TNS group [mean difference between treatments 0.85 log10 colony-forming units/mL (CI 0.03 to 1.67), p=0.05]. IV tobramycin was associated with a greater urinary protein leak [mean difference between treatments 0.59mg/24hr (0.30 to 0.87), p=0.0005] and higher urinary levels of markers of acute renal tubular injury: N-acetylglucosaminidase [0.72IU/mmol (0.37 to 1.07), p=0.0004], alanine aminopeptidase [1.19IU/mmol (0.70 to 1.68), p=0.0001], and beta2-microglobulin [0.44mug/mmol (0.16 to 0.72), p=0.0046] than TNS. Compared with IV tobramycin, TNS treatment prolonged the time to next exacerbation requiring hospitalisation (p<0.001). Patient satisfaction was similar with both treatments, and no serious adverse effects were recorded. The authors concluded that nebulised tobramycin (TNS) (if combined with IV colisitin)  is effective in treating acute exacerbations of Psa in CF patient), but with a renal sparing potential compared with the IV preparation.

–  A useful study in view of the increasing problem of renal damage resulting from numerous  courses of intravenous aminoglycosides over many years. The efficacy of the inhaled route would need further confirmation in a longer study but the renal sparing factor is very important although, with regard to efficacy in this trial, it should be noted that both groups also received IV colistin which is an effective anti-pseudomonal agent.

Dr. Mohamed Al-Aloul  (fig. 1) is Respiratory Physician BMI The Alexandra Hospital and the Transplant Centre Wythenshawe Hospital Manchester.

Al-Zubeidi D. Hogan PG. Boyle M. Burnham CA. Fritz SA. Molecular epidemiology of methicillin-resistant Staphylococcus aureus isolated in serial cultures from the respiratory tract of children with cystic fibrosis. Infect Dis J 2014; 33(6):549-53. [PubMed]
Little is known about strain relatedness of methicillin-resistant Staphyloccocus aureus (MRSA) isolated at serial time points from the respiratory tract of patients with cystic fibrosis. The authors identified 54 CF patients with serial MRSA cultures (145 distinct cultures). Over time, 45 (83%) patients maintained the same strain type and 9 (17%) possessed at least 2 distinct strain types.

Data suggest that sustained presence of MRSA in CF patients is most commonly attributable to identical strain types. Acquisition of distinct MRSA strains in the airway is infrequent.

— It seems that early eradication of S. aureus is not a high priority for some clinicians in view of the very high incidence of chronic infection in some clinics. This is unfortunate for S. aureus is a proven very dangerous pathogen for people with CF.

Al-Malky G. Suri R. Sirimanna T. Dawson SJ. Normal hearing in a child with the m.1555A>G mutation despite repeated exposure to aminoglycosides. Has the penetrance of this pharmacogenetic interaction been overestimated?. J Pediatr Otorhinolaryngol 2014; 78(6):969-73. [PubMed]

Fig 2. Ghada Al-Malky LinkedIn

The mtDNA m.1555A>G mutation causes increased susceptibility to aminoglycoside ototoxicity resulting in significant hearing loss in 100% of reported exposed cases.
Genetic and audiological assessments were conducted in a sample of 59 children with cystic fibrosis undergoing aminoglycoside treatment. Of the two m.1555G patients identified one had severe-profound deafness. Surprisingly, the second m.1555G patient exhibited well-preserved hearing despite repeated exposure to aminoglycosides.
The authors suggest that this may be a rare case of intact hearing in an m.1555G individual with aminoglycoside use. Alternatively, its penetrance may have been previously overestimated due to recruitment bias. They suggest further studies are required to determine the true penetrance to inform m.1555A>G genetic testing in similar clinical scenarios.

—  It has been suggested that the rarity of this mutation would preclude the routine testing of patients receiving courses of intravenous aminoglycosides. Only 3 of 10 preterm m.1555A>G carriers who were exposed to aminoglycosides failed hearing screening (Goplel G et al, 2014.[PubMed]) and not all small preterm infants with the mutation have subsequently been found to have hearing loss. These authors suggest further research would be helpful.

Dr. Ghada Al-Malky (fig. 2) is Senior lecturer at the UCL Ear Institute London and Director of Clinical Education. She collaborates with the paediatric department at Great Ormond Street concerning ototoxicity of aminoglycosides.

Andersen C. Kahl BC. Olesen HV. Jensen-Fangel S. Norskov-Lauritsen N. Intravenous antibiotics given for 2 weeks do not eradicate persistent Staphylococcus aureus clones in cystic fibrosis patients. Clin Microbiol Infect 2014; 20(5):O285-91.[PubMed]

Fig 3. Niels Norskov-Lauritsen

Of 65 patients chronically infected with S. aureus, 37 received 139 courses of IV antimicrobial agents with activity against S. aureus (mean duration, 15 days; range, 6-31 days). Administration of IV antibiotics increased the time to the next sample with growth of S. aureus: the mean interval between two positive samples was 68 days if IV treatment had been administered, in contrast to 49 days if no IV treatment had been administered (p 0.003).

When S. aureus recurred in sputum after IV treatment, the isolate belonged to a different clone in 33 of 114 (29%) intervals, in comparison with 68 of 232 (29%) intervals where IV treatment had not been prescribed (OR 0.98, 95% CI 0.60-1.61). In conclusion, this shows that 2 weeks of IV antimicrobial treatment can significantly suppress chronic staphylococcal infection in CF, but is not associated with the eradication of persistent bacterial clones.

—  These findings are to be expected.    S. aureus can be eradicated by antibiotic therapy provided it is not allowed to become an established chronic infection – somewhat analogous to P. aeruginosa where eradication of a recently acquired infection is usually successful but eradication of chronic infection virtually never achieved.

Dr. Niels Norskov-Lauritsen (fig. 3)  is at the Department of Clinical Medicine Klinisk Mikrobiologi Aarthus, Denmark

Anonymous. Inhaled mannitol and cystic fibrosis. Unnecessary bronchial irritation. [Review] Prescrire International 2014; 23(148):89-91[PubMed]
Mannitol in the form of capsules of powder for inhalation, is authorised in the European Union for use as a mucolytic in adults with cystic fibrosis. Two double-blind randomised trials have compared two doses of inhaled mannitol (400 mg or 50 mg, twice a day) in a total of 642 patients (57% adults) with cystic fibrosis. After 26 weeks of treatment, there was no difference between the groups in terms of clinical criteria such as the frequency of pulmonary exacerbations, quality of life, hospitalisation, or rescue antibiotic use. Inhaled mannitol increases the risk of bronchospasm and can also cause coughing and haemoptysis. A pretreatment test, used to exclude patients with bronchial hyperresponsiveness to mannitol, can also have noteworthy adverse effects.

The authors of this review consider this treatment is inconvenient, requiring inhalation of the contents of 10 mannitol capsules morning and evening; the capsules have to be placed one by one in the inhalation device, and the device must be replaced every week. In practice, patients with cystic fibrosis would be well advised to avoid inhaled mannitol.

—   This is a interesting article in an independent French journal expressing one view on the use of inhaled mannitol – a drug authorised in the European Union but not used in the USA. (See Topics -> Mucolytics – Mannitol for some of the previous work)

Anstead M. Saiman L. Mayer-Hamblett N. Lands LC. Kloster M. Goss CH. Rose L. Burns JL. Marshall B. Ratjen F. Pulmonary exacerbations in CF patients with early lung disease. J Cyst Fibros 2014; 13(1):74-9. [PubMed]

Fig 4. Michael Anstead ResearchGate

Current definitions of pulmonary exacerbation (PE) in cystic fibrosis are based on studies in participants with significant lung disease and may not reflect the spectrum of findings observed in younger patients with early lung disease.
The authors used data from a recent trial assessing the efficacy of azithromycin in children to study signs and symptoms associated with PEs and related changes in lung function and weight. While increased cough was present in all young patients with PEs, acute weight loss and reduction in oxygen saturation were not observed. Changes in lung function did not differ between subjects who did experience a PE and those who were exacerbation-free.

Cough was the predominant symptom in CF patients with early lung disease experiencing a PE. There was no significant difference in mean 6-month change in lung function or weight among subjects with one or more exacerbations and those without an exacerbation.

— This conclusion confirms the observations of many clinicians who tend to treat exacerbations very early in young patients e.g a new cough that doesn’t clear quickly is for many paediatricians, even without any other signs, is an indication for vigorous treatment with IV antibiotics.

Dr. Michael Anstead (fig. 4) is Medical Director of the Center for Lung Transplant and of the Adult Cystic Fibrosis Center, University of Kentucky College of Medicine.

Archibald AD. Massie J. Smith MJ. Dalton DG. du Sart D. Amor DJ.  Population-based genetic carrier screening for cystic fibrosis in Victoria. J Aust 2014; 200(4):205-6. [PubMed].

Fig. 5 Alison Archibald      X.com

 This is  a letter to the Med J Aust.  “Cystic fibrosis (CF) is the most common inherited life-shortening condition affecting Australian children, with a carrier frequency of 1 in 25. Most children with CF (94%) have no family history of the condition.       The Human Genetics Society of Australasia recommends that couples planning or in the early stages of pregnancy be made aw.are of the availability of CF carrier screening.  In Victoria, since 2006, CF carrier screening has been available to individuals and couples as a fee-for-service program.     3 The program initially screened for 12 mutations (2006–2012) and now screens for 38 mutations (2012–2013) at a cost of $150 per patient. The program was established through collaboration between Victorian Clinical Genetics Services, the CF clinic at the Royal Children’s Hospital in Melbourne, obstetricians and Cystic Fibrosis Victoria”.

Alison Archibald  (fig. 5) is Associate Genetic Counsellor Clinical Genetics Service University of Melbourne

Awadalla M. Miyawaki S. Abou Alaiwa MH. Adam RJ. Bouzek DC. Michalski AS. Fuld MK. Reynolds KJ. Hoffman EA. Lin CL. Stoltz DA. Early airway structural changes in cystic fibrosis pigs as a determinant of particle distribution and deposition. Ann Biomed Eng 2014; 42(4):915-27.c [PubMed]

Fig 6. David A Stoltz medicine.uiowa.e

Cystic fibrosis pigs develop lung disease similar to humans with CF. At birth, before infection and inflammation, CF pigs have airways that are irregularly shaped and have a reduced caliber compared to non-CF pigs. The authors hypothesised that these airway structural abnormalities affect airflow patterns and particle distribution. To test this hypothesis they used computational fluid dynamics (CFD) on airway geometries obtained by computed tomography of newborn non-CF and CF pigs.
The irregular particle distribution and increased deposition in newborn CF pig airways suggest that early airway structural abnormalities might contribute to CF disease pathogenesis.

In contrast to the cystic fibrosis mice, the pigs have airway abnormalities that are similar to those in affected infants and apparently are proving very useful in explainduing certain features present in cystic fibrosis infants.

David A Stoltz (fig. 6) is Pulmonologist and Professor at University of Iowa Hospitals and Clinics

Barry PJ, Jones AM, Webb AK, Horsley AR. Chloride is not a useful marker of clinical response to Ivacaftor. Thorax 2014; 69(6):586-7. [PubMed]
Clinical trials have revealed that Ivacaftor significantly reduces sweat chloride in patients with cystic fibrosis who carry the G551D mutation. This finding has been incorporated into the commissioning guidelines in the UK with a sweat chloride reduction of 30% or below 60 mmol/L, specified as the main criteria for continued funding of Ivacaftor for individual patients.
In a cohort of 24 adults who were prescribed Ivacaftor, there was no correlation between absolute or relative reductions in sweat chloride and improvements in lung function.

These findings question the validity of sweat chloride as a surrogate marker of clinical efficacy (as suggested by Accurso FJ et al al. 2014 above [PubMed]).

Barillova P. Tchesnokova V. Dubbers A. Kuster P. Peters G. Dobrindt U. Sokurenko EV. Kahl BC. Prevalence and persistence of Escherichia coli in the airways of cystic fibrosis patients – an unrecognized CF pathogen?. Int J Med Microbiol 2014; 304(3-4):415-21. [PubMed]
Escherichia coli has not been considered as a significant CF pathogen although at times appearing in the sputum cultures. In a total of 176 patients were observed over 5.6 years, in 45 patients (25.6%) E. coli was cultured at least once. In 19 patients (10.8%) the same E. coli strain was isolated at least 3 times within a period of more than 6 months, with a mean persistence of 29 months. E. coli was occasionally or persistently isolated in a quarter of CF patients, mostly in very young or older patients.

The authors suggest the relatively high bacterial load of E. coli colonisation, the distinct association with the highly virulent extra-intestinal B2 clonal group and phenotypic variability in the long-term colonising strains suggests a previously unrecognised clinical significance of E. coli as a CF pathogen. This confirms the impression that certain people with CF tend to grow E.coli frequently and are presumably chronically infected by the organism.

Petra Barillova is at Medical Microbiology, University Hospital Muenster, Muenster, Germany; Department of Microbiology, University of Washington, Seattle, WA, USA.

Barry PJ. Plant BJ. Nair A. Bicknell S. Simmonds NJ. Bell NJ. Shafi NT. Daniels T. Shelmerdine S. Felton I. Gunaratnam C. Jones AM. Horsley AR. Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease. Chest 2014; 146(1):152-8. [PubMed]

Fig 7. Peter J Barry cfmatters.eu

Patients with an FEV1 < 40% predicted were excluded from phase 3 clinical trials of ivacaftor, and the effectiveness of the drug in this population is, therefore, unknown. Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype.
Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted (P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg (P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y (P = .001) and median total IV treatment days decreased from 74 to 38 d/y (P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects.

— So the authors concluded Ivacaftor was clinically effective in patients with CF who carry the G551D mutation even if they had severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

Dr. Peter J Barry (fig. 7) is  physician at the CF Centre Wythenshawe Manchester

Bedi P. Sidhu MK. Donaldson LS. Chalmers JD. Smith MP. Turnbull K. Pentland JL. Scott J. Hill AT. A prospective cohort study of the use of domiciliary intravenous antibiotics in bronchiectasis. Primary Care Respiratory Medicine. 24:14090, 2014[PubMed]
116 patients with non-cystic fibrosis bronchiectasis received 196 courses of IV antibiotics either as inpatient treatment, early supported discharge or as domiciliary therapy. The authors concluded on all parameters domiciliary IV antibiotic therapy in bronchiectasis is clinically effective and safe in their cohort of patients.

— Here is further welcome evidence (admittedly would be considered anecdotal by Cochrane reviewers!) of the benefit and safety of home IV antibiotics, in this case in non-CF patients. It is welcome in view of the recent rather negative Cochrane Review where most of the publications didn’t come up to standard. It is recalled that the introduction of intravenous antibiotics some 40 years ago and their administration at home, avoiding hospitalisation, were one of the major advances for patients who had cystic fibrosis and their families. Although intravenous antibiotics were not a major component of Harry Shwachman’s treatment they did, in my view, represent one of the major advances in cystic fibrosis care following their more widespread use in the late Seventies and early Eighties.

Dr. Pallavi Bedi is a Clinical Research Fellow, MRC Centre for Inflammation Research University of Edinburgh.

Boinot C. Jollivet Souchet M. Ferru-Clement R. Becq F. Searching for combinations of small-molecule correctors to restore f508del-cystic fibrosis transmembrane conductance regulator function and processing. J Pharmacol Exp Ther 2014; 350(3):624-34. [PubMed]

Fig. 8 Fred Becq    author’s photo

The mutated protein F508del-cystic fibrosis transmembrane conductance regulator (CFTR) failed to traffic properly as a result of its retention in the endoplasmic reticulum and functions as a chloride (Cl(-)) channel with abnormal gating and endocytosis.
Small chemicals (called correctors) individually restore F508del-CFTR trafficking and Cl(-) transport function, but recent findings indicate that synergistic pharmacology should be considered to address CFTR defects more clearly.
We studied the function and maturation of F508del-CFTR expressed in HeLa cells using a combination of five correctors [miglustat, IsoLAB (1,4-dideoxy-2-hydroxymethyl-1,4-imino-l-threitol), Corr4a (N-[2-(5-chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]bithiazolyl-2′-yl]-benzamide), VX-809 [3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid], and suberoylamilide hydroxamic acid (SAHA)].

Using the whole-cell patch-clamp technique, the current density recorded in response to CFTR activators (forskolin + genistein) was significantly increased in the presence of the following combinations: VX-809 + IsoLAB; VX-809 + miglustat + SAHA; VX-809 + miglustat + IsoLAB; VX-809 + IsoLAB + SAHA; VX-809 + miglustat + IsoLAB + SAHA. These combinations restored the activity of F508del-CFTR but with a differential effect on the appearance of mature c-band of F508del-CFTR proteins. Focusing on the VX-809 + IsoLAB cocktail, we recorded a level of correction higher at 370C versus room temperature, but without amelioration of the thermal instability of CFTR. The level of functional rescue with VX-809 + IsoLAB after 4 hours of incubation was maximal and similar to that obtained in optimal conditions of use for each compound (i.e., 24 hours for VX-809 + 4 hours for IsoLAB). Finally, we compared the stimulation of F508del-CFTR by forskolin or forskolin + VX-770 [N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide] with cells corrected by VX-809 + IsoLAB.

The authors consider their results open new perspectives for the development of a synergistic polypharmacology to rescue F508del-CFTR and show the importance of temperature on the effect of correctors and on the level of correction, suggesting that optimized combination of correctors could lead to a better rescue of F508del-CFTR function.

Clement Boinot is at the  Signalisation et Transports Ioniques Membranaires, Université de Poitiers, Centre National de la Recherche Scientifique (CNRS), Poitiers, France.

