Helen E JoTamera J Corte Stephen J WortNeil D EvesAmanda PiperClaire Wainwright    Year in review 2015: Interstitial lung disease, pulmonary vascular disease, pulmonary function, sleep and ventilation, cystic fibrosis and paediatric lung diseaseRespirology. 2016 Apr;21(3):556-66.doi: 10.1111/resp.12749. Epub 2016 Feb 24   Free article    [PubMed]

Fig. 1 Helen Jo

There is a section on cystic fibrosis by Claire Wainwright dealing with Genotype, new therapies, adherence and mental health

Dr Helen E Jo (fig. 1) is respiratory physician  in the Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.University of Sydney, Sydney, New South Wales, Australia.

Adrienne P SavantSusanna A McColley. Pediatric Pulmonology year in review 2015: Part 4.  Pediatr Pulmonol 2016 Jul;51(7):754-65.doi: 10.1002/ppul.23470 .Epub 2016 May 12..    [PubMed]
In this article, the authors highlight cystic fibrosis (CF) research published in Pediatric Pulmonology during 2015. Articles from other journals that reflect similar themes, and those of special importance, are also included.

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.

Zemanick ET; Ong T; Daines CL; Dellon EP; Muhlebach MS; Esther CR Jr. Highlights from the 2015 North American Cystic Fibrosis Conference. [Review] Pediatr Pulmonol 2016; 51(6):650-7.   [PubMed]

Fig. 2 Edith Zemanick childrenscolorado.org

The 29th Annual North American Cystic Fibrosis Conference was held in Phoenix, Arizona on October 8-10, 2015. Abstracts were published in a supplement to Pediatric Pulmonology.(1) In this review, the authors summarise presentations in several of the topic areas addressed at the conference. Their  goal was to provide an overview of presentations with relevance to emerging or changing concepts in several areas rather than a comprehensive review. Citations from the conference are by first author and abstract number or symposium number, as designated in the supplement.

Dr Edith Zemanick (fig.2) is Associate Professor of Pediatrics – Pulmonology, University of  Colorado School of Medicine.

This is a very detailed and excellent review of the highlights of this 2015 meeting


Al-Malky G; Dawson SJ; Sirimanna T; Bagkeris E; Suri R.  High-frequency audiometry reveals high prevalence of aminoglycoside ototoxicity in children with cystic fibrosis. J Cyst Fibros 2015; 14(2):248-54. [PubMed]

Fig. 3 Ghada Al-Malky LinkedIn

Intravenous aminoglycoside (IV AG) antibiotics have ototoxic complications in some patients. Audiological monitoring, if performed, uses only standard pure-tone audiometry (PTA). This study determined the most appropriate audiological tests and to identify possible risk factors. Auditory assessment was performed using standard pure tone audiometry (PTA), extended high-frequency (EHF) audiometry and distortion-product otoacoustic emissions (DPOAE).70 CF children, mean (SD) age 10.7 (3.5) years, were recruited. Of the 63 children who received IV AG, 15 (24%) children had ototoxicity detected by EHF audiometry and DPOAE.
Standard PTA only detected ototoxicity in 13 children. Eleven of these children had received at least 10 courses of IV AG courses. A 25 to 85 dBHL hearing loss (mean+/-SD: 57.5+/-25.7 dBHL) across all EHF frequencies and a significant drop in DPOAE amplitudes at frequencies 4 to 8 kHz were detected. However, standard PTA detected a significant hearing loss (>20 dBHL) only at 8 kHz in 5 of these 15 children and none in 2 subjects who had significantly elevated EHF thresholds.
The number of courses of IV AG received, age and lower lung function were shown to be risk factors for ototoxicity. CF children who had received at least 10 courses of IV AG had a higher risk of ototoxicity.Extended high frequency audiometry identified 2 more children with ototoxicity than standard PTA and depending on facilities available, should be the test of choice for detecting ototoxicity in children with CF receiving IV aminoglycosides.

—  Both the renal toxicity and ototoxicity of intravenous aminoglycosides are of concern in people with CF particularly in view of the numerous courses over years that many patients received also the substantial quantities if inhaled tobramycin that many receive over years  It is clear that the less toxic tobramycin and not gentamicin should be used.

Dr Ghada Al-Malky (fig. 3) is Senior lecturer at University College London Ear Institute, 332 Gray’s Inn Road, London WC1X 8EE, UK.

Audrézet MP, Munck A, Scotet V, Claustres M, Roussey M, Delmas D, Férec C, Desgeorges M. Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis, genetic counseling, and mutation-specific therapy.  Genet Med. 2015 Feb; 17(2):108-16. doi: 10.1038/gim.2014.113. Epub 2014 Aug 14. [PubMed]
Newborn screening (NBS) for cystic fibrosis (CF) was implemented throughout France in 2002.  During the 8-year period, 5,947,148 newborns were screened for cystic fibrosis. The data were collected by the Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant. The mutations identified were classified into four groups based on their potential for causing disease, and a diagnostic algorithm was proposed.
Combining the genetic and sweat test results, 1,160 neonates were diagnosed as having cystic fibrosis. The corresponding incidence, including both the meconium ileus (MI) and false-negative cases, was calculated at 1 in 4,726 live births. The CF30 kit, completed with a comprehensive CFTR gene analysis, provides an excellent detection rate of 99.77% for the mutated alleles, enabling the identification of a complete genotype in 99.55% of affected neonates. With more than 200 different mutations characterized, we confirmed the French allelic heterogeneity.