Frederic Becq (fig.8) is at the Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, Centre National de la Recherche Scientifique (CNRS), Poitiers, France

Bourget P. Amin A. Dupont C. Abely M. Desmazes-Dufeu N. Dubus JC. Jouani BL. Merlette C. Nove-Josserand R. Pages J. Panzo R. Vidal F. Voge F. Hubert D. How to minimize toxic exposure to pyridine during continuous infusion of ceftazidime in patients with cystic fibrosis?. Antimicrob Agents Chemother 2014; 58:2849-55. [PubMed]
Ceftazidime is widely used in cystic fibrosis patients. Thus, the spontaneous production of pyridine, which is a toxic product, raises some concern. This study was to examine the kinetics of degradation of ceftazidime in portable infusion pumps either at 4C, 22C, or 33C and to propose some recommendations in order to reduce the pyridine exposure. Two administration models were studied in vitro. In model 1, 12 g of ceftazidime was infused over 23 h (once-daily infusion) compared to 6 g infused over 11.5 h in model 2 (twice-daily regimen). Regardless of the conditions, the production of pyridine was significantly lower in model 2, whereas the total delivery amount of ceftazidime is significantly higher at 4C and 33C compared to that in model 1.

These findings led to the authors’ three major recommendations: (i) exposing a solution of ceftazidime to over 22C should be strictly avoided, (ii) a divided dose of 6 g over 11.5 hrs instead of a once-daily administration is preferred, and (iii) infusion should be administered immediately after reconstitution.

— In view of the increasing tendency to administer prolonged infusions of ceftazidime as the ideal way to achieve a recommended constant blood level, the findings reported here would appear to be of practical importance.

Philippe Bourget is Head Chief of the Clinical Pharmacy Department at the University Hospital Necker-Enfants Malades, Clinical Pharmacy Department, Paris, France.

Boyle MP. Bell SC. Konstan MW. McColley SA. Rowe SM. Rietschel E. Huang X. Waltz D. Patel NR. Rodman D. VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2014; 2(7):527-38[PubMed]

Fig. 8 Michael Boyle hopkinscf.org

This important multicentre study tested combination treatment with lumacaftor, an investigational CFTR corrector that increases trafficking of phe508del CFTR to the cell surface, and ivacaftor, a CFTR potentiator that enhances chloride transport of CFTR on the cell surface.
The authors assessed three successive cohorts, with the results of each cohort informing dose selection for the subsequent cohort. They recruited patients from 24 cystic fibrosis centres in Australia, Belgium, Germany, New Zealand, and the USA. Eligibility criteria were: confirmed diagnosis of cystic fibrosis, age at least 18 years, and a forced expiratory volume in 1s (FEV1) of 40% or more than predicted.
Cohort 1 included phe508del CFTR homozygous patients randomly assigned to either lumacaftor 200 mg once per day for 14 days followed by addition of ivacaftor 150 mg or 250 mg every 12 h for 7 days, or 21 days of placebo.
Together, cohorts 2 and 3 included phe508del CFTR homozygous and heterozygous patients, randomly assigned to either 56 days of lumacaftor (cohort 2: 200 mg, 400 mg, or 600 mg once per day, cohort 3: 400 mg every 12 h) with ivacaftor 250 mg every 12 h added after 28 days, or 56 days of placebo.

The primary outcomes for all cohorts were change in sweat chloride concentration during the combination treatment period in the intention-to-treat population and safety (laboratory measurements and adverse events). (The study is registered with ClinicalTrials.gov, number NCT01225211, and EudraCT, number 2010-020413-90).

Cohort 1 included 64 participants. Cohort 2 and 3 combined contained 96 phe508del CFTR homozygous patients and 28 compound heterozygotes. Treatment with lumacaftor 200 mg once daily and ivacaftor 250 mg every 12 h decreased mean sweat chloride concentration by 9.1 mmol/L (p<0.001) during the combination treatment period in cohort 1.

In cohorts 2 and 3, mean sweat chloride concentration did not decrease significantly during combination treatment in any group. Frequency and nature of adverse events were much the same in the treatment and placebo groups during the combination treatment period; the most commonly reported events were respiratory. 12 of 97 participants had chest tightness or dyspnoea during treatment with lumacaftor alone. In pre-planned secondary analyses, a significant decrease in sweat chloride concentration occurred in the treatment groups between day 1 and day 56 (lumacaftor 400 mg once per day group -9.1 mmol/L, p<0.001; lumacaftor 600 mg once per day group -8.9 mmol/L, p<0.001; lumacaftor 400 mg every 12 h group -10.3 mmol/L, p=0.002). These changes were significantly greater than the change in the placebo group. In cohort 2, the lumacaftor 600 mg once per day significantly improved FEV1 from day 1 to 56 (difference compared with placebo group: +5.6 percentage points, p=0.013), primarily during the combination period. In cohort 3, FEV1 did not change significantly across the entire study period compared with placebo (difference +4.2 percentage points, p=0.132), but did during the combination period (difference +7.7 percentage points, p=0003). Phe508del CFTR heterozygous patients did not have a significant improvement in FEV1.

This complex trial provided evidence that combination lumacaftor and ivacaftor improves FEV1 for patients with cystic fibrosis who are homozygous for phe508del CFTR, with a modest effect on sweat chloride concentration. These results support the further exploration of combination lumacaftor and ivacaftor as a treatment in this setting.

The abstract of this important and rather complex study is reproduced in full.

Dr Michael Boyle (fig. 8) at this time is Vice President, Therapeutics Developments at The CF Foundation and Adjunct Professor of Medicine, Johns Hopkins School of Medicine. Eventually Michael Boyle became President and Chief Executive Officer of the Cystic Fibrosis Foundation.

Boyle MP. Sabadosa KA. Quinton HB. Marshall BC. Schechter MS. Key findings of the US Cystic Fibrosis Foundation’s clinical practice benchmarking project. Quality & Safety 2014; 23 Suppl 1:i15-i22. [PubMed]
Benchmarking is the process of using outcome data to identify high-performing centres and determine practices associated with their outstanding performance. The US Cystic Fibrosis Foundation (CFF) Patient Registry contains centre-specific outcomes data for all CFF-certified paediatric and adult cystic fibrosis (CF) care programmes in the USA. The CFF benchmarking project analysed these registry data, adjusting for differences in patient case mix known to influence outcomes, and identified the top-performing US paediatric and adult CF care programmes for pulmonary and nutritional outcomes. Separate multidisciplinary paediatric and adult benchmarking teams each visited 10 CF care programmes, five in the top quintile for pulmonary outcomes and five in the top quintile for nutritional outcomes. Key practice patterns and approaches present in both paediatric and adult programmes with outstanding clinical outcomes were identified and could be summarised as systems, attitudes, practices, patient/family empowerment and projects.
These included: (1) the presence of strong leadership and a well-functioning care team working with a systematic approach to providing consistent care; (2) high expectations for outcomes among providers and families; (3) early and aggressive management of clinical declines, avoiding reliance on ‘rescues’; and (4) patients/families that were engaged, empowered and well informed on disease management and its rationale. In summary, assessment of practice patterns at CF care centres with top-quintile pulmonary and nutritional outcomes provides insight into characteristic practices that may aid in optimising patient outcomes.

— This study has clearly identified the characteristics of good CF care with which few would disagree – strong leadership, high expectations, early and aggressive management and engaged, empowered, well-informed families.

Brown PS. Pope CE. Marsh RL. Qin X. McNamara S. Gibson R. Burns JL. Deutsch G. Hoffman LR. Directly sampling the lung of a young child with cystic fibrosis reveals diverse microbiota. Ann Amer Thorac Soc 2014; 11:1049-55[PubMed]

Fig. 9  Perry Brown stlukesonline.org

Tissue of a child who underwent lobectomy for severe, localised CF lung disease was examined using DNA methods and identified diverse, and anatomically heterogeneous, bacterial populations in the lung tissue that contained both culturable and non-culturable species, including abundant Haemophilus, Ralstonia, and Propionibacterium species whereas routine clinical cultures identified only Staphylococcus aureus.
The authors concluded that diverse and spatially heterogeneous microbiota, not necessarily dominated by “traditional CF pathogens,” are present in the airways of young, symptomatic children with early CF lung disease.

Previous studies of this type have all been in lungs affected by advanced disease. The presence of these additional organisms now seems established in CF patients with even mild degrees of lung involvement but their significance is still not entirely clear.

Perry Brown (fig. 9)  is at the Department of Pediatrics, St. Luke’s Regional Medical Center, Boise, Idaho.

Bruns F. Bremer M. Dettmer A. Janssen S. Low-dose splenic irradiation in symptomatic congestive splenomegaly: report of five cases with literature data. [Review] Oncology. 9:86, 2014. [PubMed]
Five patients (only 1 with CF) with symptomatic congestive splenomegaly received splenic irradiation with a total dose of 3 Gy (single dose: 0.5 Gy). One patient was re-irradiated after long-term failure with the same treatment schedule. Four patients obtained long term relief of splenic pain during the follow-up time of median 20 (range: 2-36) months. Four patients showed haematological response after irradiation with an increase of erythrocytes, leucocytes and/or platelets. A slightly decrease in spleen size was found in two patients.
The authors concluded low-dose splenic irradiation in symptomatic congestive splenomegaly is feasible and effective.

— Splenic size in itself sometimes becomes a physical embarrassment to respiration and the space in the abdominal cavity. In such cases splenectomy has proved beneficial – radiation is obviously an alternative particularly if major surgery were to be contraindicated by the patient’s general condition.

Frank Bruns is in the Department of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany

Bruzzese E. Callegari ML. Raia V. Viscovo S. Scotto R. Ferrari S. Morelli L. Buccigrossi V. Lo Vecchio A. Ruberto E. Guarino A. Disrupted intestinal microbiota and intestinal inflammation in children with cystic fibrosis and its restoration with Lactobacillus GG: a randomised clinical trial. ONE [Electronic Resource]. 9(2):e87796, 2014. [PubMed]
Intestinal inflammation is a hallmark of cystic fibrosis (CF). Administration of probiotics can reduce intestinal inflammation and the incidence of pulmonary exacerbations. The authors investigated the composition of intestinal microbiota in children with CF and analysed its relationship with intestinal inflammation. They also investigated the microflora structure before and after Lactobacillus GG (LGG) administration in children with CF with and without antibiotic treatment.
Compared with healthy controls, children with CF had significantly different intestinal microbial core structures. The levels of Eubacterium rectale, Bacteroides uniformis, Bacteroides vulgatus, Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Faecalibacterium prausnitzii were reduced in children with CF. A similar but more extreme pattern was observed in children with CF who were taking antibiotics.
Lactobacillus GG administration reduced fecal calprotectin (CLP) and partially restored intestinal microbiota. There was a significant correlation between reduced microbial richness and intestinal inflammation.

The authors concluded CF causes qualitative and quantitative changes in intestinal microbiota, which may represent a novel therapeutic target in the treatment of CF. Administration of probiotics restored gut microbiota, supporting the efficacy of probiotics in reducing intestinal inflammation and pulmonary exacerbations

Eugenia Bruzzese is in the Department of Translational Medical Science, Section of Pediatrics, University Federico II, Naples, Italy.

Chuang S. Doumit M. McDonald R. Hennessy E. Katz T. Jaffe A. Annual Review Clinic improves care in children with cystic fibrosis. J Cyst Fibros 2014; 13(2):186-9. [PubMed]

Fig. 10 Sandra Chuang unsw.edu.au

It is unclear whether annual multidisciplinary reviews in cystic fibrosis (CF) patients should be conducted in dedicated annual review (AR) clinics or during continuous assessments throughout the year. The aim of this study was to assess the effect of introducing an AR clinic.
A retrospective written and electronic record review of CF patients was carried out for 2007 (no AR Clinic) and 2010 (established AR Clinic) calendar years. An internet-based satisfaction survey was distributed to families attending the AR clinic.
In total, 123 children (mean age 9.5 years, range 1.32-18.8 years) and 141 children (8.3 years, 1.1-18.3 years) were included in 2007 and 2010 respectively. There was a significant increase in multidisciplinary reviews (documented annual review 28% vs 85%, P < 0.001; dietary assessment 46% vs 92%, P < 0.001) and investigations (OGTT 2% vs 74%, P < 0.001; abdominal ultrasound 35% vs 85%, P < 0.001) conducted after the introduction of AR clinic. The majority of the families surveyed (85%) were satisfied or very satisfied with the AR clinic. The authors concluded that a CF AR clinic significantly improves the number of annual investigations and multidisciplinary reviews performed. Families were satisfied with this new process.

Dr Sandra Chang (fig. 10) is a paediatric respiratory specialist in the Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick 2031, Australia; School of Women’s and Children’s Health, University of New South Wales, Randwick 2031, Australia.

— Annual reviews have been routine in the Leeds CF clinics since 1980. We reported favourable experience with reviews in a number of publications (Littlewood JM, Kelleher J, Rawson I, Gilbert J, Firth J, Morton S, Wall C. Comprehensive assessment of patients at a CF centre identifies suboptimal treatment and improves management, symptoms and conditions. 10th International Cystic Fibrosis Congress, Sydney 1988 Excerpta Medica Asia Pacific Services. 89-90). Also in 1993 (Littlewood JM. The value of comprehensive assessment and investigation in the management of cystic fibrosis. In Clinical Ecology of Cystic Fibrosis. H Escobar, CF Baquero Suarez (Eds). Elsevier Science Publishers. 1993:181-187).
Most subsequent publications have found the process useful and acceptable to both parents and patients. The provision of Comprehensive Cystic Fibrosis Assessments (Annual Assessments) with detailed advice on treatment, was undoubtedly the reason for the build up and popularity of the Leeds CF Centre during the Eighties and subsequently.

Please see also Littlewood et al in 1988 and 1993 sections of this History for further details of early Leeds work on comprehensive assessments.

Chinazzo C. De Alessandri A. Menoni S. Romanisio G. Rebora A. Rongioletti F. Aquagenic wrinkling of the palms and cystic fibrosis: an Italian study with controls and genotype-phenotype correlations. dermatology 2014; 228(1):60-5. [PubMed]
Fifty-eight patients with CF underwent a hand immersion test in tap water. Twenty-three of their CF carrier relatives and 7 subjects with a negative genetic test for CF were recruited as controls. Secondary analyses explored associations with genotype, pulmonary function, and sweat electrolyte levels in all subjects with and without AWP. Additional information about atopic diathesis, hyperhidrosis of the palms and drug intake were also collected.

Thirty-one of the patients with CF (53.4%) exhibited AWP, in contrast to only 2 carriers (8.7%) and none in the control group. No correlation was found between CF genotype and AWP score severity. Twenty-three (39.7%) CF patients reported a history of hyperhidrosis, and in 17 of them (74%) AWP had been provoked. No correlation with history of atopy and lung function was noted. The difference between CF patients with hyperhidrosis and those without was highly significant (p = 0.016). Salt concentrations were significantly higher in patients with AWP.

Aquagenic wrinkling of the palms is obviously linked to CF and recognition indicates the need for a sweat test for CF. The authors found a significant association with hyperhidrosis and sweat electrolytes which they consider supports the ‘hyperconcentrated sweat’ pathogenetic theory of AWP.

Cholon DM. Quinney NL. Fulcher ML. Esther CR Jr. Das J. Dokholyan NV. Randell SH. Boucher RC. Gentzsch M. Potentiator ivacaftor abrogates pharmacological correction of F508 CFTR in cystic fibrosis. Translational Medicine 2014; 6(246):246ra96. [PubMed]

Fig. 12 Deborah Cholon

Fig 11. Martina Gentzsch

In studies of human primary airway epithelial cells, both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies. In contrast, chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated CFTR correction in F508 homozygous cultures. This result reflected the destabilisation of corrected F508 CFTR by VX-770, markedly increasing its turnover rate. Chronic VX-770 treatment also reduced mature wild-type CFTR levels and function.

The authors consider their findings demonstrate that chronic treatment with CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies. Combining these drugs to maximise rescue of F508 CFTR may require changes in dosing and/or development of new potentiator compounds that do not interfere with CFTR stability.

Dr Deborah Cholon (fig. 12) is at  the Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Dr. Martina Gentzsch (fig.11) is Associate Professor at the Marsico Lung Institute, UNC School of Medicine

Collie JT. Massie RJ. Jones OA. LeGrys VA. Greaves RF. Sixty-five years since the New York heat wave: advances in sweat testing for cystic fibrosis. [Review] Pediatr Pulmonol 2014; 49(2):106-17. [PubMed]

Fig. 13 Jake Collie

The sweat test remains important as a diagnostic test for cystic fibrosis (CF) and has contributed greatly to our understanding of CF as a disease of epithelial electrolyte transport. The standardization of the sweat test, by Gibson and Cooke [Gibson and Cooke (1959) Pediatrics 1959;23:5], followed observations of excessive dehydration amongst patients with CF and confirmed the utility as a diagnostic test. Quantitative pilocarpine iontophoresis remains the gold standard for sweat induction, but there are a number of collection and analytical methods. The pathophysiology of electrolyte transport in sweat was described by Quinton [Quinton (1983) Nature 1983;301:421-422], and this complemented the developments in genetics that discovered the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial-based electrolyte transport protein. Knowledge of CF has since increased rapidly and further developments in sweat testing include: new collection methods, further standardization of the technique with international recommendations and age related reference intervals. More recently, sweat chloride values have been used as proof of effect for the new drugs that activate CFTR. However, there remain issues with adherence to sweat test guidelines in many countries and there are gaps in our knowledge, including reference intervals for some age groups and stability of sweat samples in transport. Furthermore, modern methods of elemental quantification need to be explored as alternatives to the original analytical methods for sweat electrolyte measurement. The purpose of this review is therefore to describe the development of the sweat test and consider future directions.

Jake Collie (fig. 13) is at the School of Applied Sciences, RMIT University, Melbourne, Victoria, Australia; Dorevitch Pathology, Heidelberg, Victoria, Australia; Murdoch Children’s Research Institute, Parkville, Victoria, Australia.

Comment: suggest reader consults Topics -> Diagnosis -> Sweat test where the discovery of the sweat abnormality and early details of the sweat test are described as follows –  “Undoubtedly the major advance during the Fifties was the recognition of the increased salt content of the sweat in people with CF by Paul di Sant’Agnese in 1953 (below). This followed the report of Kessler and Andersen in 1951 (below) of heat prostration in children with CF that occurred during a New York heat wave in August 1948. Subsequently the availability of the sweat test permitted an accurate diagnosis when CF was suspected and gradually replaced the more invasive duodenal intubation. Diagnosis by sweat analysis became more practicable, accurate, safe and more generally available when localised sweating was stimulated by the pilocarpine iontophoresis, as described by Gibson & Cooke, in 1959, (below) rather than by the various potentially dangerous methods of heating the whole patient to stimulate sweating”.

Paul di Sant’Agnese discovered the sweat abnormality – the first real major advance for which he must be given true recognition. Gibson and Cooke described an excellent method of obtaining sweat. The relevant articles to which I refer are abstracted under their dates in this History and also in the”Sweat Test” in the Topics section mentioned above.

Conway S. Balfour-Lynn IM. De Rijcke K. Drevinek P. Foweraker J. Havermans T. Heijerman H. Lannefors L. Lindblad A. Macek M. Madge S. Moran M. Morrison L. Morton A. Noordhoek J. Sands D. Vertommen A. Peckham D. European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre. J Cyst Fibros 2014; 13 Suppl 1:S3-22. [PubMed]
A significant increase in life expectancy in successive birth cohorts of people with cystic fibrosis (CF) is a result of more effective treatment for the disease. It is also now widely recognised that outcomes for patients cared for in specialist CF Centres are better than for those who are not.
Key to the effectiveness of the specialist CF Centre is the multidisciplinary team (MDT), which should include consultants, clinical nurse specialist, microbiologist, physiotherapist, dietitian, pharmacist, clinical psychologist, social worker, clinical geneticist and allied healthcare professionals, all of whom should be experienced in CF care. Members of the MDT are also expected to keep up to date with developments in CF through continued professional development, attendance at conferences, auditing and involvement in research. Specialists CF Centres should also network with other Centres both nationally and internationally, and feed Centre data to registries in order to further the understanding of the disease.

– This paper provides a framework for the specialist CF Centre, including the organisation of the Centre and the individual roles of MDT members, as well as highlighting the value of CF organisations and disease registries. This document is welcome as, surprisingly, there are still occasional consultants in the UK who question the need for CF centre care.

Cunningham F. Lewis S. Curnow L. Glazner J. Massie J. Respiratory physicians and clinic coordinators’ attitudes to population-based cystic fibrosis carrier screening. J Cyst Fibros 2014; 13(1):99-105. [PubMed]
Attitudes of Australian CF healthcare professionals toward population-based cystic fibrosis carrier screening were examined. A purpose-designed questionnaire was distributed to 111 respiratory physicians and 30 CF clinic coordinators throughout Australia. Seventy-one questionnaires (52 physicians and 19 coordinators (46.8%, 63.3% respectively)) were returned. Forty respondents (56.3%) supported population-based carrier screening for CF. Support for screening was associated with rating the factors: carrier risk being 1 in 25 (OR 1.72 (1.12, 2.65)), reassurance when both partners test negative (OR 1.67 (1.12, 2.46)) and the daily treatment regimen for CF patients (OR 1.59 (1.05, 2.42)) as important. Opposition to screening was associated with identifying potential discrimination against carriers as a disadvantage (OR 0.3 (0.12, 0.88)), and limitations of predicting clinical outcomes as a barrier (OR 0.46 (0.25, 0.83)).

– So there is moderate support for population-based carrier screening for CF by Australian CF healthcare professionals. They consider the perceived barriers to implementation are surmountable.

Fiona Cunningham is in the Department of Paediatrics, University of Melbourne, Melbourne, 3052, Australia.

Dean NC. Van Boerum DH. Liou TG. Rib plating of acute and sub-acute non-union rib fractures in an adult with cystic fibrosis: a case report. Research Notes 2014; 7: 681.[PubMed]
A-37-year old white male with cystic fibrosis with a pulmonary exacerbation had an acute 5th rib fracture and chronic non-united 6th and 7th right rib fractures. Under general anaesthesia, he had a successful open reduction and internal fixation of the right 5th, 6th and 7th rib fractures with a Synthes Matrix rib set, although the immediate post-op period required close attention and care.

The authors suggest repair of rib fractures may be of benefit in selected CF patients who have suffered multiple rib fractures that were healing poorly.

Delatycki MB, Burke J, Christie L, Collins F, Gabbett M, George P, Haan E, Ioannou L, Martin N, McKenzie F, O’Leary P, Scoble-Williams N, Turner G, Massie J. Human genetics society of Australasia position statement: population-based carrier screening for cystic fibrosis. Hum Genet 2014; 17:578-83. [PubMed]

Fig 14. Martin Delatycki

Since the discovery in 1989 of mutations in cystic fibrosis transmembrane conductance regulator (CFTR) it has been possible to identify heterozygous mutation carriers at risk of having affected children. The Human Genetics Society of Australasia has produced a position statement with recommendations in relation to population-based screening for CF. These include: (1) that screening should be offered to all relatives of people with or carriers of CF (cascade testing) as well as to all couples planning to have children or who are pregnant; (2) the minimum CFTR mutation panel to be tested consists of 17 mutations which are those mutations that are associated with typical CF and occur with a frequency of 0.1% or higher among individuals diagnosed with CF in Australasia; (3) that genetic counselling is offered to all couples where both members are known to have one or two CFTR mutations and that such couples are given the opportunity to meet with a physician with expertise in the management of CF as well as a family/individual affected by the condition.

– This is a clear recommendation from the Human Genetics Society of Australasia that screening for CFTR mutations be offered to both to known carriers but also to all couples either planning pregnancies or in early pregnancy. The first report of antenatal couple screening for CF in the Edinburgh maternity hospitals (Mennie ME et al. Lancet 1992; 340:214-216. [PubMed]) described 4348 women, 14% declined prenatal screening and 13% were not screened for other reasons. Amongst 3165 women there were 111 carriers detected of whom four had carrier partners and all 4 couples opted for prenatal diagnosis. One pregnancy with an affected fetus was terminated. The importance of adequate counselling was stressed. Antenatal screening for CF then became routine in Edinburgh (where it had been pioneered by the late David Brock) but surprisingly it was eventually discontinued in 2005 for various reasons including the introduction of neonatal screening in Scotland and the improving prognosis for CF. Also national antenatal CF carrier screening had not been introduced in the UK by 2016. Although antenatal screening had been accepted in principle by the UK National Screening Committee having been recommended in a Health Technology Assessment (Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J. Screening for cystic fibrosis. Health Technol Assess 1999; 3(8):1-104.[PubMed]. Free full text) The high cost of providing genetic counselling was stated as the main reason for not introducing it.

– This reviewer considers that failure to provided pre-conceptional and antenatal carrier screening in the UK must now be regarded as suboptimal health care and a major missed opportunity.   [Please see also Topics section on ‘Diagnosis’ where more of the early papers are reviewed]

Prof. Martin Delatycki (fig.14) is Co-Director of the Bruce Lefroy Centre and Clinical Director of Genetics at Austin Health.

De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation.  J Cyst Fibros. 2014 Dec;13(6):674-80. doi: 10.1016/j.jcf.2014.09.005. Epub 2014 Sep 2 [PubMed]

Fig. 15  Kris de Boeck gbiomed.kuleuven.be

Ivacaftor is used to treat patients with CF and a G551D gating mutation; the KONNECTION study assessed the efficacy and safety of ivacaftor in patients with CF and a non-G551D gating mutation.   Patients with CF ≥6-years- old with non-G551D gating mutations ivacaftor 150mg q12h or placebo for 8weeks in this 2-part, double-blind crossover study (Part 1) with a 16-week open-label extension (Part 2). The primary efficacy was the outcome of treatment.                      Eight weeks of ivacaftor resulted in significant improvements in percent predicted FEV1, BMI, sweat chloride, and CFQ-R scores that were maintained through 24weeks. Ivacaftor was generally well tolerated

– Ivacaftor was efficacious in a group of patients with CF who had selected non-G551D gating mutations.

Kris de Boeck (fig. 15) is Professor in the University Hospital Gasthuisberg, Leuven, Belgium.

Di Nardo G. Oliva S. Menichella A. Pistelli R. De Biase RV. Patriarchi F. Cucchiara S. Stronati L.Lactobacillus reuteri ATCC55730 in cystic fibrosis. J Pediatr Gastroenterol Nutr 2014; 58(1):81-6. [PubMed]

Fig. 16 Giovanni Di Nardo

The aim of this study was to evaluate in patients with cystic fibrosis (CF) the effect of Lactobacillus reuteri (LR) on the rate of respiratory exacerbations and of the infections of both upper respiratory and gastrointestinal tracts. Prospective randomised, double-blind, placebo-controlled study enrolling 61 patients with CF with mild-to-moderate lung disease at the Regional Center for CF of the Department of Pediatrics, University of Rome “La Sapienza.”
Main outcomes were number of episodes of pulmonary exacerbations and hospital admissions for pulmonary exacerbations, number of gastrointestinal and upper respiratory tract infections. FEV1, fecal calprotectin, and cytokine profile in induced sputum and plasma were assessed at baseline and at the end of the trial. (full details in PubMed)

– The authors concluded LR reduces pulmonary exacerbations and upper respiratory tract infections in patients with CF with mild-to-moderate lung disease. LR administration may have a beneficial effect on the disease course of CF.

Giovanni Di Nardo (fig. 16) is associate professor in the Department of Pediatrics, Pediatric Gastroenterology and Liver Unit †Regional Center for Cystic Fibrosis, University of Rome.

Czy S. Stawinska-Witoszynska B. Madry E. Krzywinska-Wiewiorowska M. Szczepanik M. Walkowiak J. Kwiecien J. Non-invasive detection of Helicobacter pylori in cystic fibrosis–the fecal test vs. the urea breath test. Eur Rev Med Pharmacol Sci 2014; 18:2343-8. [PubMed]
Recently it has been shown that cystic fibrosis (CF) patients have the same prevalence of Helicobacter pylori (HP infection) as the general population, as well as the same spectrum of changes caused by this pathogen. The two most popular noninvasive tests, the urea breath test (UBT) and the fecal test (FT) were assessed in diagnosing HP infection in CF patients.
There was convincing evidence of divergent UBT and FT results in the CF patients, so the authors suggest that UBT is kept as the standard method for HP detection in this population.

—  The infection has never seemed to be a major practical problem amongst people with cystic fibrosis. But this is useful information and the infection should be considered and not overlooked.

Slawomirea Drzymała-Czy is Professor of Pediatrics, Department of Pediatric Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.

Eckford PD. Ramjeesingh M. Molinski S. Pasyk S. Dekkers JF. Li C. Ahmadi S. Ip W. Chung TE. Du K. Yeger H. Beekman J. Gonska T. Bear CE. VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface. Chem Biol 2014; 21(5):666-78. [PubMed]
The most common mutation causing cystic fibrosis (CF), F508del, impairs conformational maturation of CF transmembrane conductance regulator (CFTR), thereby reducing its functional expression on the surface of epithelia. Corrector compounds including C18 (VRT-534) and VX-809 have been shown to partially rescue misfolding of F508del-CFTR and to enhance its maturation and forward trafficking to the cell surface.
The authors show that there is an additional action conferred by these compounds beyond their role in improving the biosynthetic assembly. In vitro studies show that these compounds bind directly to the metastable, full-length F508del-CFTR channel. Cell culture and patient tissue-based assays confirm that in addition to their cotranslational effect on folding, certain corrector compounds bind to the full-length F508del-CFTR after its partial rescue to the cell surface to enhance its function. These findings may inform the development of alternative compounds with improved therapeutic efficacy.

Paul D W Eckford is with the Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.

Farrelly PJ. Charlesworth C. Lee S. Southern KW. Baillie CT. Gastrointestinal surgery in cystic fibrosis: a 20-year review. J Pediatr Surg 2014; 49(2):280-3. [PubMed]

Fig. 17 Paul Farrelly

The purpose of this study was to evaluate outcomes of the surgical management for meconium ileus (MI) and Distal Intestinal Obstruction Syndrome (DIOS) in children born between 1990 and 2010.
Seventy-five of 376 neonates presented with meconium ileus. Fifty-four (92%) required laparotomy. Contrast enema decompression was attempted in nineteen. There were no post-operative deaths. Thirty-nine (72%) neonates with MI were managed with stomas. LOS was longer in those managed with stomas (p=0.001) and in complex MI (p=0.002).
Thirty-five patients were treated for DIOS. Twenty-five patients were managed with gastrografin. Ten patients underwent surgical management of DIOS. Overall, MI did not predispose to later development of DIOS. There was a significantly greater incidence of laparotomy for DIOS in children who had MI.
The proportion of neonates with complex meconium ileus was high (49%) and may explain the infrequent utilisation of radiological decompression. Complex MI or management with stomas both significantly increase LOS. Re-laparotomy rate is high (22%) in MI irrespective of the type of management. DIOS is not a benign condition, particularly when the child has had previous abdominal surgery. Early referral to a surgical team is essential in these children.

–  A recent 20 year review of intestinal obstruction in cystic fibrosis from Liverpool, the source of much early work on the treatment of MI, the first use of gastrografin and later the first description of fibrosing colonopathy (see Topics section).

Paul J Farrelly (fig. 17) is a paediatric surgeon in the Department of Paediatric Surgery, Alder Hey Children’s NHS Foundation Trust, West Derby, Liverpool, L12 2AP, United Kingdom.

Fischer AJ. Singh SB. Adam RJ. Stoltz DA. Baranano CF. Kao S. Weinberger MM. McCray PB Jr. Starner TD. Tracheomalacia is associated with lower FEV1 and Pseudomonas acquisition in children with CF. Pediatr Pulmonol 2014; 49:960-70. [PubMed]

Fig 18. Timothy Den Starner FindaTopDoc

Tracheomalacia (TM) occurs in approximately 1 in 2,100 children. Because the trachea develops abnormally in animal models of cystic fibrosis (CF), the authors examined the prevalence and clinical consequences of TM in children with CF. TM was defined as dynamic collapse of the trachea, and the severity was recorded.
Eighty-nine percent of children with CF had at least one bronchoscopy (n=97/109). Fifteen percent of these children had TM described in any bronchoscopy report (n=15/97 16%), eight of these had meconium ileus (P=0.003) and all were pancreatic insufficient. Pseudomonas aeruginosa infection occurred 1.3 years earlier among children with TM (P=0.01). Life-threatening episodes of airway obstruction occurred in 3 of 15 patients with CF and TM, including one leading to death.

–   So tracheomalacia is significantly more common in infants and children with CF than in the general population and is associated with airway obstruction and earlier Pseudomonas acquisition.
Intractable expiratory wheeze poorly responsive to treatment related to tracheomalacia is a major problem in occasional CF infants. The findings of abnormal tracheal development, analogous to that recently described in CF animals, is obviously an explanation. Such infants may present a really difficult management problem and in the early years obviously require extra close supervision at a cystic fibrosis centre.

Dr. Timothy Den Starner (fig. 18) is  a Pulmonologist and Associate Professor of Pediatrics in Iowa

Gifford AH. Alexandru DM. Li Z. Dorman DB. Moulton LA. Price KE. Hampton TH. Sogin ML. Zuckerman JB. Parker HW. Stanton BA. O’Toole GA. Iron supplementation does not worsen respiratory health or alter the sputum microbiome in cystic fibrosis. J Cyst Fibros 2014; 13(3):311-8. [PubMed]

Fig. 19 Alex Gifford

Iron supplementation for hypoferremic anaemia could potentiate bacterial growth in the cystic fibrosis (CF) lung, but clinical trials testing this hypothesis are lacking. Twenty-two adults with CF and hypoferremic anaemia participated in a randomised, double-blind, placebo-controlled, crossover trial of ferrous sulfate 325mg daily for 6weeks. Ferrous sulfate increased serum iron by 22.3% and transferrin saturation (TSAT) by 26.8% from baseline (p<0.05) but did not affect haemoglobin, sputum iron, Akron PES, and the sputum microbiome. Low-dose ferrous sulfate improved hypoferremia without correcting anaemia after 6 weeks. The authors did not observe significant effects on sputum iron, Akron PES, and the sputum microbiome. Although they did not identify untoward health effects of iron supplementation, they suggest a larger blinded randomised controlled trial would be needed to fully demonstrate safety.

–    There were discussions in the Eighties as to the need for and the danger of correcting the iron deficiency present in so many people with cystic fibrosis. Although this short term study does little to finally settle the question, harm did not appear to result from iron supplementation which should be given in the presence of clinical iron deficiency anaemia.

Alex H Gifford (fig. 19)  Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, United States. Subsequently Director of the Adult Cystic Fibrosis Program at University Hospitals,  Case Western Reserve.

Gory I. Brown G. Wilson J. Kemp W. Paul E. Roberts SK. Increased risk of colorectal neoplasia in adult patients with cystic fibrosis: a matched case-control study. Scand J Gastroenterol 2014; 49:1230-6. [PubMed]

Fig. 20 Ilana Gory

A matched case-control study of adult CF patients in Melbourne undergoing colonoscopy in a 5-year period from 2007 to 2012. Controls were matched in a 2:1 ratio for age, gender, and colonoscopy indication. A total of 50 patients with CF who underwent colonoscopy were identified. Among CF patients, there were 5 (10%) cases with colorectal cancer (CRC), 1 (2%) with ileal adenocarcinoma, 13 (26%) with adenomas, and 16 (32%) with advanced adenomas. In contrast in controls there was 1 (1%) case with CRC, 11 (11%) with adenomas, and 6 (6%) with advanced adenomas.
Compared to controls, CF was associated with a 10-fold increased risk of CRC, threefold increased risk of adenomas and sevenfold increased risk of advanced adenomas.
The authors suggest that CF patients are at significantly increased risk of CRC compared to age, sex, and colonoscopy-indication matched controls. They suggest that consideration should be given to the introduction of a CRC surveillance program in the CF population.