—  The very good sensitivity, specificity, and positive predictive value obtained suggest that the four-tiered IRT/DNA/IRT/sweat test procedure provides an effective strategy for newborn screening for cystic fibrosis.

Marie Pierre Audrézet is at  Laboratoire de Génétique Moléculaire et d’Histocompatibilité, CHU de Brest, Brest, France [2] INSERM U1078, Brest, France.

Albert BB,Jaksic M, Ramirez J, Bors J, Carter P, Cutfield WS, Hofman PL. An unusual cause of growth failure in cystic fibrosis: A salutary reminder of the interaction between glucocorticoids and cytochrome P450 inhibiting medication. J Cyst Fibros. 2015 Jul;14(4):e9-11. doi: 10.1016/j.jcf.2014.09.007. Epub 2014 Oct 5. [PubMed]

Fig. 4 Benjamin Albert royalsociety.org.nz

A 12 ½ year old male with cystic fibrosis presented with growth failure after itraconazole was added to a treatment regimen including inhaled and intranasal glucocorticoids. Investigations showed severe adrenal suppression. This case demonstrates the potential for exogenous glucocorticoids to accumulate when their degradation is inhibited by a CYP3A4 inhibitor.

–  There are previous reports of similar problems (De Wachter E et al. 2003 [PubMed] . An important observation as both itraconazole and corticosteroids are likely to be prescribed together in people with CF Aspergillus problems.

Dr Benjamin B Albert (fig. 4) is a paediatrician and endocrinologist at the Liggins Institute, University of Auckland, Auckland, New Zealand.

Alton EW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Buchan R, et al, UK Cystic Fibrosis Gene Therapy Consortium. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.  Lancet Respir Med. 2015 Jul 3. pii: S2213-2600(15)00245-3. doi: 10.1016/S2213-2600(15)00245-3. [Epub ahead of print] [free text available]. [PubMed]

Fig. 5 Eric Alton Imperial College London

Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. The authors aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis.A randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol.Between June 12, 2012, and June 24, 2013, patients were randomly assigned, 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population.There was significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months’ follow-up (3·7%, 95% CI 0·1-7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. There was no significant difference noted in treatment-attributable adverse events between groups.

Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials.

Commentary  by Scott Bell on the Alton et al publication. Bell SC. A new phase of CFTR treatment for cystic fibrosis? Lancet Respir Med 2015; 3(9):662-663. no abstract. [PubMed]

Fig 6 Scott Bell Health Translation Queensland

After mention of the developments in CFTR treatments Scott Bell reviews in some detail the UK Gene Therapy Consortium’s randomised, double-blind, placebo-controlled, phase 2b study of multi-dose nebulised gene–liposome complex (pGM169/GL67A) in patients with cystic fibrosis (FEV 50–90% predicted) and any combination of CFTR mutation (Alton EWFW et al, 2015).  Therapy with pGM169/GL67A was well tolerated, with no excess treatment-associated adverse effects. Nasal and lower airway gene transfer analyses, showed modest concentrations of pGM169 plasmid DNA. Of the roughly one in five participants who had an improvement in FEV of more than 5%, 70% had received the gene–liposome complex. Another notable finding was that patients with more severe lung disease (FEV 49·6–69·2% predicted) tended to have a greater treatment effect (6·4%) than those with milder lung disease (FEV 69·6–89·9% predicted; treatment effect 0·2%; p=0·065).Commenting on the use of physiological saline as placebo – Bell suggested future trials should included a CFTR depleted plasma liposome placebo also effect on quality of life and pulmonary exacerbations (not an end point in this trial). He noted the increasing awareness of the complexity of the interactions between the CFTR protein and complex intracellular protein networks and suggested an even broader understanding of the cellular biology of CFTR would be necessary for successful correction of the numerous CFTR mutations.

This is the main gene therapy trial which the Gene Therapy Consortium, under the leadership of Eric Alton (fig. 5), have been working towards since their formation in 2001.

Andersen C, Kahl BC, Olesen HV, Jensen-FangeS, Nørskov-Lauritsen N. Intravenous antibiotics given for 2 weeks do not eradicate persistent Staphylococcus aureus clones in cystic fibrosis patients.  Clin Microbiol Infect. 2014 May;20(5):O285-91. doi: 10.1111/1469-0691.12406. Epub 2013 Nov 4. Full text available. [PubMed]
Staphylococcus aureus is the most commonly isolated pathogen in respiratory tract secretions from young patients with cystic fibrosis (CF), and several treatment strategies are used to control the infection. One thousand and sixty-one S. aureus isolates cultured from 2526 samples from 130 CF patients during a 2-year study period were subjected to spa typing. Intervals between positive samples and the occurrence of clone replacements were calculated in relation to courses of IV antimicrobial agents. 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). The authors concluded antibiotics significantly suppress chronic staphylococcal infection in CF, but is not associated with the eradication of persistent bacterial clones.