— Further evidence supporting previous studies reporting an increased risk of colorectal carcinoma in adults with CF.

Ilana Gory (fig 20) is a gastroenterologist in the Department of Gastroenterology, The Alfred Hospital , Melbourne , Australia.

Griese M. Eismann C. Borner G. Denk O. Schierholz JM. Keller M. Mazurek H. Kappler M. A pharmacokinetics and safety comparison of a highly concentrated tobramycin solution with TOBI. J Aerosol Med Pulm D 2014; 27(3):185-92. [PubMed]

Fig 21. Mathias Griese

Improved inhalation device/drug combinations are necessary to advance inhaled antibiotic therapy in cystic fibrosis (CF). Previously, for a novel drug/inhaler combination, equivalent lung deposition was demonstrated; here, we investigated its safety and pharmacokinetics. METHODS: In a randomised, open-labeled, multicenter, active controlled, parallel 28-day study, we compared a new tobramycin formulation (T100 PARI, 150 mg/1.5 mL) nebulized with a drug-specific PARI eFlow() nebuliser and TOBI() (300 mg/5 mL) nebulized with a PARI LC PLUS() nebuliser in 78 CF patients. RESULTS: Non-inferiority of the primary endpoint peak plasma tobramycin concentrations and the secondary endpoint area under the concentration time curves in plasma were observed. Sputum concentrations exceeded expected minimum inhibitory concentrations of Pseudomonas aeruginosa and were the same across both treatment groups, as were tolerability and safety. The nebulisation time (4.6 vs. 16.1 min) was much shorter for the new drug/device combination.

–   The authors concluded inhaled therapy with T100 PARI delivered by an investigational eFlow offers a patient treatment time benefit and comparable safety and pharmacokinetics

Professor Mathias Griese  (figure 21) is Professor of Paediatrics at the Children’s Hospital, Munich

Habash MB. Park AJ. Vis EC. Harris RJ. Khursigara CM. Synergy of silver nanoparticles and aztreonam against Pseudomonas aeruginosa PAO1 biofilms. Antimicrob Agents Chemother 2014; 58:5818-30. [PubMed]
The goal of this study was to assess the efficacy of citrate-capped silver nanoparticles (AgNPs) of various sizes, alone and in combination with the monobactam antibiotic aztreonam, to inhibit Pseudomonas aeruginosa PAO1 biofilms. 10-nm nanoparticles were most effective in inhibiting the recovery of P. aeruginosa biofilm cultures and showed synergy of inhibition when combined with sub-MIC levels of aztreonam likely caused by better penetration of the small AgNPs into the biofilm matrix.
These data suggest that small AgNPs synergistically enhance the antimicrobial effects of aztreonam against P. aeruginosa in vitro, and they reveal a potential role for combinations of small AgNPs and antibiotics in treating patients with chronic infections.

–     There are a number of anecdotal reports of the favourable effect of silver preparations on the respiratory infections of people with cystic fibrosis (Baral VR. Colloidal silver for lung disease in cystic fibrosis. J R Soc Med. 2008;101 Suppl 1:S51-2. Free article available).

Marc B Habash is at the School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada

Hayes D Jr. Long FR. McCoy KS. Sheikh SI. Improvement in Bronchiectasis on CT Imaging in a Pediatric Patient with Cystic Fibrosis on Ivacaftor Therapy. Respiration. 2014;88:345. [PubMed]

Hayes D Jr. McCoy KS. Sheikh SI. Improvement of sinus disease in cystic fibrosis with ivacaftor therapy. Am J Resp Crit Care Med 2014; 190(4):468. [PubMed]

Fig 22. Don Hayes Jr

A 19-year old woman with CF (d508/G551D) experienced significant general improvement after 15 months ivacaftor therapy and in particular major improvement in previously troublesome sinus disease. Impressive changes in the MCT scan reproduced in the link from the abstract.

Hayes D Jr, McCoy KS, Sheihk SL. Resolution of cystic fibrosis-related diabetes with ivacaftor therapy. Am J Resp Crit Care 2014;190(5):590-1. [PubMed]

A 25-year-old male with CF (DF508/G551D genotype) and pancreatic insufficiency who was diagnosed with CFRD 6 year earlier was started on ivacaftor therapy. His CFRD was well controlled on 20 units daily of insulin glargine, with him being otherwise healthy (spirometry at that time was FVC of 7.25 L [138% predicted] and FEV1of 5.20 L [118% predicted]).
After 9 months of ivacaftor, his insulin  dose was reduced to 10 units daily and then was completely stopped 4 months later. Over the next year, he has had normoglycemia and normal hemoglobin A1C measurements without diabetic therapy. Moreover, a recent oral glucose tolerance test revealed blood sugars of 82 mg/dl and 114 mg/dl fasting and 2 hours after glucose load, respectively. With 25 months of ivacaftor therapy, his sweat chloride decreased from 98 to 64 mmol/L, his body mass index increased from 25.3 to 26.6 kg/m2 and his spirometry improved slightly: FVC 7.56 L (143% predicted) and FEV15.41 L (124% predicted).   Respiratory cultures persistently isolated mucoidal Pseudomonas aeruginosa.

– One of the welcome extra pulmonary beneficial effects of ivacaftor. Subsequent reports were less encouraging.

Don Hayes Jr  (Fig. 22) is a paediatric pulmonologist at Ohio State University College of Medicine Columbus, Ohio. Subsequently at Cincinnati Children’s Hospital Medical Center.

Higgins AS. Flanagan JD. Von Wald T. Hansen KA. Preconception cystic fibrosis screening in infertile couples using an expanded carrier screening test. Obstet Gynecol 2014; 123 Suppl 1:97S. (No abstract on PubMed)
The American College of Obstetricians and Gynecologists recommends offering preconception and prenatal screening to all couples for cystic fibrosis, whereas the American College of Medical Genetics also recommends screening for spinal muscular atrophy. Both groups suggest specific screening if there is a family or personal history of a genetic disease or if the individual is from a high-risk ethnic group. The purpose of this study was to determine whether availability of a more comprehensive, affordable genetic screening tool increased the number of infertility patients choosing to be screened for cystic fibrosis and other genetic diseases.
This was a retrospective chart review of new infertility patients evaluated between May 2010 and May 2013. These couples had a detailed pedigree and were offered the Counsyl expanded carrier screening test.

Sixteen hundred sixty-nine new infertility couples were offered Counsyl expanded carrier screening. The carrier frequency for cystic fibrosis was 6.8% with 0% of the couples concordant heterozygotes. The carrier frequency for spinal muscular atrophy was 2.51% with 0% of the couples concordant heterozygotes. Fragile X premutation was found in 2.78% (2/72).

The authors concluded with availability of the Counsyl screening test, the percentage of new infertility patients choosing to have preconception genetic screening increased from 2% to 8%. The largest increase (17.5% of new patients) in screening followed the reduction in out-of-pocket expense in May 2012. Infertility patients are in a unique position to investigate their family history, discuss appropriate preconception genetic screening, and, if discovered to be at high risk of a genetic illness, review their reproductive options.

Xue Ioannou L. McClaren BJ. Massie J. Lewis S. Metcalfe SA. Forrest L. Delatycki MB. Population-based carrier screening for cystic fibrosis: a systematic review of 23 years of research. Genet Med 2014; 16(3):207-16. [PubMed]
This review provides a systematic evaluation of the literature from the past 23 years on population-based carrier screening for cystic fibrosis, focusing on the following: uptake of testing; how to offer screening; attitudes, opinions, and knowledge; factors influencing decision making; and follow-up after screening. Recommendations are given for the implementation and evaluation of future carrier-screening programme.

Suggest see also –

Ioannou L et al. Attitudes and opinions of pregnant women who were not offered cystic fibrosis carrier screening. Eur J Hum Genet 2014; 22(7):859-65. [PubMed]
Majority (80.5%) consider screening should be offered; 49.7% would have liked it in their present pregnancy.

Ioannou L et al. No thanks – reasons why pregnant women declined an offer of cystic fibrosis carrier screening. J Commun Genet 2014; 5(2):109-17. [PubMed]

Fig. 23 Liane Ioannou research.monash.edu

The main reasons for declining screening were having no family history of CF (58%) and not considering a termination of pregnancy for CF (53%). Providers and consumers should be informed that most children born with autosomal-recessive conditions such as CF have no family history of the condition.

Liane Ioannou (fig. 23) is a Senior Research Fellow at the Murdoch Childrens Research Institute, Parkville, Victoria, Australia.   Department of Medicine, Monash University, Clayton, Victoria, Australia.

Janssens S. De Paepe A. Borry P. Attitudes of health care professionals toward carrier screening for cystic fibrosis. A review of the literature. J Community Genet 2014; 5(1):13-29. [PubMed]

Fig. 24 Sandra Janssens

Eleven studies were retrieved describing the attitudes toward carrier screening for CF. Health care providers state willingness to be involved in a carrier screening program, but there is need for appropriate education as well as adequate support given the time constraints already present in consultation. The prospect of an increasing number of genetic disorders for which screening becomes possible, and the potential increasing demand for such screening in the future calls for the need for further debate on the desirability of carrier screening and relevant questions such as the conditions screened, the providers involved, the information provision, and counselling.

Sandra Janssens (fig. 24) is a clinical geneticist and Professor at the Centre for Medical Genetics, Ghent.

Knibbs LD. Johnson GR. Kidd TJ. Cheney J. Grimwood K. Kattenbelt JA. O’Rourke PK. Ramsay KA. Sly PD. Wainwright CE. Wood ME. Morawska L. Bell SC. Viability of Pseudomonas aeruginosa in cough aerosols generated by persons with cystic fibrosis. Thorax 2014; 69(8):740-5. [PubMed]

Fig 25. Luke Knibbs sydney.edu.au

Using purpose-built equipment, the authors measured viable P aeruginosa in cough aerosols at 1, 2 and 4 m from the subject (distance) and after allowing aerosols to age for 5, 15 and 45 min in a slowly rotating drum to minimise gravitational settling and inertial impaction (duration). Aerosol particles were captured and sized employing an Anderson Impactor and cultured using conventional microbiology. Sputum was also cultured and lung function and respiratory muscle strength measured.
Viable P aeruginosa were detected in cough aerosols from all 19 patients with CF, but not from controls; travelling 4 m in 17/18 (94%) and persisting for 45 min in 14/18 (78%) of the CF group. Marked inter-subject heterogeneity of P aeruginosa aerosol colony counts was seen and correlated strongly (r=0.73-0.90) with sputum bacterial loads. Modelling decay of viable P aeruginosa in a clinic room suggested that at the recommended ventilation rate of two air changes per hour almost 50 min were required for 90% to be removed after an infected patient left the room.
The authors concluded that viable P. aeruginosa in cough aerosols travel further and last longer than recognised previously, providing additional evidence of airborne transmission between patients with CF.

—  Important information for those organising the management of a CF clinic and fully justifying elaborate arrangements to avoid cross infection which nonetheless have been questioned by some clinicians.

Dr. Luke Knibbs (fig.25) is Senior Lecturer in Environmental Health at the International Laboratory for Air Quality and Health, Brisbane, Queensland.

Kent L. Reix P. Innes JA. Zielen S. Le Bourgeois M. Braggion C. Lever S. Arets HG. Brownlee K. Bradley JM. Bayfield K. O’Neill K. Savi D. Bilton D. Lindblad A. Davies JC. Sermet I. De Boeck K. European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) Standardisation Committee. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros 2014;13(2):123-38.[PubMed]
The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group’s work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease.

—   This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF. This method of respiratory function testing, applicable to all age groups, has undoubtedly been one of the major advances in recent years.

L Kent is at the Centre for Health and Rehabilitation Technologies (CHaRT), Institute for Nursing and Health Research, University of Ulster, Newtown Abbey, UK; Regional Cystic Fibrosis Centre, Belfast Health and Social Care Trust, Belfast, UK.

Kerem E. Konstan MW. De Boeck K. Accurso FJ. Sermet-Gaudelus I. Wilschanski M. Elborn JS. Melotti P. Bronsveld I. Fajac I. Malfroot A. Rosenbluth DB. Walker PA. McColley SA. Knoop C. Quattrucci S. Rietschel E. Zeitlin PL. Barth J. Elfring GL. Welch EM. Branstrom A. Spiegel RJ. Peltz SW. Ajayi T. Rowe SM. Cystic Fibrosis Ataluren Study Group. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med 2014; 2(7):539-47.[PubMed]
A randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged > 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV1] > 40% and < 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205.

Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% [95% CI -0.8 to 6.3]; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 [95% CI 0.57-1.05]; p=0.0992).

However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% [-4.0 to 2.1] vs -6.4% [-9.8 to -3.7]; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluren group (1.42 events [0.9-1.9] vs 2.18 events [1.6-2.7]; rate ratio 0.60 [0.42-0.86]; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group.

The authors concluded that although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, but it might be beneficial for patients not taking chronic inhaled tobramycin.

—   There has been some difference of opinion as to the action of ataluren and as to whether the drug actually does promote read through of nonsense mutations. It has been suggested that the assay using luciferase as the reporter gene when positive, rather than indicating transcription, merely indicates direct stimulation of the reporter gene.

Kettle AJ. Turner R. Gangell CL. Harwood DT. Khalilova IS. Chapman AL. Winterbourn CC. Sly PD. AREST CYSTIC FIBROSIS. Oxidation contributes to low glutathione in the airways of children with cystic fibrosis. Respir J 2014; 44(1):122-9.[PubMed]

Fig 26. Tony Kettle hrc.govt.nz

Glutathione is an important antioxidant in the lungs but its concentration is low in the airways of patients with cystic fibrosis. The concentration of glutathione was lower in bronchoalveolar lavage from children with cystic fibrosis, whereas glutathione sulfonamide, a specific oxidation product of hypochlorous acid, was higher. Oxidised glutathione and glutathione sulfonamide correlated with myeloperoxidase and a biomarker of hypochlorous acid. The percentage of glutathione attached to proteins was higher in children with cystic fibrosis than controls. Pulmonary infections in cystic fibrosis resulted in lower levels of glutathione but higher levels of oxidised glutathione and glutathione sulfonamide in bronchoalveolar lavage.
The concentration of glutathione is low in the airways of patients with cystic fibrosis from an early age. Increased oxidation of glutathione by hypochlorous acid and its attachment to proteins contribute to this deficiency. Therapies targeted against myeloperoxidase may boost antioxidant defence and slow the onset and progression of lung disease in cystic fibrosis.

–  Further work on glutathione – a compound that has received increasing attention in recent years.(please see Topic)

Tony Kettle (fig.26) is Principal Investigator and Research Professor, Centre for Free Radical Research, University of Otago, Christchurch.

Kopeikin Z. Yuksek Z. Yang HY. Bompadre SG. Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels. J Cyst Fibros 2014; 13:508-14.[PubMed]
VX-770, a clinically approved drug for treatment of CF patients carrying the G551D mutation, and VX-809, a corrector shown in vitro to increase membrane expression of mutant channels, are currently undergoing clinical trials, but functional data at the molecular level is still lacking. The effect of VX-770 and VX-809 on the multiple functional defects of F508del-CFTR was assessed via excised inside-out patch-clamp experiments.
VX-770 completely restores the low opening-rate of F508del-CFTR, with smaller open-time increase, in temperature-corrected and VX-809-treated channels. The shorter locked-open time of hydrolysis-deficient F508del-CFTR is also prolonged by VX-770. VX-809 does not improve channel function by itself as previously reported.
The authors concluded these studies can be interpreted as an equilibrium shift toward the open-channel conformation of F508del-CFTR channels.

Konstan MW. Wagener JS. Pasta DJ. Millar SJ. Morgan WJ. Clinical use of tobramycin inhalation solution (TOBI) shows sustained improvement in FEV1 in cystic fibrosis. Pulmonology 2014; 49(6):529-36. [PubMed]
Tobramycin inhalation solution (TIS; TOBI) has improved forced expiratory volume in 1sec (FEV1 ) in cystic fibrosis (CF) trials. Using data from the Epidemiologic Study of CF (ESCF), the authors assessed the change in level and trend of FEV1 % predicted over a 2-year period associated with initiation of TIS during routine clinical practice.

–  Initiating chronic TIS therapy in the routine clinical care of patients with CF was associated with improvement in FEV1 % predicted but no change in rate of decline, indicating this benefit was sustained over the 2 years studied.

Lahiri T. Guillet A. Diehl S. Ferguson M. High-dose ibuprofen is not associated with increased biomarkers of kidney injury in patients with cystic fibrosis. Pediatr Pulmonol 2014; 49(2):148-53. [PubMed]
The authors examined the association of high-dose ibuprofen (IBU) with markers of acute kidney injury (AKI) in patients with CF. The effect of aminoglycoside (AG) exposure on AKI biomarkers was also examined. The AKI markers, kidney injury molecule-1 (KIM), N-acetyl-beta-glucosaminidase (NAG) and urine protein, normalised for creatinine, were chosen as they are more sensitive indicators of kidney injury than changes in serum creatinine. Urine samples from 52 patients, 26 from patients who were treated with IBU, were analysed. There was no significant association between IBU treatment and KIM-1, NAG or protein levels, compared to patients never treated with IBU. While there was an association between AG courses and KIM-1 levels, there were no differences in biomarker levels between IBU and non-IBU groups with respect to AG courses.

–   These preliminary results suggest that high dose ibuprofen treatment in patients with CF may be safe with respect to renal toxicity. Although relatively few patients are currently treated with IBU it is reassuring that the drug does not appear to contribute to renal injury which is an increasing problem with age in people with CF as a result of repeated course of IV aminoglycosides.

Lim MT. Wallis C. Price JF. Carr SB. Chavasse RJ. Shankar A. Seddon P. Balfour-Lynn IM. Diagnosis of cystic fibrosis in London and South East England before and after the introduction of newborn screening. Arch Dis Child 2014; 99(3):197-202. [PubMed]
Newborn screening (NBS) for cystic fibrosis (CF) was introduced to London and South East England in 2007. 347 patients were diagnosed with CF. 126 patients were not screened (born before or abroad), and had a median age at diagnosis of 2.4 years, excluding those with meconium ileus (MI). Their median time to diagnosis from initial symptoms was 1 year, and in 10% it was >6 years.
After NBS started, 170 were diagnosed by NBS (48% were already symptomatic); 7 moved into the region after NBS elsewhere; 34 presented with MI (6 were negative on NBS); and 10 screened children were missed (false negative cases). Median age of diagnosis was 3 weeks. Prevalence was 1 in 3991 live births. By 2 years of age (with data on 104 patients), 49 children (47%) had their first isolation of Pseudomonas aeruginosa, while 37 (36%) had their first growth of Staphylococcus aureus from respiratory cultures.

–  The authors concluded NBS has significantly reduced the age of diagnosis, although many were symptomatic even at 3 weeks of age. A small number of patients with CF can still be missed by the screening programme, and the diagnosis should be considered even with a negative screen result there suggestive symptoms and signs.

Lourenco BM. Costa KM. da Silva Filho M. Voice disorder in cystic fibrosis patients. ONE [Electronic Resource]. 9(5):e96769, 2014 [PubMed]
The authors tested vocal parameters, using both objective physical measures and the GRBAS subjective evaluation method, in male and female cystic fibrosis patients undergoing conventional treatment and compared them to age and sex matched controls. They found that cystic fibrosis patients had a significantly lower vocal intensity and harmonic to noise ratio, as well as increased levels of jitter and shimmer. In addition, cystic fibrosis patients also showed higher scores of roughness, breathiness and asthenia, as well as a significantly altered general grade of dysphonia. When they segregated the results according to sex, we observed that, as a group, only female cystic fibrosis patients had significantly lower values of harmonic to noise ratio and an abnormal general grade of dysphonia in relation to matched controls, suggesting that cystic fibrosis exerts a more pronounced effect on vocal parameters of women in relation to men.
Overall, the dysphonic characteristics of CF patients can be explained by dysfunctions in vocal fold movement and partial upper airway obstruction, potentially caused by the accumulation of mucus and chronic cough characteristic of CF symptomatology. These results show that CF patients exhibit significant dysphonia and suggest they may potentially benefit from voice therapy as a parallel treatment strategy.

–   With the intrinsic mucosal abnormalities and long term inhalation therapy advised, it is not surprising there are minor voice abnormalities in many people with CF.

Lamas A. Luis M. de Valbuena, Ruiz M. Gonzalez-Casbas, Jose Manuel. Suarez, Lucrecia. Subcutaneous implant with etonogestrel (Implanon) for catamenial exacerbations in a patient with cystic fibrosis: a case report. BMC Pulm Med 2014; 14:165. [PubMed]
Women with CF have a more rapid decline in lung function than men for which female hormones have been implicated. A 20 year old woman had impressive cessation of pulmonary exacerbations (PE) that were related to menstrual periods (catamenial = relating to menstruation), and recovery of lung function following the insertion of a subcutaneous implant with 68 mg of etonogestrel (Implanon, Organon Espanola S.A. Laboratories, Madrid, Spain), supporting role of female hormones in the development of PE and in the decline of lung function in this woman with CF.

–   A report which would encourage clinicians check if exacerbations in their female CF patients were related to their menstrual periods. Although there is an impressive chart in the original article, the improvement also appears to coincide with the introduction of tobramycin solution for inhalation!

MacKenzie T. Gifford AH. Sabadosa KA. Quinton HB. Knapp EA. Goss CH. Marshall BC. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the cystic fibrosis foundation patient registry. Ann Int Med 2014; 161:233-41.[PubMed]

Fig. 27 Todd A MacKenzie Geisel News

Between 2000 and 2010, the number of patients in the Cystic Fibrosis Foundation Registry (CFFPR) increased from 21,000 to 26,000, median age increased from 14.3 to 16.7 years, and adjusted mortality decreased by 1.8% per year (95% CI, 0.5% to 2.7%).
The authors concluded that children born and diagnosed with CF in the United States in 2010 are expected to live longer than those born earlier. This has important implications for prognostic discussions and suggests that the health care system should anticipate greater numbers of adults with CF.

Todd MacKenzie (fig. 27)  of  Dartmouth–Hitchcock Medical Center, Clinical Research Section, 1 Medical Center Drive, DHMC, Lebanon, NH 03756.

Marcorelles P. Friocourt G. Uguen A. Lede F. Ferec C. Laquerriere A. Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain: Comparative Immunohistochemical Study between Patients with Normal and Mutated CFTR. J Histochem Cytochem 2014; 62:791-801.[PubMed]
Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein has recently been shown to be expressed in the human adult central nervous system (CNS). As CFTR expression has also been documented during embryonic development in several organs, such as the respiratory tract, the intestine and the male reproductive system, suggesting a possible role during development the authors decided to investigate the expression of CFTR in the human developing CNS. In addition, as some, although rare, neurological symptoms have been reported in patients with CF, they compared the expression of normal and mutated CFTR at several fetal stages. Immunohistochemistry was performed on brain and spinal cord samples of fetuses between 13 and 40 weeks of gestation and compared with five patients with CF of similar ages.
This study showed that CFTR is only expressed in neurones and has an early and widespread distribution during development. Although they did not observe any cerebral abnormality in patients with CF, they observed a slight delay in the maturation of several brain structures. They also observed different expression and localisation of CFTR depending on the brain structure or the cell maturation stage.

—  Their findings, along with a literature review on the neurological phenotypes of patients with CF, suggest that this gene may play previously unsuspected roles in neuronal maturation or function.    A number of neurological conditions have been described in people with CF; also some slight reduction in head circumference of CF infants has been reported (please see Topics – CNS section for more details).

Professor Pascale Marcorelles    Pathology Laboratory, Pole Pathologie-Biologie, Brest University Hospital, Brest, France and many other locations listed on PubMed

Marson FA. Bertuzzo CS. Ribeiro AF. Ribeiro JD. Polymorphisms in the glutathione pathway modulate cystic fibrosis severity: a cross-sectional study. BMC Medical Genetics 2014; 15:27.[PubMed]

Fig. 28 Fernando Augusto Lima Marson scholar.google.com.br

A cross-sectional study of 180 CF patients was carried out from 2011 to 2012. The authors analysed CFTR mutations, polymorphisms (GSTM1 and GSTT1 deletions, GSTP1 + 313A > G, GCLC-129C > T, and GCLC-3506A > G) in modifier genes and CF clinical severity as assessed by 28 clinical and laboratory variables. (please see PubMed for details)

—  Apparently these results show that, although a monogenic disease, CF is heavily influenced in its clinical characteristics, evolution and severity by polymorphisms in modifier genes. Nevertheless, there is apparently still a long way before the dynamics of polymorphisms in genes active in the GSH metabolic pathway and involved in detoxification in CF are fully understood.

Dr Fernando Augusto de Lima Marson (fig. 28) is at the Center for Investigation in Pediatrics, Faculty of Medical Sciences, University of Campinas, Tessália Vieira de Camargo, 126, Cidade Universitária “Zeferino Vaz”, CEP: 13083-887 Campinas, São Paulo, Brazil.

Mainz JG. Schien C. Schiller I. Schadlich K. Koitschev A. Koitschev C. Riethmuller J. Graepler-Mainka U. Wiedemann B. Beck JF. Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: a double-blind placebo-controlled cross-over trial. J Cyst Fibros 2014; 13:461-70. [PubMed]

Fig. 29 Jochen Mainz ResearchGate

Either dornase alfa (Pulmozyme) or isotonic saline were inhaled for 28 days with the Pari-Sinus and after 28 days (wash-out) crossed over to the alternative treatment. Primary nasal symptoms improved significantly with dornase alfa compared with no treatment, while small improvements with isotonic saline did not reach significance.
Vibrating sinonasal inhalation of dornase alfa reduces rhino sinusitis symptoms in CF and also incidentally improved lung function.

Jochen G Mainz ((fig.29) at the  Department of Paediatrics, CF-Center, Jena University Hospital, Jena, Germany. Subsequently Professor and Director of CF Center, Medizinische Hochschule Brandenburg University.

Mall MA. Graeber SY. Stahl M. Zhou-Suckow Z. Early cystic fibrosis lung disease: Role of airway surface dehydration and lessons from preventive rehydration therapies in mice. Int J Biochem Cell Biol 2014; 52:174-9. pubmed.ncbi.nlm.nih.gov/24561284/

Fig. 30 Marcus A Mall  DocPlayer.org

Airway surface dehydration is a key disease mechanism in CF, however, its role in the in vivo pathogenesis and as therapeutic target in early lung disease remains poorly understood. Mice with airway-specific over expression of the epithelial Na(+) channel (betaENaC-Tg) recapitulate airway surface dehydration and phenocopy CF lung disease. Recent studies in neonatal betaENaC-Tg mice demonstrated that airway surface dehydration produces early mucus plugging in the absence of mucus hyper secretion, which triggers airway inflammation, promotes bacterial infection and causes early mortality. Preventive rehydration therapy with hypertonic saline or amiloride effectively reduced mucus plugging and mortality in neonatal betaENaC-Tg mice.

The authors suggest these results support clinical testing of preventive/early rehydration strategies in infants and young children with CF.

—  This study provides further evidence of the basic importance of dehydration within the airways. Interesting that amiloride “effectively reduced mucus plugging” in view of its disappointing performance in previous clinical trials – usually explained by the very short lived action of amiloride.

Marcus Mall (fig.30) in the Department of Translational Pulmonology and Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Translational Lung Research Center Heidelberg (TLRC).

John MassieLiane IoannouMartin Delatycki. Prenatal and preconception population carrier screening for cystic fibrosis in Australia: where are we up to? Aust N Z J Obstet Gynaecol   2014 Dec;54(6):503-9.doi: 10.1111/ajo.12255.Epub 2014 Oct 28. [PubMed}

Fig.31  John Massie Melbourne Paediatric Specialists 

Aims: To describe prenatal and preconception population carrier screening for cystic fibrosis (CF) in Australia and consider progress towards establishing a universal program.
Method: Medline and Embase databases (1989-2013) were searched for all publications with Australian data. Existing programs for CF carrier screening in Australia were reviewed and professional peak body websites accessed to determine recommendations.
Results: Twenty-two studies met the inclusion criteria. Key stakeholder groups believe that prenatal and preconception carrier screening for CF should be available. Health-economic analyses support that CF carrier screening can be cost-effective. There are small programs for CF carrier screening, in Victoria, New South Wales and Queensland. The Human Genetics Society of Australasia (HGSA) specifically recommend that screening be offered to women and couples planning a pregnancy and in the early stages of pregnancy. Other peak bodies indirectly endorse the availability of CF carrier screening. Barriers to screening include not being offered screening, the cost of testing, inequity of access and an incorrect perception that not having a family history of CF lowers risk.
Conclusions: There is support for prenatal and preconception CF carrier screening by the community, health professionals and peak professional bodies in Australia. The barriers to development of a national screening program could be overcome with greater physician engagement and government support.
Implications: In the interest of equity, government funded testing should be routinely offered to all pregnant women and couples planning a pregnancy.

Prof. John Massie (fig 31) of the Department of Respiratory Medicine, Royal Children’s Hospital, Parkville, Victoria, Australia; Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, Victoria, Australia.

Mauch RM. Levy CE. Serum antibodies to Pseudomonas aeruginosa in cystic fibrosis as a diagnostic tool: a systematic review. J Cyst Fibros 2014; 13:499-507. [PubMed]

Fig. 32 Renen Marrichi Mauch LinkedIn

A systematic literature review of the last 40 years on the research of serum antibodies to Pseudomonas aeruginosa in cystic fibrosis and its utility as a diagnostic tool. 26 studies were assessed. ELISA technique was the most commonly used technique to detect serum P. aeruginosa antibodies. The most consistent results were those in which the response against the antigen St-Ag:1-17 was evaluated. The accuracy levels of the ELISA technique remain controversial, but most studies showed a good correlation between antibody titres and microbiological culture.
The detection of serum antibodies to P. aeruginosa shows capacity for early detection of this pathogen and potential utility and viability of incorporation in the diagnostic routine of patients with cystic fibrosis.

—   There is now a vast literature on the value (or lack of it) of Pseudomonas antibodies in management of people with cystic fibrosis. In clinics such as Leeds and Copenhagen, these antibodies have been in routine use for many years since the Eighties and the clinicians find their practical value is beyond doubt. This review is useful in summarising the present position as we believe the test should be available in all CF centres.

Renen Marrichi Mauch (fig 32) is a laboratory scientist in the Faculty of Medical Sciences, State University of Campinas, Brazil.and Lund University.

 McCauley LA. Thomas W. Laguna TA. Regelmann WE. Moran A. Polgreen LE. Vitamin D deficiency is associated with pulmonary exacerbations in children with cystic fibrosis. Ann Am Thor Soc 2014; 11(2):198-204. [PubMed]
A study to assess associations between vitamin D and % predicted lung function, pulmonary exacerbations, and first Pseudomonas aeruginosa infection in children with CF. This is a retrospective longitudinal study of 130 children aged 6 to 18 years between 2000 and 2012 examined 25-OHD levels classed in three vitamin D groups: sufficient (>30 mug/L), insufficient (20-29 mug/L), and deficient (<20 mug/L). Longitudinal models followed individuals’ changing vitamin D groups over time to compare numbers of pulmonary exacerbations (defined by hospitalisation), incidence of first P. aeruginosa infection, and % predicted lung function. Cross-sectional comparisons between vitamin D groups were performed at ages 8, 12, and 16 years.
The prevalence of vitamin D deficiency and insufficiency increased slowly through adolescence. The rate of exacerbations for the deficient vitamin D group, aged 15 to 18 years, was 13.1 per 10 patient-years, significantly higher than 4.3 per 10 patient-years for the insufficient and e sufficient vitamin D groups (P < 0.05), which were not significantly different There were no differences between vitamin D groups in pulmonary function or incidence of first P. aeruginosa infection, which was about 2 per 10 patient-years.

The authors concluded that higher 25-OHD levels in children with CF were associated with lower rates of pulmonary exacerbations and, in adolescents, higher FEV1.

—   It is possible patients with higher vitamin D levels may have received a better general standard of care, with closer attention to nutrition, than those allowed to become vitamin deficient and hence also have had fewer exacerbations. The low vitamin D being one aspect of suboptimal care.  It is surprising the number of patients who are still allowed to become deficient in fat soluble vitamins when the need for regular monitoring of fat soluble vitamin levels in cystic fibrosis has been recognised for over 30 years!!

Laura A McCauley is in the Department of Pediatrics, Marshfield Clinic, Marshfield, Wisconsin.

McKone EF, Borowitz D, Drevinek P, Griese M, Konstan MW, Wainwright C, Ratjen F, Sermet-Gaudelus I, Plant B, Munck A, Jiang Y, Gilmartin G, Davies JC. VX08-770-105 (PERSIST) Study Group Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med 2014 Nov; 2(11):902-10. doi: 10.1016/S2213-2600(14)70218-8. Epub 2014 Oct 9.

Fig. 33 Edward McKone LinkedIn

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. The authors assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION).
Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study.

At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study.

— This is reassuring data on the sustained effects and longterm safety of these drugs when added to the usual treatment.

Edward McKone (fig. 33) is Professor at the School of Medicine, St. Vincent’s University Hospital, Dublin.

Maqbool A. Schall JI. Mascarenhas MR. Dougherty KA. Stallings VA. Vitamin B(12) status in children with cystic fibrosis and pancreatic insufficiency. J Pediatr Gastroenterol Nutr 2014; 58:733-8.[PubMed]

Fig. 34 Asim Maqbool LinkedIn

Serum B12 status was assessed in 106 subjects (5-18 years) and categorised as elevated (serum B12 above reference range for age and sex [Hi-B12]) or within reference range (serum B12 within reference range for age and sex) for age and sex.
The serum B12 was elevated in the majority of children with CF and PI. However, supplement-based B12 intake was 6 to 10 times the RDA, and strongly predicted elevated serum B12 status.
The authors conclude that health consequences of lifelong high supplement-based B12 intake and high serum B12 are unknown and require further study, as does the inverse correlation between serum B12 and forced expiratory volume at 1 second.

(See also Rucker RW et al, 1973. N Engl J Med 1973; 289:329   Also Topics -> gastroenterology -> vitamins -> Vitamin B)

Dr Asim Maqbool (fig.34) is in the Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA.