—   Fifty percent (65/130) of the CF patients attending the Aarhus CF clinic (one of the two major CF centres in Denmark) were chronically infected with S. aureus. The present findings are no surprise and confirm the expected failure to eradicate chronic S. aureus. As occurs with P. aeruginosa, once chronic infection is established, as appears to be the case in a surprisingly high proportion of these patients, suppression is the best one can achieve – eradication is usually impossible.
It is surprising that in so many clinics S. aureus infection is not treated as early and aggressively as is P. aeruginosa, where chronic infection was at one time considered to be inevitable but can usually be avoided by early aggressive antibiotic treatment. It is interesting that the incidence of chronic S. aureus infection in the other Danish CF Centre in Copenhagen was only 14% where a more aggressive anti-staphylococcal policy has been adopted for many years (Dalboge CS et al, 2013 [PubMed])

C Andersen is at the Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark.

Andres Floto R, Haworth CS. The growing threat of non-tuberculous mycobacteria in CF. J Cyst Fibros 2015; 14(1):1-2. Editorial. [PubMed]

Fig. 7 R Andres Floto royal papworth.nhs.uk

The authors note the recent growing awareness of the threat of non-tuberculous mycobacteria (NTM) to individuals with cystic fibrosis (CF) and an increasing appreciation of the difficulties in screening, diagnosing and treating NTM-pulmonary infection in the context of CF lung disease. They provide a useful summary of the present situation.  There are two main groups of NTM that cause the majority of infections in individuals with CF: the Mycobacterium avium complex (MAC) consisting of M. avium, M. intracellulare and M. chimaera; and the M. abscessus complex (MABSC) made up of three subspecies, M. abscessus spp. abscessus, M. abscessus. spp. massiliense and M. abscessus spp. bolettii. While MAC is the more common infection in the US [PubMed], studies have suggested that MABSC is more frequent in Europe [PubMed] and elsewhere [PubMed]. Moreover, the rates of MABSC infection appear to be rising across the world[PubMed]; CFF Registry 2010]; a positive sputum culture for MABSC is more likely to indicate the presence of NTM-mediated lung damage (termed ‘NTM pulmonary disease’) rather than asymptomatic colonisation [PubMed]; and treatment of MABSC remains extremely difficult.

Prof. R Andres Floto (fig.7) is a Wellcome Trust Investigator and Professor of Respiratory Biology in the Molecular Immunity Unit of the University of Cambridge.

Banton GL, Hall GL, Tan M, Skoric B, Ranganathan SC, Franklin PJ, Pillow JJ, Schulzke SM, Simpson SJ. Multiple breath washout cannot be used for tidal breath parameter analysis in infants. Pediatr Pulmonol. 2015 Oct 5. doi: 10.1002/ppul.23326. [Epub ahead of print][PubMed]

Fig. 8 Giorgia L Banton telethonkids.org.au

Multiple breath washout (MBW) testing with SF6 gas mixture is routinely used to assess ventilation distribution in infants. It is currently unknown whether SF6 changes tidal breathing parameters during MBW in infants. We investigated if SF6 does change tidal breathing parameters in infants and whether a separate tidal breathing trace prior to MBW testing is necessary.The authors found differences in tidal breathing parameters during MBW testing with SF6 in infants. It is, therefore, important to measure a separate tidal breathing trace in room air, prior to MBW testing to ensure rigour of tidal breath indices derived from analysis.

Georgia L Banton (fig.8) is a researcher at the Telethon Kids Institute, University of Western Australia, Subiaco, Australia.

Bar-On O; Mussaffi H; Mei-Zahav M; Prais D; Steuer G; Stafler P; Hananya S; Blau H. Increasing nontuberculous mycobacteria infection in cystic fibrosis. J Cyst Fibros 2015; 14(1):53-62.  [PubMed]
Patient records, 2002-2011, were reviewed for NTM infection. FEV1, pancreatic function, sputum microbiology, and serum cytokines were compared in patients with and without NTM infection.The incidence of NTM infection increased from nil in 2002 to 8.7% in 2011 (p<0.001). NTM infection prevalence increased 3-fold from 5% (4/79) in 2003 to 14.5% (16/110) in 2011 (p=0.05).  NTM incidence and prevalence have increased dramatically in the CF clinic in the Graub CF Center in Israel, associated with a severe CF genotype and phenotype. M. abscessus, the most prevalent NTM, caused prolonged infection despite therapy. There has been some decrease in the prevalence of NTM lung disease since 2009.

–  A useful record of longitudinal experience from a major clinic in Israel documenting the increasing problem of non-tuberculous mycobacterial infection.

Ophir Bar-On is at the Graub CF Center, Pulmonary Institute, Schneider Children’s Medical Center of Israel, Israel.

Berkhout MC, van Velzen AJ, Touw DJ, de Kok BM, Fokkens WJ, Heijerman HG.  Systemic absorption of nasally administered tobramycin and colistin in patients with cystic fibrosis.  Antimicrob Chemother 2014; 69(11):3112-5. doi: 10.1093/jac/dku239. Epub 2014 Jul 11. [PubMed]

Fig. 9 Mevrouw Berkhout ziekehuisamstelland.nl

A study was to investigate the systemic absorption of nasally administered tobramycin (300mg), colistin (administered as colistin sulfomethate sodium; CMS 160mg) and a combination of same doses of both drugs using systemic absorption as surrogate for safety. In addition, tolerability of the nasal irrigations was examined.In ten adult patients nasal irrigations with tobramycin, CMS and a combination of tobramycin and CMS resulted in safe serum levels and were well tolerated. Following the tobramycin and the combined irrigation, only two patients had detectable tobramycin serum levels, with the highest being 0.054 mg/L. Serum levels of colistin A and B were not detectable.

—   The possibility of absorption of topically administered aminoglycosides is a concern in patients requiring repeated or longterm administration by inhalation. Although the amount absorbed appears to be small, the repeated or chronic exposure could be a significant factor as has been shown in a number of studies. Also, tobramycin inhalations to the chest using eFlow nebulisers may result in potentially worrying serum levels over 1mg/L, raised urinary NAG levels suggesting the possibility of renal toxicity .(Guy EL et al. 2010. [PubMed]

Mevrouw  C Berkhout (fig. 9) is in the Department of Pulmonology, Haga Teaching Hospital, Leyweg 275, 2545 CH The Hague, The Netherlands

Beam KT, Coop CA. Steroid sparing effect of omalizumab in seropositive allergic bronchopulmonary aspergillosis. Allergy Rhinol (Providence). 2015 Jan;6(2):143-5. doi: 10.2500/ar.2015.6.0128. [PubMed]
A patient with CF with serologic ABPA who did not tolerate therapy with antifungals, was able to significantly reduce (by nearly 80%) her average daily steroid use while receiving anti-IgE therapy with omalizumab added to her other respiratory medications.

—  Omalizumab may reduce corticosteroid dependence in patients with allergic bronchopulmonary aspergillosis for patients unable to tolerate antifungals, though the authors warn the use may be limited by cost.  Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that specifically binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid and to membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes (Schulman ES. Am J Respir Crit Care Med 2001; 164(8 Pt 2):s6-11. [PubMed]).

Keith T Beam is in the Department of Medicine, San Antonio Military Medical Center, San Antonio, Texas, USA.

Bielicky L; Braun-Falco M; Ruzicka T; Maier T.  Aquagenic wrinkling of the palms: morphological changes in reflectance confocal microscopy and high-definition optical coherence tomography. Dermatology 2015; 230(3):208-12 pubmed.ncbi.nlm.nih.gov/25660502/

Fig. 11. Top: pre-ivacaftor
Lower: after ivacaftor

Aquagenic wrinkling of the palms (AWP) is a rare condition, which is characterized by appearance of whitish papules and plaques, and an excessive wrinkling and swelling of the palmar skin after exposure to water. In most cases, young women are affected, and an association of AWP with cystic fibrosis (CF) has been described.Two cases of AWP, not related to CF, in whom we used two innovative imaging techniques, namely high-definition optical coherence tomography and reflectance confocal microscopy, to show in vivo skin changes occurring after exposure of the skin to tap water in comparison to the findings in a healthy control person.

The image is from Grasemann H et al. Aquagenic wrinkling of the palms in a patient with cystic fibrosis. N Eng J Med 2013; 369:2362-2363. Letter.

The patient’s palm (fig. 11) is shown before (top Panel A) and after (Panel B) 1 month of treatment with ivacaftor. The images shown were obtained after the patient’s left hand was submerged in a water bath at 37°C for 5 minutes.

Lea Bielicky is in the Department of Dermatology and Allergology, Ludwig Maximilian University of Munich, Munich, Germany.

Bodewes FA; Verkade HJ; Taminiau JA; Borowitz D; Wilschanski M; Working group Cystic Fibrosis and Pancreatic Disease of the European Society for Paediatric Gastroenterology.  Cystic fibrosis and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR modulation.  Hepatology and Nutrition (ESPGHAN).  J Cyst Fibros 2015;14(2):169-77.    [PubMed]

Fig. 12 Frank Bodewes umcg.nl

The currently available and accepted clinical endpoints, FEV1 and BMI, have limitations. The aim of this report is to draw attention to the need and the ample possibilities for the development and validation of relevant gastrointestinal clinical endpoints for scientific evaluation of CFTR modulation treatment, particularly in young children and infants.
The gastrointestinal tract offers very good opportunities to measure CFTR protein function and systematically evaluate CF related clinical outcomes based on the principal clinical gastrointestinal manifestations of CF: intestinal pH, intestinal transit time, intestinal bile salt malabsorption, intestinal inflammation, exocrine pancreatic function and intestinal fat malabsorption.

—  The article contains a descriptive analysis of a variety of gastrointestinal outcome measures for clinical relevance, reliability, validity, responsiveness to interventions, feasibility in particular in young children and the availability of reference values.
An attractive feature of the new drugs that they directly affect CFTR function in that they act systemically and not merely on the airways. Already changes in pancreatic function and insulin production are described in patients on ivacaftor (Belin MD et al. 2013. [PubMed]).Some such form of extrapulmonary measure of change in CFTR function may be helpful particularly in young children where respiratory function tests are a problem.