Mitilian D. Sage E. Puyo P. Bonnette P. Parquin F. Stern M. Fischler M. Chapelier A. Foch Lung Transplant Group. Techniques and results of lobar lung transplantations. Eur J Cardiothorac Surg 2014; 45(2):365-9. (also discussion 369-70, 2014). pubmed.ncbi.nlm.nih.gov/23900745/
Since 1988, 50 lobar lung transplants (LLTs) were done for cystic fibrosis (n=35), fibrosis (n=7), bronchiectasis (n=3), emphysema (n=3) and lymphangiomyomatosis (n=2). There were 44 females and 6 males (mean age 31+13 years, mean size 155+5.5 cm and mean predicted total lung capacity (TLC) 4463+598 ml). Mean ratio between donor and recipient-predicted TLC was 1.65+0.26. Six patients were listed in high emergency, 2 of them on ECMO as a bridge to transplantation. Forty middle/lower right lobe with left lower LLT, four bilateral lower LLT and six split left lung LLT were performed through a clamshell incision (n=12) or a bilateral antero-lateral thoracotomy (n=38), with epidural analgesia in 17 cases. Thirty-two patients were transplanted under circulatory support (CPB n=16, veno-arterial ECMO n=16). In 11 cases, the right venous anastomosis was enlarged by a pericardial cuff. Ischaemic time was 4.4+1.2 h for the first lobe and 6.1+1.3 h for the second.

Median mechanical ventilation weaning time was 10.5 (1-136) days. Four patients were extubated in the operating room. Ten patients needed ECMO for primary graft dysfunction. In-hospital mortality was 28% related to sepsis (n=6), PGD (n=3), haemorrhage (n=2), broncho-vascular fistula (n=1), and multiorgan failure (n=2). Eight patients required endoscopic treatments for airway complications. Mean best FEV1 was 72+16% of the theoretical value. The actuarial 3-year and 5-year survival rates were 60 and 46%, respectively.

The authors conclude that lobar lung transplantations are a reliable solution and can be performed with satisfactory functional results and survival rates.

Dr Delphine Mitilian is a cardiothoracic surgeon in the Department of Thoracic Surgery and Lung Transplantation, Hôpital Foch, Suresnes, France.

Michon Anne-Laure, Jumas-Bilaket E, Chiron R, Lamy B, Marchandin H. Advances toward the Elucidation of Hypertonic Saline Effects on Pseudomonas aeruginosa from Cystic Fibrosis Patients. PLoS One 2014;9:e90164; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3938589/pdf/pone.0090164.pdf).

Fig. 35 Anne-laure Michon LinkedIn

Nebulized hypertonic saline (HTS) has beneficial effects including reducing pulmonary exacerbations in Cystic Fibrosis (CF) patients. Several mechanisms may explain these effects but antimicrobial activity of NaCl remains largely unexplored. The study aimed to measure the antimicrobial effect of NaCl on Pseudomonas aeruginosa isolated from the respiratory tract in CF patients.
It was found that NaCl inhibited the growth of all isolates and killed 38% of tested isolates within concentration range currently used in therapeutics.

–   The results suggest that anti-pseudomonal activity is another mechanism of action of HTS to add to those already established. The authors noted that further studies are needed to determine the ideal NaCl volume, frequency of administration and mode of administration to optimise the potential bactericidal effects of hypertonic saline therapy in CF.

Dr Anne Laure Michon (fig.35)  is in Bacteriologie Team in the University Hospital of Montpellier.     Recently Directrice des opérations Hôpital Européen Georges Pompidou, Greater Paris Metropolitan Region.

Moodie M. Lal A. Vidmar S. Armstrong DS. Byrnes CA. Carlin JB. Cheney J. Cooper PJ. Grimwood K. Robertson CF. Tiddens HA. Wainwright CE. Costs of bronchoalveolar lavage-directed therapy in the first 5 years of life for children with cystic fibrosis. Cystic Fibrosis Bronchoalveolar Lavage Study Investigators. J Pediatr 2014;165:564-569.[PubMed]

Fig. 36 Marj Moodie

To determine whether bronchoalveolar lavage (BAL)-directed therapy for infants and young children with cystic fibrosis (CF), rather than standard therapy, was justified on the grounds of a decrease in average costs and whether the use of BAL reduced treatment costs associated with hospital admissions.
Mean costs per child during the 5 year study period were Australian dollars (AUD) 92,860 in BAL-directed therapy group and AUD 90,958 in standard therapy group. Mean hospital costs per child during the study period were AUD 57,302 in the BAL-directed therapy group and AUD 66,590 in the standard therapy group.
The authors concluded that BAL-directed therapy did not result in either lower mean hospital admission costs or mean costs overall compared with managing patients with CF by a standard protocol based upon clinical features and oropharyngeal culture results alone.

—  Following on their previous findings that BAL-directed treatment offers no clinical advantage over standard therapy at age 5 years (Wainwright CE, et al. JAMA. 2011; 306:163-71.[PubMed]) the authors could not recommend flexible bronchoscopy with BAL for the routine management of preschool children with CF on the basis of overall cost savings.

Marj Moodie (fig 36) Professor Marj Moodie is a Principal Research Fellow at Deakin University where she is Deputy Head (Research) of the Deakin Health Economics.

Morrow CB. Raraigh KS. Green DM. Blackman SM. Cutting GR. Collaco JM. Cat and dog exposure and respiratory morbidities in cystic fibrosis. Pediatrics 2014; 165:830-5.[PubMed]
A total of 703 subjects with CF were recruited through the US CF Twin-Sibling Study. There were no differences in prevalence and age of acquisition for the common CF respiratory pathogens Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus between cat/dog owners and non-cat/dog owners. Within the sample, 47% of subjects reported owning a dog, and 28% reported owning a cat.
The authors found that cat ownership was associated with a greater frequency of developing nasal polyps and combined cat-dog ownership was associated with a greater rate of wheezing.

Please see also Topics section -> Microbiology -> Cross infection where there is an article on sources of infection where pets are discussed.

Christopher B Morrow is at Eudowood Division of Pediatric Respiratory Sciences, Baltimore, MD.

Morro M. Teichenne J. Jimenez V. Kratzer R. Marletta S. Maggioni L. Mallol C. Ruberte J. Kochanek S. Bosch F. Ayuso E. Pancreatic transduction by helper-dependent adenoviral vectors via intraductal delivery. Gene Ther 2014; 25:824-36. [PubMed]
Helper-dependent adenoviral vectors (HDAds) are promising tools for gene therapy because of their large cloning capacity, high levels of transgene expression, and long-term persistence in immunocompetent animals. Nevertheless, the ability of HDAds to transduce the pancreas in vivo has not been investigated yet. Here, the authors generated HDAds carrying pancreas-specific expression cassettes, that is, driven either by the elastase or insulin promoter, using a novel and convenient plasmid family and homologous recombination in bacteria. These HDAds were delivered to the pancreas of immunocompetent mice via intrapancreatic duct injection. HDAds, encoding a CMV-GFP reporter cassette, were able to transduce acinar and islet cells, but transgene expression was lost 15 days post-injection in correlation with severe lymphocytic infiltration. When HDAds encoding GFP under the control of the specific elastase promoter were used, expression was detected in acinar cells, but similarly, the expression almost disappeared 30 days post-injection and lymphocytic infiltration was also observed. In contrast, long-term transgene expression (>8 months) was achieved with HDAds carrying the insulin promoter and the secretable alkaline phosphatase as the reporter gene. Notably, transduction of the liver, the preferred target for adenovirus, was minimal by this route of delivery.
The authors suggest that these data indicate that HDAds could be used for pancreatic gene therapy but that selection of the expression cassette is of critical importance to achieve long-term expression of the transgene in this tissue.

–   Although most attention regarding gene therapy in CF has been devoted to treatment of the lungs, the long term effects of pancreatic damage, in particular the diabetes mellitus, are of increasing importance as survival increases. In this respect it is encouraging that the new mutation specific drug ivacaftor is reported to have a favourable effect on insulin secretion in people with cystic fibrosis and the GF551D mutation (Bellin MD et al. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes. 2013;14:417-21. [PubMed] Free article available).

Dr Meritxell Morro is a postdoctoral researcher at the Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona , Bellaterra 08193, Spain .

Minkoff H. Berkowitz R. The case for universal prenatal genetic counseling. Obstet Gynecol 2014; 123(6):1335-8. [PubMed]

Fig 37. Howard Minkoff Facebook

Scientific advances in human genetics and prenatal diagnostic technologies challenge the counselling infrastructure of most obstetric services.
All women, not just those surpassing some poorly defined level of risk, deserve genetic counselling.
Approaches for achieving this goal are discussed.

Howard Minkoff (figure 37) is Professor of Obstetrics and Gynecology. Kings County Hospital Centre, New York

Nguyen TT. Thia LP. Hoo AF. Bush A. Aurora P. Wade A. ookChudleigh J. Lum S. Stocks J. London Cystic Fibrosis Collaboration (LCFC). Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants. Thorax 2014; 69:910-7. [PubMed]
A study to assess changes in pulmonary function during the first year of life in CF infants detected by newborn screening. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRCpleth)) and forced expired volume (FEV 0.5) were measured at 3 months and 1 year of age.
Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV 0.5 improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p<0.01) in CF infants between 3 months and 1 year, and by 1 year, FEV 0.5 was only 0.52 (0.89 to 0.15) z-scores less than in controls. LCI and FRCpleth remained stable throughout the first year of life, being on average 0.8 z-scores higher in infants with CF. Pulmonary function at 1 year was predicted by that at 3 months. Among the 45 CF infants with entirely normal LCI and FEV 0.5 at 3 months, 80% remained so at 1 year, while 74% of those with early abnormalities remained abnormal at 1 year.

—  This is the first study reporting improvements in FEV 0.5 over time in stable NBS CF infants treated with standard therapy. Milder changes in lung function occurred by 1 year than previously reported. Lung function at 3 months predicts a high-risk group, who should be considered for intensification of treatment and enrolment into RCTs.
A very interesting study from the London CF Collaboration with implications for early management. The importance of early involvement and of identifying this early at risk group at 3 months, who may require more intensive treatment and supervision (at a specialist centre rather than care shared with a local hospital), is emphasised.

Dr The Thanh-Diem Nguyen is at the Portex Unit: Respiratory Physiology and Medicine, UCL Institute of Child Health, London, UK and the Department of Respiratory Medicine, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada.

Palermo J. Szabo F. 50 Years ago in The Journal of Pediatrics: hypoproteinemia and edema in infants with cystic fibrosis of the pancreas. Pediatr 2014; 164(3):638.[PubMed]
(Article in question – Fleisher DS, DiGeorge AM, Barnes LA, Cornfeld D. J. Pediatr 1964;64:341-8)

Fig. 38  Joseph Palermo cincinnatichildrens.org

When cystic fibrosis (CF) was first described in the 1500s, these children were thought to be bewitched. By the 1800s, the disease and its prognosis were depicted in a German children’s song: “The child will soon die whose forehead tastes salty when kissed.” Life expectancy was 1 year.
In the 1900s, malnutrition and diarrhea were the hallmarks of the disease described as a “celiac syndrome.” In 1964, Fleisher et al reported their findings that breast milk or soy formula fed infants were significantly more malnourished with edema and hypoproteinemia and fared worse than those fed cow milk-based formula. Treatment for “cystic fibrosis of the pancreas” emphasized the importance of high fat diet and the use of pancreatic enzymes. Life expectancy was still limited, with 80% death rate by age 5 years.
In the following decades, significant strides were made in disease management without full understanding of its etiology, and life expectancy increased to almost 20 years by the 1980s. The landmark discovery of disease-causing mutations in the cystic fibrosis transmembrane regulator gene (CFTR) in 1989 provided a new focus in CF research.
State screens now help diagnose CF in infancy, resulting in earlier intervention and better outcomes. From 2000-2011, diagnoses through state screen increased from 10% to 60%. Life expectancy has risen significantly from 20 years to 37 years in just 2 decades. However, with improved survival, other complications of CF arise, including CF-related diabetes and liver disease with portal hypertension.
We are now entering a revolutionary era in CF with the development of breakthrough disease-modifying drugs targeting the CFTR protein defect. CFTR modulators are small molecules classified as potentiators, correctors, or premature stop codon suppressors. The first approved small molecule, Kalyedco (ivacaftor) is specific to less common CFTR mutations and increases CFTR channel opening. Other promising small molecules in clinical trials (http://www.cff.org/treatments/Pipeline) may be beneficial to those with classic delta F508 mutations.
Although previous advances in CF therapy mitigated the effects of CFTR dysfunction, the combination of early detection and initiation of personalized medicine targeting CFTR mutations may soon keep foreheads from tasting salty and truly alter the course of this devastating disease.

Joseph Palermo (fig.38) is at the Department of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.

Perano SJ. Couper JJ. Horowitz M. Martin AJ. Kritas S. Sullivan T. Rayner CK. Pancreatic enzyme supplementation improves the incretin hormone response and attenuates postprandial glycemia in adolescents with cystic fibrosis: a randomized crossover trial. J Clin Endocr Metabol 2014; 99(7):2486-93. [PubMed]

Fig. 39 Shiree J Perano google.com

A study to determine the effect of pancreatic enzyme replacement therapy (PERT) on postprandial glycemia in adolescents with cystic fibrosis (CF). This was a double-blinded randomised crossover trial. Subjects consumed a high-fat pancake, with either PERT (50 000 IU lipase) or placebo. Gastric emptying was measured by a breath test and blood sampled frequently for plasma blood glucose, insulin, glucagon, GLP-1, and GIP. Data were also compared with seven healthy subjects.
Fourteen adolescents (13.1 + 2.7 y) with pancreatic-insufficient CF and seven healthy age-matched controls participated in the study. Postprandial hyperglycaemia was measured as peak glucose and area under the curve for blood glucose at 240 minutes.
CF subjects had postprandial hyperglycaemia compared with controls (area under the curve, P < .0001). PERT reduced postprandial hyperglycaemia (P = .0002), slowed gastric emptying (P = .003), and normalised GLP-1 and GIP secretion (P < .001 for each) when compared with placebo, without affecting insulin.
In young people with pancreatic insufficient CF, PERT markedly attenuates postprandial hyperglycemia by slowing gastric emptying and augmenting incretin hormone secretion.

—   So pancreatic replacement therapy had a number of significant beneficial effects – not least reducing post prandial hyperglycaemia.[“Incretins” are hormones that cause release of insulin from the islets of Langerhans]

Dr Shiree J Perano  is a paediatrician in the Departments of Diabetes and Endocrinology,  Women’s and Children’s Hospital, North Adelaide, South Australia 5006, Australia.

Pabary R. Severe pulmonary exacerbation in cystic fibrosis caused by cat allergy. Paediatr Respir Rev 2014; 15 Suppl 1:29-31. [PubMed]

Fig. 40 Rishi Pabary eMedEvents

A preschool child who had persistent symptoms suggestive of significant cystic fibrosis lung disease over a period of eighteen months following first isolation of Pseudomonas aeruginosa. Despite vigorous anti-infective treatment and extensive investigations seeking undetected infection, improvement only occurred once severe cat allergy was diagnosed and cats were removed from the household.

—   A reminder that it is important to consider non-infective pathologies when the response to anti-infective antibiotic treatment is unexpectedly poor. Similar suboptimal response to intravenous antibiotics may be observed when Aspergillus, rathe ather than bacterial infection, is the main cause of the patients symptoms.

Dr Rishi Pabary (fig. 40) a  consultant paediatrician  in Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London; Imperial College, London.

Previs RA. Edwards JM. Secord AA. Nucci MR. Bentley RC. Hall AH. Cystic fibrosis involving the cervix, mimicking a well-differentiated adenocarcinoma: a case report. J Gynec Path 2014; 33(1):100-4. [PubMed]

Fig. 41 Rebecca A Previs

The authors describe clinicopathologic and immunohistochemical features of an unusual case of cystic fibrosis manifesting in the cervix as a mass lesion, mimicking cervical adenocarcinoma. A 24-year-old nulligravida with cystic fibrosis developed heavy postcoital vaginal bleeding 4 months after starting oral contraceptives and was found to have a cervical mass. She underwent a loop electrosurgical excision of the mass, and microscopic examination revealed a florid endocervical proliferation, extending to the margins. This lesion was initially interpreted as an invasive, well-differentiated endocervical adenocarcinoma. However, on subsequent review, the lesion was found to have a low rate of proliferation, no evidence of an infiltrative growth pattern, and abundant acute inflammation. Given these findings and the absence of any residual endocervical lesion on a subsequent cold knife conization, they determined that this was a benign, likely reactive, lesion.

—   This case, together with previous studies, suggests that women with cystic fibrosis can develop proliferative endocervical lesions and that oral contraceptives may contribute to their development.

Rebecca A Previs (fig.41) is an obstetrician-gynecologist in the Division of Gynecologic Oncology, Duke Cancer Institute Departments of Obstetrics and Gynecology ,Duke University Medical Center, Durham, North Carolina

Reznikov LR. Abou Alaiwa MH. Dohrn CL. Gansemer ND. Diekema DJ. Stoltz DA. Welsh MJ. Antibacterial properties of the CFTR potentiator ivacaftor. J Cyst Fibros 2014; 13:515-9.[PubMed]

Fig.42 Leah R Reznikov

As ivacaftor structurally resembles quinolone antibiotics, the authors tested the hypothesis that ivacaftor possesses antibacterial properties. Bioluminescence, colony forming unit, and minimal inhibitory concentration assays were used to assess viability of Staphylococcus aureus, Pseudomonas aeruginosa and multiple clinical microbial isolates. Ivacaftor induced a dose-dependent reduction in bioluminescence of S. aureus and decreased the number of colony forming units. There was a similar but less robust effect in P. aeruginosa following outer membrane permeabilisation. Ivacaftor inhibited the growth of respiratory isolates of S. aureus and Streptococcus pneumoniae and exhibited positive interactions with antibiotics against lab’ and respiratory strains of S. aureus and S. pneumoniae.

–   The authors consider these data indicate that ivacaftor exhibits antibacterial properties and raise the possibility that ivacaftor might have an antibiotic effect in people with CF.

Leah R Resnikov (fig. 42) is Assistant Professor, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, USA

Rodriguez Hortal MC. Hjelte L. Time point to perform lung function tests evaluating the effects of an airway clearance therapy session in cystic fibrosis. Respir Care 2014; 59:1537-41.2014. [PubMed]
The authors found that performing spirometry 30 min after a session in adults and immediately after in children appeared to be optimal if individual peak time values cannot be used.