Frank A J Bodewes (fig.12)  is at the Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands.

Burgess JC, Bridges N, Banya W, Gyi KM, Hodson ME, Bilton D, Simmonds NJ.  HbA1c as a screening tool for cystic fibrosis related diabetes.  J Cyst Fibros. 2015 Apr 10. pii: S1569-1993(15)00068-5. doi: 10.1016/j.jcf.2015.03.013. [Epub ahead of print] [PubMed]
Early diagnosis of cystic fibrosis (CF) related diabetes (CFRD) is important to improve outcomes. International guidelines recommend an oral glucose tolerance test (OGTT) for all CF patients aged ≥10years – this approach is controversial.   The aim of this study was to develop an effective screening tool and reduce the need for a universal OGTT.Adult CF patients (without CFRD) attending an annual review assessment were recruited prospectively (March 2009-July 2012) into two sequential studies – a primary investigative study followed by validation study. All patients underwent an OGTT and were simultaneously screened by predetermined biochemical/clinical criteria to identify their risk of CFRD. A sensitivity/specificity analysis was performed using the World Health Organisation diabetes criteria as gold standard; modifications were made to improve the screening tool’s accuracy and determine the optimal screening thresholds.
This was tested in the validation study.429 patients (primary, n=94; validation, n=335: mean age=31.7±10.4(SD), 43% female, 77% on pancreatic supplements). Primary study: in predicting a positive OGTT, the test sensitivity was 66.7% and specificity 60%. HbA1c was carried over to the validation study as it was the most discriminative (optimal threshold ≥5.8% (40mmol/mol); receiver operating curve, ROC, score 0.60). Validation study: the number of patients with a normal, impaired and diabetic OGTT was 268(80%), 51(15.2%) and 16(4.8%), respectively. HbA1c provided a test sensitivity, specificity and ROC score of 93.8%, 53.0% and 0.73, respectively.
The authors conclude the use of HbA1c≥5.8%(40mmol/mol) is an effective tool for CFRD screening and reduced the need for an OGTT by 50.7%.

Comment: Marie-Angela Schnyder, Christian Benden, Christoph Schmid  HbA1c: An effective screening tool for cystic fibrosis related diabetes? Caution “Overall, we concur that clinical criteria remain important in diagnostic strategies and treatment decisions, and that in CF patients in good clinical condition, low HbA1c could possibly serve as a tool to reduce the number of oGTTs; however, we strongly recommend oGTTs in patients with advanced CF lung disease and poor clinical condition with a high pretest probability of insulinopenia; since these patients may well benefit from insulin treatment, beyond the control of hyperglycaemia, ideally improving muscle and lung functions”

Comment: John Widger, Shihab Hameed, Chee Y. Charles VergeUsing HbA1c as a screening tool for Cystic Fibrosis Related Diabetes  DOI:
Support “The HbA1c is a relatively cheap and simple one off blood test that would seem to fit the brief perfectly”.

Juliana C Burgess is a Research Nurse at the National Heart and Lung Institute, Imperial College, London, United Kingdom; Adult Cystic Fibrosis Centre, Royal Brompton Hospital, London, United Kingdom.

Bernarde C, Keravec M, Mounier J, Gouriou S, Rault G, Férec C, Barbier G, Héry-Arnaud G. Effect of the CFTR-Potentiator Ivacaftor on Airway Microbiota in Cystic Fibrosis Patients Carrying A G551D Mutation. PLoS One. 2015 Apr 8;10(4):e0124124. doi: 10.1371/journal.pone.0124124. eCollection 2015. [PubMed]
The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyro-sequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment.

129 operational taxonomy units (OTUs), representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01) and that of Streptococcus 1 (S. mitis group) decreased (p<0.05), possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05). The study confirmed the presumed positive role of anaerobes in lung function.

The authors concluded that several airway microbiota components, notably anaerobes (obligate or facultative anaerobes), could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.

—   Another potentially important consequence of taking ivacaftor. It is reassuring that the varieus additional effects of the drug are receiving attention as well as the dramatic effects on the usual measured parameters.

Cédric Bernarde is at EA 3882-Laboratoire Universitaire de Biodiversité et Ecologie Microbienne, Université de Brest, Brest, France.

Burgel PR, Bellis G, Olesen HV, Viviani L, Zolin A, Blasi F, Elborn JS; ERS/ECFS Task Force on The Provision of Care for Adults with Cystic Fibrosis in Europe. Future trends in cystic fibrosis demography in 34 European countries.Eur Respir J. 2015 Mar 18. pii: ERJ-01963-2014. [Epub ahead of print] [PubMed]

Fig. 13 Pierre-Regis Burgel ResearchGate.net

The aim of this study was to estimate the number of children and adults with CF in 34 European countries by 2025. Western European countries’ forecasts indicate that an increase in the overall number of CF patients by 2025, by approximately 50%, corresponds to an increase by 20% and by 75% in children and adults, respectively. In Eastern European countries the projections suggest a predominant increase in the CF child population, although the CF adult population would also increase.  It was concluded that a large increase in the adult CF population is expected in the next decade. A significant increase in adult CF services throughout Europe is urgently required.

Pierre-Regis Burgell (fig. 13) is at the Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Casciaro R, Naselli A, Cresta F, Ros M, Castagnola E, Minicucci L. Role of nebulized amphotericin B in the management of allergic bronchopulmonary aspergillosis in cystic fibrosis: Case report and review of literature.  J Chemother. 2015 Oct;27(5):307-11. doi: 10.1179/1973947814Y.0000000194. Epub 2014 May 14. [PubMed]

Fig. 14  Rosaria Casciario. fibrosicisticaricerca.it

The authors used nebulized liposomal amphotericin B (L-AMB) in a patient affected by CF, complicated by ABPA. The previous combined treatment with oral steroids and azoles had no respiratory benefit and caused relevant side effects. Amphotericin B has always been well tolerated and permitted a slight steroid tapering. They also observed benefits in pulmonary function and laboratory tests.

—   Few data are available in literature about the use of nebulized AMB in CF and there are no RCTs evaluating anti-fungals in CF-ABPA. In this reviewer’s  opinion, the reported case suggests that nebulized L-AMB could represent a possible strategy in ABPA management in CF patients.
There is an encouraging later RCT of nebulised budesonide +/- amphotericin in 21 asthmatic patients with ABPA. Over a year 66.7% of the controls but only 8.3% of the treated patients had exacerbations of their ABPA (Ram et al.2016.[PubMed])

Rosaria Casciari (fig. 14) is at the Cystic Fibrosis CenterIRCCS Istituto Giannina Gaslini, Genova, Italy

Carter S, Kelly S, Caples E, Grogan B, Doyle J, Gallagher CG, McKone EF.  Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T.  J Cyst Fibros. 2015 Jul; 14(4):e4-5. doi: 10.1016/j.jcf.2015.01.010. Epub 2015 Feb 16. 

Fig. 15 Suzanne Carter irishthoracicsociety.com

R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor.  A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease.  The authors report a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease.

A 45-year-old male with CF (F508del/R117H/IVS8-5T/9T), was diagnosed at the age of 16 years old. His CF is complicated by advanced lung disease (FEV1=31% predicted, SaO2=95% on 1l O2 at rest), chronic infection with Burkholderia multivorans and pancreatic insufficiency (faecal elastase=135mcg/g (normal>200mcg/g)); frequent exacerbations necessitated continuous IV antibiotic therapy. There was substantial improvement on inacaftor therapy. After 5 months of treatment, his weight is up by 4.3kg with an increase in FEV1 to 1.50l (42% predicted). Immediate improvements in FEV1 were seen at 2weeks and continued up to a peak at day 75.  The patient also reports improved sputum volume and colour although is still growing B. multivorans in his sputum. Exercise capacity is much improved with an improvement in 6-minute walk test distance and decreased oxygen requirements at rest and with exercise. CRP levels have reduced to between 14 and 28mmol/l, the lowest seen in 12months. Faecal elastase is now in the normal range (355mcg/g; repeat 1month later 492mcg/g). Sweat chloride on ivacaftor has reduced to 46mmol/l. As a result, his continuous iv antibiotics have now been stopped and on 28th March he was taken off the active lung transplant list. To date, he continues to do well and is being followed closely by his CF team in conjunction with the lung transplant team.

—  There are useful references in the paper to the various mutations that respond to ivacaftor therapy (Van Goor F et al. J Cyst Fibros 2014; 13(1):29-36.[PubMed]) including the R117H-CFTR mutation (Moss RB et al. J Cyst Fibros 2014; 13(S2):44).
The improvement in faecal elastase is interesting and has been noted previously (Bellin et al. 2013. [PubMed]; Hayes D et al. 2014. [PubMed])  It is tempting to speculate that early ivacaftor therapy may delay or even avoid diabetes mellitus which is such a burden to people with CF.

Dr Suzanne Carter (Fig. 15) is a consultant physician at the National Referral Centre for Adult Cystic Fibrosis, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland.

Calabrese C; Tosco A; Abete P; Carnovale V; Basile C; Magliocca A; Quattrucci S; De Sanctis S; Alatri F; Mazzarella G; De Pietro L; Turino C; Melillo E; Buonpensiero P; Di Pasqua A; Raia V. Randomized, single blind, controlled trial of inhaled glutathione vs. placebo in patients with cystic fibrosis. J Cyst Fibros 2015; 14(2):203-10. [PubMed]
Fifty four adult and 51 pediatric patients were randomised to receive inhaled GSH or placebo twice daily for 12 months.  Twelve months treatment with inhaled GSH did not achieve the predetermined primary outcome measure of 15% improvement in FEV1%. Only in patients with moderate lung disease, 3, 6 and 9 months therapy with GSH resulted in a statistically significant increase of FEV1 values from the baseline. Moreover GSH therapy improved 6-minute walking test in pediatric population. GSH was well tolerated by all patients.The authors concluded that based on the results of this clinical trial, the treatment with inhaled GSH is assumed to lead an almost immediate improvement in the FEV1 in patients with moderate lung disease, a stabilization of BMI in adult population and an improvement of 6 minute walking test in children. In a prospective observational study that is currently ongoing in their center they have selected Lung Clearance Index as a more sensitive alternative to spirometry for detecting efficacy of GSH therapy also in patients with CF and mild lung disease. inhaled GSH has slight positive effects in CF patients with moderate lung disease warranting further study.