Maria Cecilia Rodriguez Horton is in the Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. Department of Physical Therapy

Rowe SM. Heltshe SL. Gonska T. Donaldson SH. Borowitz D. Gelfond D. Sagel SD. Khan U. Mayer-Hamblett N. Van Dalfsen JM. Joseloff E. Ramsey BW. GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. J Respir Crit Care Med 2014; 190(2):175-84. [PubMed]

Fig 43. Seven Rowe emedevents.com

To evaluate ivacaftor in a post-approval setting and determine mechanism of action and response of clinically relevant markers the authors conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, beta-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology   A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing g clinical mechanisms underlying the therapeutic benefit of ivacaftor.

The authors concluded clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.

Steven Rowe (fir. 43) is professor in the Department of Medicine University of Alabama at Birmingham, Alabama.

Ramsey KA, Ranganathan S, Park J, Skoric B, Adams AM, Simpson SJ, Robins-Browne RM, Franklin PJ, de Klerk NH, Sly PD, Stick SM, Hall GL, AREST CF. Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis.   Am J Respir Crit Care Med. 2014 Nov 15;190(10):1111-6. doi: 10.1164/rccm.201407-1277OC. [PubMed]

Fig. 44 Kathryn A Ramsey    Telethon Kids Institute

Pulmonary inflammation, infection, and structural lung disease occur early in life in children with cystic fibrosis. The authors hypothesized that the presence of these markers of cystic fibrosis lung disease in the first 2 years of life would be associated with reduced lung function in childhood.  Lung function (forced expiratory volume in the first three-quarters of a second [FEV0.75], FVC) was assessed in individuals with cystic fibrosis diagnosed after newborn screening and healthy subjects during infancy (0-2 yr) and again at early school age (4-8 yr). Individuals with cystic fibrosis underwent annual bronchoalveolar lavage fluid examination, and chest computed tomography. The authors  examined which clinical outcomes (pulmonary inflammation, infection, structural lung disease, respiratory hospitalizations, antibiotic prophylaxis) measured in the first 2 years of life were associated with reduced lung function in infants and young children with cystic fibrosis, using a mixed effects model.

Children with cystic fibrosis (n = 56) had 8.3% (95% confidence interval [CI], -15.9 to -6.6; P = 0.04) lower FEV0.75 compared with healthy subjects (n = 18). Detection of proinflammatory bacterial pathogens (Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Aspergillus species, Streptococcus pneumoniae) in bronchoalveolar lavage fluid was associated with clinically significant reductions in FEV0.75 (ranging between 11.3 and 15.6%).

—   The onset of lung disease in infancy, specifically the occurrence of lower respiratory tract infection, is associated with low lung function in young children with cystic fibrosis. Deficits in lung function measured in infancy persist into childhood, emphasising the need for targeted therapeutic interventions in infancy to maximise functional outcomes later in life.

Kathryn A Ramsey (fig.44) is Associate Professor  Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia.

Rushworth GF. Megson IL Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014; 141(2):150-8. [PubMed]

Fig. 45 Gordon Rushworth ResearchGate

N-acetyl-l-cysteine (NAC) has long been used therapeutically for the treatment of acetaminophen (paracetamol) overdose, acting as a precursor for substrate(l-cysteine) in synthesis of hepatic glutathione (GSH) depleted through drug conjugation. Other therapeutic uses of NAC have also emerged, including the alleviation of clinical symptoms of cystic fibrosis through cysteine-mediated disruption of disulfide cross-bridges in the glycoprotein matrix in mucus. More recently, however, a wide range of clinical studies have reported on the use of NAC as an antioxidant, most notably in the protection against contrast-induced nephropathy and thrombosis. The results from these studies are conflicting and a consensus is yet to be reached regarding the merits or otherwise of NAC in the antioxidant setting.

This review seeks to re-evaluate the mechanism of action of NAC as a precursor for GSH synthesis in the context of its activity as an “antioxidant”. Results from recent studies are examined to establish whether the pre-requisites for effective NAC-induced antioxidant activity (i.e. GSH depletion and the presence of functional metabolic pathways for conversion of NAC to GSH) have received adequate consideration in the interpretation of the data. A key conclusion is a reinforcement of the concept that NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH in deficient cells and it is likely to be ineffective in cells replete in GSH.

— There is an extensive literature on the use of NAC in cystic fibrosis. Despite most impressive early papers showing obvious increase in sputum following administration of the drug, the current view seems to be that there is no significant benefit from its use – which is surprising (suggest see Topics -> Mucolytics -> N-acetylcysteine).

Dr Gordon F Rushworth  (fig. 45) is at the Highland Clinical Research Facility, Centre for Health Science, Old Perth Road, Inverness IV2 3JH, UK.

Simoneau T. Bazzaz O. Sawicki GS. Gordon C. Vitamin D status in children with cystic fibrosis. Associations with inflammation and bacterial colonization. Ann Am Thorac Soc 2014; 11(2):205-10. [PubMed]

Fig. 46 Tregony Simoneau ATSconferencenews.org

Patients with cystic fibrosis (CF) have high rates of vitamin D insufficiency. The relation between vitamin D status and inflammation in patients with CF is poorly understood. Vitamin D deficiency was defined as a serum 25(OH)D, less than 20 ng/ml and insufficiency as serum 25(OH)D 20 to 29.9 ng/ml.
Data were collected for 148 children. The mean serum 25(OH)D concentration was 32.4 ng/ml (SD, 8.9). Seven percent (10 of 148) were vitamin D deficient, and 36% (53 of 148) were vitamin D insufficient. Among the pancreatic-sufficient patients, 50% (14 of 28) were vitamin D insufficient/deficient, whereas among pancreatic-insufficient patients, 41% (49 of 120) were vitamin D insufficient/deficient. Pseudomonas aeruginosa was a more common pathogen in the patients who were vitamin D insufficient/deficient (18 of 63 vs. 11 of 85, P = 0.018). There was no difference between vitamin D-sufficient versus -insufficient groups in terms of other bacterial colonisation or inflammatory markers.
The authors concluded that overall, vitamin D insufficiency is common among young children with CF. Vitamin D insufficiency is prevalent even in children who are pancreatic sufficient. In this population, vitamin D insufficiency is associated with a history of Pseudomonas colonisation but not with classic markers of systemic inflammation.

—   There are obvious limitations to a chart review study of this type and 43% of patients who are insufficient/deficient in vitamin D suggests that the previous monitoring of their nutritional state has not included the recommended monitoring of their fat soluble vitamin levels.

Dr Tregony Simoneau (fig.46) is Assistant Professor of Pediatrics at the Children’s Hospital Boston, Division of Respiratory Diseases, Harvard Medical School, Boston, Massachusetts.

Stanojevic S. Waters V. Mathew JL. Taylor L. Ratjen F. Effectiveness of inhaled tobramycin in eradicating Pseudomonas aeruginosa in children with cystic fibrosis. J Cyst Fibros 2014;13(2):172-8. [PubMed]

Fig. 47  Sanja Stanojevic medicine.dal.ca

Inhaled tobramycin therapy has been shown to be efficacious in clinical trials for the eradication of initial Pseudomonas aeruginosa infection in children with cystic fibrosis. However, the effectiveness of different regimens in eradicating P. aeruginosa and preventing the development of chronic infection in actual clinical settings has yet to be determined.
This was an observational study of children (<18 years of age) with CF with incident P. aeruginosa infection from 2005-2012 based on data collected from the Toronto CF Database and medical charts. Patients who received inhaled tobramycin (80 mg/2 ml twice daily for 365 days) were compared to those who received tobramycin inhalation solution (TIS) (300 mg/5 ml twice daily for 28 days) with respect to eradication and development of chronic infection. The authors also examined the risk factors for recurrence of infection.
During the study period, 65 patients were identified with incident P. aeruginosa, of which 7 (11%) failed eradication therapy. Eradication failure was similar between the two treatment groups. A total of 4 patients (6%) developed chronic P. aeruginosa infection in the 12 months following the end of therapy with no differences between treatment groups. Female gender, older age, pancreatic insufficiency, lower lung function and worse nutritional status were identified as risk factors for recurrence of P. aeruginosa infection.

Both regimens of inhaled tobramycin have similar effectiveness in eradicating P. aeruginosa and preventing chronic P. aeruginosa infection in CF patients in clinical practice. Further work is needed, however, to identify patient characteristics and bacterial factors that play a role in eradication failure, in order to develop more effective antimicrobial rescue treatment strategies.

Sanja Stanojevic (fig. 47) is in the Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Canada. Subsequently Associate Professor Dept. Community Health and Epidemiology Dalhousie University.

Saiman L. Siegel JD. LiPuma JJ. Brown RF. Bryson EA. Chambers MJ. Downer VS. Fliege J. Hazle LA. Jain M. Marshall BC. O’Malley C. Pattee SR. Potter-Bynoe G. Reid S. Robinson KA. Sabadosa KA. Schmidt HJ. Tullis E. Webber J. Weber DJ. Infection prevention and control guideline for cystic fibrosis: 2013 update. Control & Hospital Epidemiology 2014; 35 Suppl 1:S1-S67. [PubMed]
These are the latest US guidelines.

Saynor ZL. Barker AR. Oades PJ. Williams CA. The effect of ivacaftor in adolescents with cystic fibrosis (G551D mutation): an exercise physiology perspective. Phys Ther 2014; 26:454-61. [PubMed]

Fig. 48 Zoe Saynor

The purpose of this report was to evaluate the influence of 12 weeks of ivacaftor treatment on the aerobic function of 2 teenage patients with cystic fibrosis (CF; F508/G551D) using a maximal cardiopulmonary exercise test.
One patient, with relatively mild disease, demonstrated no clinically meaningful changes in maximal oxygen uptake (Equation is included in full-text article. O2max). However, in the second case, with more established lung disease on imaging, the O2max improved by approximately 30%.

The authors suggest cardiopulmonary exercise testing represents an important outcome measure in the functional assessment of patients with CF.

Zoe Saynor (fig. 48) is Senior Lecturer in Phyisical Activity at the University of Portsmouth, UK

Schneiderman JE, Wilkes DL, Atenafu EG, Nguyen T, Wells GD, Alarie N, Tullis E, Lands LC, Coates AL, Corey M, Ratjen F. Longitudinal relationship between physical activity and lung health in patients with cystic fibrosis.  Eur Respir J. 2014 Mar;43(3):817-23. doi: 10.1183/09031936.00055513. Epub 2013 Oct 31. [PubMed] Free full text

Fig. 49 Jane Schneiderman ResearchGate

Exercise is beneficial for patients with cystic fibrosis (CF) but long-term effects of physical activity on lung function evolution are unknown. We evaluated the longitudinal relationship between changes in habitual physical activity (HPA) and rate of decline in lung function in patients with CF. We tracked HPA using the Habitual Activity Estimation Scale, forced expiratory volume in 1 s (FEV₁) and Stage I exercise tests in 212 patients with CF over a 9-year period. Adjusting for sex, baseline age and FEV₁, mucoid Pseudomonas aeruginosa and CF-related diabetes, mean ± sd FEV₁ % predicted decreased by 1.63 ± 0.08% per year (p<0.0001) while mean ± sd HPA increased by 0.28 ± 0.03 h·day(-1) per year (p<0.0001) over the study period. A greater increase in HPA was associated with a slower rate of decline in FEV₁ (r=0.19, p<0.0069). Dividing subjects into “high” and “low” activity (above or below the mean rate of change of activity, respectively), a steeper rate of FEV₁ decline was observed for low (-1.90% per year) compared to high (-1.39% per year) (p=0.002).

Increases in HPA are feasible despite progression of lung disease and are associated with a slower rate of decline in FEV₁, highlighting the benefit of regular physical activity, and its positive impact on lung function in patients with CF.

Jane Schneiderman (fig. 49) is an Exercise Physiologist/Registered Kinesiologist in the Div. of Respiratory Medicine at the Hospital for Sick Children in Toronto.

Shamsuddin AK. Quinton PM. Native small airways secrete bicarbonate. J Respir Cell Mol Biol 2014; 50(4):796-804. [PubMed]

Fig 50. Abulkalam Shamsuddin

Since the discovery of Cl(-) impermeability in cystic fibrosis (CF) and the cloning of the responsible channel, CF pathology has been widely attributed to a defect in epithelial Cl(-) transport. However, loss of bicarbonate (HCO3(-)) transport also plays a major, possibly more critical role in CF pathogenesis. Even though HCO3(-) transport is severely affected in the native pancreas, liver, and intestines in CF, we know very little about HCO3(-) secretion in small airways, the principle site of morbidity in CF.
The authors used a novel, mini-Ussing chamber system to investigate the properties of HCO3(-) transport in native porcine small airways (~ 1 mm)

They conclude their results indicate that two separate components for HCO3(-) secretion, likely via CFTR- and calcium-activated chloride channel-dependent processes, are physiologically regulated for likely roles in mucus clearance and antimicrobial innate defences of small airways.

Adulkalam Shamsuddin (fig. 50) is Professor of Pathology the University of Maryland School of Medicine.

Subhi R. Ooi R. Finlayson F. Kotsimbos T. Wilson J. Lee WR. Wale R. Warrier S. Distal intestinal obstruction syndrome in cystic fibrosis: presentation, outcome and management in a tertiary hospital (2007-2012). ANZ J Surg 2014; 84:740-4. [PubMed]

Fig. 51 Rami Subhi ResearchGate

A retrospective audit of CF patients at the Alfred Hospital, Melbourne from January 2007 to February 2012 who had DIOS. Forty-five encounters of 35 patients were extracted. Twenty-five (83%) patients were homozygous for the delta F508 mutations, 29 (85%) had pancreatic insufficiency and 15 (44%) had a lung transplant. Patients presented with abdominal pain (96% of encounters), nausea (76% of encounters) and vomiting (67% of encounters). Computed tomography (CT) was performed in 20 episodes. Compared with CT, abdominal X-ray had a sensitivity of 63% (95% confidence interval (CI) 30-89%) and specificity of 33% (95% CI 8-70%) for detecting DIOS with obstruction. Forty-one (91%) encounters resolved with medical management within 2-3 days. Three patients required surgical intervention in four episodes. Previous laparotomy (odds ratio (OR) 28.5, 95% CI 1.3-624, P = 0.03) and history of meconium ileus (OR 14, 95% CI 1-192, P < 0.05) were statistically significant predictors of progression to surgical management.

The authors concluded that in most patients with DIOS, the obstruction resolves with medical management. Early consultation with a CF service, assessment for a surgical abdomen and involvement of surgeons where appropriate is recommended. A history of previous laparotomy is a risk factor for the need for surgical intervention.

—  A useful record of experience from a major adult unit where only 3 patients required surgical intervention.

Rami Subbi (fig. 51) is a paediatrician and researcher in the Department of Colorectal Surgery, Alfred Health, Melbourne, Victoria , Australia.

Fig. 52 Shahid Sheikh ResearchGate

Sheikh SI. McCoy KS. Ryan-Wenger NA. Patel A. Kirkby S. Lobectomy in patients with cystic fibrosis. Can Respir J 2014; 21:e63-6. [PubMed]
Some patients with cystic fibrosis develop severe but localized lung disease or recurrent hemoptysis/pneumothorax refractory to conventional medical therapies. The outcomes of lung resection in patients with CF and worsening localized lung disease or recurrent hemoptysis/pneumothorax refractory to conventional therapy (n=15) were evaluated by reviewing the medical records of all patients with CF followed at the CF Center at Nationwide Children’s Hospital (Columbus, Ohio, USA), who underwent lobectomy over a 15-year period (1998 to 2012).

The median age of the 15 patients (93% Caucasian) was 20 years (range two to 41 years) and their mean forced expiratory volume in 1 s (FEV1) was 59.5% of predicted one year before surgery. Three patients died within two years after lobectomy; all three deaths occurred in patients with an FEV1 <40% of predicted before surgery. There were no significant changes in mean height, weight, body mass index, hospital admissions or antibiotic use over time. The mean FEV1 decreased over time. Compared with at surgery, decline in FEV1 in the year before surgery was -5.4% (P=0.024) and decline in the year after surgery was -1.3% (P=0.513); however, the difference in the rate of decline was not statistically significant.
The authors concluded that in patients with CF and localised worsening bronchiectasis and/or recurrent hemoptysis/pneumothorax, lobectomy carried a significant risk of mortality, especially in patients with FEV1 <40% of predicted, and should only be considered when all other measures fail. –    This experience in older patients differs significantly from the relatively good results for lobectomy for localised severe changes in children reported by many previous authors (see Topics -> Surgery for details of previous publications). It is not surprising that when there is extensive lung involvement in older patients lobectomy will be less beneficial as was the case in the present study.

Sahid I Sheikh (fig.52) is Professor in the Division of Pulmonary Medicine, Department of Pediatrics, Ohio State University College of Medicine, Nationwide Children’s Hospital;

Smyth AR. Bell SC. Bojcin S. Bryon M. Duff A. Flume P. Kashirskaya N. Munck A. Ratjen F. Schwarzenberg SJ. Sermet-Gaudelus I. Southern KW. Taccetti G. Ullrich G. Wolfe S. European Cystic Fibrosis Society Standards of Care: Best Practice guidelines. J Cyst Fibros 2014; 13 Suppl 1:S23-42. [PubMed] Full text available on the ECFS website.
Specialised CF care has led to a dramatic improvement in survival in CF: in the last four decades, well above what was seen in the general population over the same period. With the implementation of newborn screening in many European countries, centres are increasingly caring for a cohort of patients who have minimal lung disease at diagnosis and therefore have the potential to enjoy an excellent quality of life and an even greater life expectancy than was seen previously.