— The literature on the use of glutathione in CF is mounting but its apparent modest effects are not of a degree that would encouraged clinicians to introduce it into their patients’ already complicated treatment regimens.

Cecilia Calabresee is in the Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Italy.

Castellani C, Massie J. Newborn screening and carrier screening for cystic fibrosis: alternative or complementary? Eur Respir J. 2014 Jan;43(1):20-3. 10.1183/09031936.00125613. Free full text [PubMed]
After an interesting review of the two methods of screening the authors conclude CF newborn and carrier screening have complementary roles and neither can replace the other. In contrast to newborn screening, carrier screening allows informed reproductive choices before the birth of a child with CF. Carrier screening may get infants into medical care earlier than newborn screening, but would miss more affected babies.

—  Both population carrier screening and newborn CF screening should be available in an ideal world. Unfortunately and understandably, the new very effective mutation specific drugs have overshadowed the fact that CF is now a virtually totally preventable disease and has been for over 20 years.

Castellani C, Picci L, Tridello G, Casati E, Tamanini A, Bartoloni L, Scarpa M, Assael BM. Cystic fibrosis carrier screening effects on birth prevalence and newborn screening.  Genet Med. 2015 Jun 18. doi: 10.1038/gim.2015.68. [Epub ahead of print] [PubMed]

Fig. 16 Carlo Castellani receiving the 2015 ECFS Award from Kris De Boeck

The effects of cystic fibrosis (CF) carrier screening on birth prevalence trends and newborn screening (NBS) efficiency were compared in two Italian regions; carrier screening was performed in one region (eastern region (ER)) and not in the other (western region (WR)).Annual births of infants with CF, NBS false-positive results, NBS uncertain diagnoses (borderline sweat chloride (BSC)), carrier tests performed, and carriers detected were monitored during the 1993-2013 period.A total of 259 newborns with CF were detected. In the ER  (carrier screening), 150 carrier couples were found. Mean annual percentage of birth prevalence decrease was 9% per 10,000 (P = 0.002) and was greater in the ER (15%, P = 0.0008; WR 1%, P = ns). The WR (no carrier screening) estimated birth prevalence was 1/3,589 in 1993 and 1/3,870 in 2013; in the ER it was 1/2,730 in 1993 and 1/14,200 in 2013. The ER birth prevalence correlated inversely with the number of carrier couples (P = 0.0032). The ratio between CF cases and NBS-positive results significantly decreased in the ER (1.6%, P = 0.0001) but not in the WR. The ratio between prevalence of BSC and of CF cases increased in the ER (P = 0.008) but not in the WR (P = 0.1).

—  Carrier screening was associated with a decrease in birth prevalence of CF. This is the experience in all regions where neonatal CF screening is introduced.  Poorer newborn screening performance was observed in the carrier screening area.

Conrad C; Lymp J; Thompson V; Dunn C; Davies Z; Chatfield B; Nichols D; Clancy J; Vender R; Egan ME; Quittell L; Michelson P; Antony V; Spahr J; Rubenstein RC; Moss RB; Herzenberg LA; Goss CH; Tirouvanziam R.  Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.  J Cyst Fibros 2015; 14(2):219-27.  [PubMed]

Fig 17 Carol Conrad stanfordchildrens.org

To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways, a multicenter, randomized, double-blind proof of concept study was performed in which 70 CF subjects received NAC or placebo orally thrice daily for 24 weeks. Primary endpoints were change in sputum human neutrophil elastase (HNE) activity; secondary, FEV(1) and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF.Lung function (FEV(1) and FEF(25-75%)) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log(10). Human neutrophil elastase activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14).The authors concluded NAC recipients maintained their lung function while placebo recipients declined (24 week FEV1 treatment effect =150 mL, p<0.02). However, no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. They suggested further studies on mechanism and clinical outcome are warranted.

— Most studies with glutathione or acetylcysteine (usually oral) in CF seem to show very modest improvement in either the antioxidant status or respiratory function. However, the treatment is still not recommended in the UK by the Cochrane Reviewers for treatment of people with CF (Cochrane Database Syst Rev2013;7:CD007168). More positive evidence is required for a drug to take its place amongst the vast number of treatments patients are expected to take.  (280 papers have been appearing on this drug since 1963!!)

Carol Conrad (fig.17) is Associate Professor of Pediatrics at the Lucile Packard Children’s Hospital, Center of Excellence in Pulmonary Biology, 770 Welch Rd., #350, Stanford University, Palo Alto, CA 94304, United States.