—-   To allow high quality care to be delivered throughout Europe, a landmark document was published in 2005 that sets standards of care. The current document builds on this work, setting standards for best practice in key aspects of CF care. The objective of the document is to give a broad overview of the standards expected for screening, diagnosis, pre-emptive treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support. For comprehensive details of clinical care of CF, references to the most up to date European Consensus Statements, Guidelines or Position Papers are provided in Table 1 of the full version..
The authors hope that this best practice document will be useful to clinical teams both in countries where CF care is developing and those with established CF centres.

Stankovic Stojanovic K. Hubert D. Leroy S. Dominique S. Grenet D. Colombat M. Clement A. Fayon M. Grateau G. Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network. Amyloid 2014; 21:231-7. [PubMed]
A 30-year retrospective survey identified nine cases of AA amyloidosis in approximately 6000 patients over 30 years and sufficient data were collected in six. The clinical presentation was renal disease in four cases, a compressive goitre in one case, and epigastric pain in one case. Five patients had died, at a median age of 29 years and a median duration of 6 years after the onset of proteinuria.

– This study supports previous evidence that amyloidosis is a surprisingly rare in CF and that, when it does occur, renal involvement is predomina. .In AA amyloidosis the deposited protein is amyloid A protein, an acute phaseprotein which is normally soluble and whose plasma concentration is highest during inflammation.

Katia Stankovic Stojanovic is at the Centre de Reference pour les Amyloses d’Origine Inflammatoire et de la Fièvre Mediterraneenne Familiale, Service de Medecine Interne, Assistance Publique – Hôpitaux de Paris, Hôpital Tenon , Paris France .

Stern M. Bertrand DP. Bignamini E. Corey M. Dembski B. Goss CH. Pressler T. Rault G. Viviani L. Elborn JS. Castellani C. European Cystic Fibrosis Society Standards of Care: Quality Management in cystic fibrosis. J Cyst Fibros 2014; 13 Suppl 1:S43-59. [PubMed]Full text available on the ECFS website.

Fig. 53 Martin Stern

The quality of care for individuals with CF has become a focus at several levels: patient, centre, regional, national and international. This paper reviews the quality management and improvement issues with particular reference to indicators of health, the role of CF Centres, regional networks, national health policy, and international data registration and comparisons.

Prof. Martin Stern (fig.53) is at the University Children’s Hospital, Tübingen, Germany.


Tchernev G, Semkova K. Cardoso JC. Ananiev JJ. Wollina U. Aquagenic keratoderma. Two new case reports and a new hypothesis. Dermatology Online Journal 2014; 5(1):30-3. [PubMed]

Fig. 54 Georgi Tchernev

Aquagenic keratoderma has been described as a transient condition affecting predominantly young females and defined clinically by the appearance of palmar hyper-wrinkling accentuated after immersion in water. The authors present two new cases with aquagenic palmoplantar acrokeratoderma – a child and a young male. A significant clinical improvement was achieved after topical treatment with aluminium salts. Aquagenic palmar keratoderma may be a clue to cystic fibrosis in adolescents and young adults. Theses authors developed a new hypothesis on its pathogenesis.

Prof. Georgi Tchernev (fig. 54) is at the Department of Dermatology and Venerology, Saint Kliment Ohridski University, University Hospital Lozenetz, Bulgaria.

Thia LP. Calder A. Stocks J. Bush A. Owens CM. Wallis C. Young C. Sullivan Y. Wade A. McEwan A. Brody AS. London Cystic Fibrosis Collaboration. Is chest CT useful in newborn screened infants with cystic fibrosis at 1 year of age? Thorax 2014; 69(4):320-7.[PubMed]

Fig. 55 Lena Thai     LinkedIn

The objectives of this study were to standardise CT data collection across multiple sites; ascertain the incidence of bronchial dilatation and air trapping in newborn screened (NBS) infants with CF at 1 year; and assess the reproducibility of Brody-II, the most widely used scoring system in children with CF, during infancy.  A multicentre observational study of early pulmonary lung disease in NBS infants with CF at age 1 year using volume-controlled chest CT performed under general anaesthetic.
65 infants with NBS-diagnosed CF had chest CT in three centres. Small insignificant variations in lung recruitment manoeuvres but significant centre differences in radiation exposures were found. Despite experienced scorers and prior training, with the exception of air trapping, inter- and intraobserver agreement on Brody-II score was poor to fair (e.g, inter observer total score mean (95% CI) coefficient: 0.34 (0.20 to 0.49)). Only 7 (11%) infants had a total CT score > 12 (i.e, > 5% maximum possible) by either scorer.

The authors concluded that in NBS infants with CF, CT changes were very mild at 1 year, and assessment of air trapping was the only reproducible outcome. CT is thus of questionable value in infants of this age, unless an improved scoring system for use in mild CF disease can be developed.

– Another very useful study from the London Cystic Fibrosis Collaboration.

Dr Lena Thai (fig.55)  Clinical Research Associate at the Portex Unit: Respiratory Physiology and Medicine, UCL Institute of Child Health, London UK. Subsequently Consultant Respiratory Paediatrician in Cardiff.

Tluczek A. Laxova A. Grieve A. Heun A. Brown RL. Rock MJ. Gershan WM. Farrell PM. Long-term follow-up of cystic fibrosis newborn screening: psychosocial functioning of adolescents and young adults. J Cyst Fibros 2014; 13(2):227-34. [PubMed]

Fig 56. Audrey Tluczek

Long-term psychosocial outcomes of cystic fibrosis (CF) patients diagnosed through newborn screening remain unknown. This cross-sectional study compared three groups of youths (16 to 22 years): CF patients diagnosed through NBS (CF-NBS, n = 13), CF patients diagnosed through standard practice (CF-SP, n = 26) and healthy peers (H, n = 42), plus 72 of their parents.
Analysis showed significantly more depression among CF-NBS group parents (p = .006-.008). Parent-child cohesiveness was related to communication (p < .001). Cohesiveness and communication were associated with youth Internalising Problems (p = .037, p = .009), Emotional Symptoms (p = 0.018, p = 0.022), and Personal Adjustment (communication only, p = 0.009). Parent depression was related to youth Personal Adjustment (p = 0.022).

–  CF patients report psychosocial function similar to healthy peers. However, parents of children diagnosed with CF through NBS may be at risk for depressive symptoms when their children reach adolescence.

Audrey Tluczek (fig. 56) is Associate Professor, School of Nursing, Wisconsin.

Van Goor F. Yu H. Burton B. Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 2014; 13(1):29-36. [PubMed]
Ivacaftor (KALYDECO, VX-770) is a CFTR potentiator that increased CFTR channel activity and improved lung function in patients age 6 years and older with CF who have the G551D-CFTR gating mutation.   The aim of this in vitro study was to evaluate the effect of ivacaftor on mutant CFTR protein forms with defects in protein processing and/or channel function.   The effect of ivacaftor on CFTR function was tested in electrophysiological studies using a panel of Fischer rat thyroid (FRT) cells expressing 54 missense CFTR mutations that cause defects in the amount or function of CFTR at the cell surface.    Ivacaftor potentiated multiple mutant CFTR protein forms that produce functional CFTR at the cell surface. These included mutant CFTR forms with mild defects in CFTR processing or mild defects in CFTR channel conductance.

The authors conclude that in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.

Veit G. Avramescu RG. Perdomo D. Phuan PW. Bagdany M. Apaja PM. Borot F. Szollosi D. Wu YS. Finkbeiner WE. Hegedus T. Verkman AS. Lukacs GL. Some gating potentiators, including VX-770, diminish F508-CFTR functional expression. Translat Med 2014; 6(246): 246ra97.[PubMed]

Fig. 57  Guido Veit

Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the F508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous F508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function.
The authors show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, they examined its long-term effect in immortalised and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of F508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface F508-CFTR density and function. VX-770-induced destabilisation of F508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilisation of the nucleotide-binding domain 1 (NBD1)-NBD2 interface.

– The authors suggest that the reduced correction efficiency of F508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimisation of potentiators to maximise the clinical benefit of corrector-potentiator combination therapy in CF.

Dr Guido Veit  (fig.57)  is in the  Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.

Wang Y. Liu J. Loizidou A. Bugeja LA. Warner R. Hawley BR. Cai Z. Toye AM. Sheppard DN. Li H. CFTR potentiators partially restore channel function A561E-CFTR a cystic fibrosis mutant with similar mechanism of dysfunction as F508del-CFTR.  J Pharmacol 2014; 171:4490-503. [PubMed]

Fig. 58 Yiting Wang            ResearchGate

A561E-CFTR is a CF mutation found frequently in Portugal. Using the iodide efflux assay, CFTR potentiators, including genistein and the clinically approved small-molecule ivacaftor, partially restored function to A561E-CFTR. Interestingly, ivacaftor restored wild-type levels of channel activity (as measured by open probability) to single A561E- and F508del-CFTR Cl(-) channels. However, it accentuated the thermos instability of both mutants in cell-free membrane patches.

Dr Yiting Wang (fig. 58) is in the School of Physiology and Pharmacology, University of Bristol, Bristol, UK.

Waters V. Ratjen F. Inhaled liposomal amikacin. Rev of Respir Med 2014; 8(4):401-9. [PubMed]

Fig 59. Valerie Waters SickKids

Arikace is a novel formulation of inhaled liposomal amikacin that can penetrate deep within airway secretions and within Pseudomonas aeruginosa biofilms, making it an attractive therapeutic option for the treatment of cystic fibrosis (CF) pulmonary infections.
Initial Phase I and Phase II studies in CF patients with chronic P. aeruginosa infection demonstrated that Arikace was a safe drug that resulted in significant improvements in lung function after 14-28 days of treatment. Phase III studies of inhaled liposomal amikacin compared to tobramycin inhalation solution in CF patients with P. aeruginosa infection revealed a comparable increase in forced expiratory volume in 1 second at the end of three cycles. In addition, inhaled liposomal amikacin has other potential applications in the management of difficult-to-treat pulmonary infections.

A Phase II trial is currently underway to study the use of Arikace for the treatment of recalcitrant nontuberculous mycobacterial lung disease.

Valerie Waters (fig.59) is in the Division of Infectious Diseases, Department of Pediatrics, Hospital for Sick Children, University of Toronto 555 University Avenue, Toronto, Ontario, Canada

Welsh L, Robertson C F, Ranganathan SC. Increased rate of lung function decline in Australian adolescents with cystic fibrosis. Pediatr Pulmonol 2014; 49:873-7. [PubMed]

Fig 60. Liam Welsh

Although baseline lung function as measured by spirometry in children with cystic fibrosis has improved, the annual rate of decline had not changed significantly during the critical period of adolescence. The aim of this study was to describe factors associated with longitudinal decline in lung function in a contemporary cohort of children with CF.
The authors confirmed that FEV(1) declines at its sharpest rate during adolescence even in the presence of newborn screening. Genotype, increasing age, CFRD, PsA infection, pancreatic insufficiency and a greater number of respiratory hospitalizations are all associated with an increased rate of lung function decline in Australian children and adolescents with cystic fibrosis.

– This data from Melbourne confirms the tendency for decline in respiratory function to be a frequent occurrence during adolescence.

Liam Welsh (fig. 60) is Senior Scientist in the Respiratory Unit at the Royal Children’s Hospital Melborne.

Whiting P. Al M. Burgers L. Westwood M. Ryder S. Hoogendoorn M. Armstrong N. Allen A. Severens H. Kleijnen J. Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: a systematic review and cost-effectiveness analysis Technology Assessment (Winchester, England) 2014; 18(18):1-106. [PubMed]

Fig 61. Jos Kleijnen

To review the clinical effectiveness and cost-effectiveness of ivacaftor for the treatment of CF in patients aged > 6 years who have the G551D mutation.
Ten databases, including MEDLINE and EMBASE, were searched from inception to July 2012. Studies that evaluated ivacaftor for the treatment of adults and children (> 6 years) with at least one G551D mutation were eligible. There were insufficient data to conduct a formal meta-analysis. The manufacturer of ivacaftor, Vertex Pharmaceuticals, submitted a deterministic patient-level simulation model for the assessment of the lifetime cost-effectiveness of ivacaftor. We modified the model where values were not UK-specific or not recent, or where better estimates could be found. The only change to the model structure was the addition of lung transplantations. We changed utility values, annual decline in percentage predicted forced expiratory volume in 1 second (FEV1), and the baseline exacerbation rate, and used data from the CF Registry to estimate the relation between costs, age and percentage predicted FEV1. Estimates of treatment effect of ivacaftor came from the clinical effectiveness review. We modelled three scenarios for the longer-term effects of ivacaftor. We also modelled an ‘optimistic’ scenario for patients aged < 12 years with little lung damage. We conducted a budget impact analysis to estimate the total cost to the NHS of introducing ivacaftor in England. RESULTS: Three studies were included: a randomised controlled trial (RCT) in adults (n = 167) (> 12 years), a RCT in children (n = 26) (6-11 years), and an open-label extension study of the two RCTs. Both RCTs reported significantly greater changes from baseline in all measures of lung function in patients receiving ivacaftor than in those receiving placebo. The mean difference in change in percentage predicted FEV1 was 10.5 [95% confidence interval (CI) 8.5 to 12.5] percentage points in the adults’ study and 10.0 (95% CI 4.5 to 15.5) percentage points in the children’s study at 48 weeks. Improvements in lung function were seen across all subgroups investigated (age, sex, study region and lung function). There were significantly greater improvements in the ivacaftor group than in the placebo group for all outcomes assessed (exacerbations, quality of life, sweat chloride and weight) with the exception of quality of life in children. Improvements were maintained in the open-label trial. Adverse events were mainly minor and comparable across treatment groups. Both RCTs reported more withdrawals in the placebo group than in the ivacaftor group.

The incremental cost-effectiveness ratio varied between £335,000 and £1,274,000 per quality-adjusted life-year gained. The total additional lifetime costs for all eligible CF patients in England ranged from £438M to £479M; the lifetime cost for standard care only was £72M.

The authors concluded that available evidence suggests that ivacaftor is a clinically effective treatment for patients with CF and the G551D mutation; the high cost of ivacaftor may prove an obstacle in the uptake of this treatment. The main priority for further research is the long-term effectiveness of ivacaftor.

This study emphasises the very high cost of ivacaftor in a UK perspective. The authors observe that the high cost may prove an obstacle – there can be no doubt that it will prove a major problem.

From Kleijnen Systematic Reviews Ltd York UK of which Dr Jos Kleijnen (fig.61) is Director. KSR Ltd prepares systematic reviews and meta-analyses, rapid reviews, and health technology assessments to support policy making, licensing and reimbursement decisions (fourth hurdle processes), local decision-making about commissioning health services, economic evaluations and guideline development.

W S Yapa S. Li J. Patel K. Wilson JW. Dooley MJ. George J. Clark D. Poole S. Williams E. Porter CJ. Nation RL. McIntosh MP. Pulmonary and systemic pharmacokinetics of inhaled and intravenous colistin methanesulfonate in cystic fibrosis patients: targeting advantage of inhalational administration. Antimicrob Agents Chemother 2014; 58:2570-9. [PubMed]  Free article available.

Fig 62 Shalini Wickramaratne Senarath Yapa LinkedIn

The purpose of this study was to define the pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following intravenous (i.v.) and inhaled administration in cystic fibrosis (CF) patients. The pharmacokinetic parameters for CMS following i.v. delivery were consistent with previously reported values. Sputum concentrations of formed colistin were maintained at <1.0 mg/liter for 12 h postdose. Nebulization of CMS resulted in relatively high sputum concentrations of CMS and formed colistin compared to those resulting from i.v. administration. The systemic availability of CMS was low following nebulisation of 2 and 4 million IU (7.93% + 4.26% and 5.37% + 1.36%, respectively), and the plasma colistin concentrations were below the limit of quantification. Less than 2 to 3% of the nebulized CMS dose was recovered in the urine samples in 24 h.
The therapeutic availability and drug targeting index for CMS and colistin following inhalation compared to i.v. delivery were significantly greater than 1. Inhalation of CMS is an effective means of targeting CMS and formed colistin for delivery to the lungs, as high lung exposure and minimal systemic exposure were achieved in CF subjects.

Shalini Yapa (fig. 62) is Clinial Pharmacologist at the Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.

Wooldridge JL. Schaeffer D. Jacobs D. Thieroff-Ekerdt R. Long-Term Experience With ZENPEP in Infants With Exocrine Pancreatic Insufficiency Associated With Cystic Fibrosis. J Pediatr Gastroenterol Nutr 2014; 59:612-5. [PubMed]

Fog. 63 Jamie L Wooldridge urmt.rochester.edu

A study to determine whether young infants with CF and pancreatic insufficiency would tolerate long-term treatment with ZENPEP (pancrelipase) delayed-release capsules, containing 3000 US Pharmacopeia units of lipase/capsule, and demonstrate consistent long-term growth.
Long-term treatment (up to 12 months) of infants with exocrine pancreatic insufficiency owing to cystic fibrosis with ZENPEP was well tolerated and associated with improved growth parameters.

— This is the first long-term study of pancreatic enzyme replacement therapy conducted in this patient population. This ZENPEP (EUR-1008) had previously been assessed for safety and efficacy in older CF children (Wooldridge JL et al. J Cyst Fibros 2009; 8:405-17. [PubMed]) and seems to be an efficient preparation.
It is reassuring that the enteric coated beads do not contain the copolymer in the covering that many of us believe may have been related to the very rare but very serious fibrosing colonopathy seen is some children with CF on large doses of certain pancreatic preparations.

Jamie L Wooldridge (fig.63) is at the Saint Louis University School of Medicine, Cardinal Glennon Children’s Medical Center, St Louis, MO Division of Pulmonology/Allergy, Nemours Children’s Clinic, Jacksonville, FL Aptalis Pharma US, Bridgewater, NJ.