Chang EH; Tang XX; Shah VS; Launspach JL; Ernst SE; Hilkin B; Karp PH; Abou Alaiwa MH; Graham SM; Hornick DB; Welsh MJ; Stoltz DA; Zabner J. Medical reversal of chronic sinusitis in a cystic fibrosis patient with ivacaftor. Forum of Allergy & Rhinology 2015; 5(2):178-81.   [PubMed]

Fig. 18 Eugene H Chang  University of Arizona

Case report of 1 patient with long-standing chronic sinus disease and a new diagnosis of CF with a mild mutation (P205S) and a severe mutation (G551D). Clinical changes in symptoms, radiographic findings, nasal potential difference testing, and nasal pH values before and after treatment with ivacaftor are reported.
The authors then developed primary sinonasal epithelial cell cultures from a biopsy of the patient to determine changes in airway surface liquid (ASL) pH and ASL viscosity after ivacaftor treatment.Ivacaftor treatment reversed CT findings of CF sinus disease, increased nasal voltage and pH, and resolved sinus symptoms after 10 months of therapy. Ivacaftor significantly increased ASL pH and decreased ASL viscosity in primary airway cultures.
The authors state that this report documents the reversal of CF sinus disease. Based on their in vivo and in vitro results, they speculate that ivacaftor may reverse CF sinusitis by increasing ASL pH and decreasing ASL viscosity.

Eugene H Chang (fig.18) is a Fellow  at the Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA. Subsequently he was Professor of Otolaryngology-Head and Neck Surgery, University of Arizona.

Davis SD, Ratjen F, Brumback LC, Johnson RC, Filbrun AG, Kerby GS, Panitch HB, Donaldson SH, Rosenfeld M; ISIS Study Group. Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis. J Cyst Fibros. 2015 Nov 4. pii: S1569-1993(15)00249-0. doi: 10.1016/j.jcf.2015.10.007. [Epub ahead of print]  [PubMed]

Fig. 19 Stephanie D Davis unchealthcare.org

The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilise infant pulmonary function tests (iPFTs) as an endpoint. However, the authors concluded iPFTs are, as yet, not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. However, they suggest raised volume measures have potential to serve as secondary endpoints in future clinical CF trials.

Stephanie D Davis (fig.19) is in the Section of Pediatric Pulmonology, Allergy and Sleep Medicine, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA. Subsequently, in 2018 Chair of the Department of Pediatrics at the UNC School of Medicine and Physician in Chief of UNC Children’s Hospital

Davies J, Sheridan H, Bell N, Cunningham S, Davis SD, Elborn JS, Milla CE, Starner TD, Weiner DJ, Lee PS, Ratjen F.  Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial.  Lancet Respir Med. 2013 Oct;1(8):630-8. doi: 10.1016/S2213-2600(13)70182-6. Epub 2013 Sep 10. pubmed.ncbi.nlm.nih.gov/24461666/

Fig.20 Jane Davies imperial.ac.uk

Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV1) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry.
The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV1 >90% predicted.
This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV1 >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg.
Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days’ treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI.

Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group).Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor.

The authors concluded that in patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in Lung Clearance Index. They suggested that LCI might be a more sensitive alternative to FEV1 in detecting response to intervention in these patients with mild lung disease.

Jane Davies (fig.20) is Professor of Paediatric Respiratory Medicine and Experimental Medicine, National Heart and Lung Institute and Hon. Consultant at the  Royal Brompton Hospital  London, England, UK.

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; Human Genetics Society of Australasia.   Human Genetics Society of Australasia position statement: population-based carrier screening for cystic fibrosis. Twin Res Hum Genet. 2014 Dec;17(6):578-83. doi: 10.1017/thg.2014.65.   [PubMed]

Fig. 21 Martin Delatycki mcri.edu.au

Since 1989 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 counseling 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.

—  These are welcome recommendations.  It is important to emphasise that CF is now a preventable disorder although in many countries, such as the UK, advantage of the opportunity to identify CF carriers in the general population or antenatal clinic is not being taken for a variety reasons – not always financial.

Martin Delatycki (fig. 21 ) is Professor and Clinical  Geneticist Murdoch Children’s Research Institute and at Clinical Genetics, Austin Health,Melbourne,Victoria,Australia.

Dell’Edera D, Benedetto M, Gadaleta G, Carone D, Salvatore D, Angione A, Gallo M, Milo M, Pisaturo ML, Pierro G, Mazzone E, Epifania AA.  Analysis of cystic fibrosis gene mutations in children with cystic fibrosis and in 964 infertile couples within the region of Basilicata, Italy: a research study.  J Med Case Rep. 2014 Oct 10;8:339. doi: 10.1186/1752-1947-8-339.  [PubMed]

Fig. 22 Domenico Dell’Edera

This study reports the results of a molecular screening of cystic fibrosis using DNA samples of patients enrolled from January 2009 to December 2013. Patients were referred for cystic fibrosis screening for infertile couples. In addition, gene mutations were identified in 76 patients affected by cystic fibrosis in the pediatric population of Basilicata.
In the 964 infertile couples examined, 132 subjects (13.7%) (69 women and 63 men) were heterozygous for one of the CFTR mutations, with an occurrence of carriers of 6.85%. The occurrence of carriers in infertile couples is significantly higher from the hypothetical value of the general population (4%).In the Basilicata region of Italy the CFTR phenotype is caused by a small number of mutations. The authors aim to develop a kit able to detect not less than 96% of CTFR gene mutations.

–    Not sure if there is any general message here other than, in this particular region, the incidence of CF carriers in infertile couples is slightly higher than in the general population.

Domenico Dell’Edera (fig. 22) is in the Unit of Cytogenetics and Molecular Genetics, ‘Maddonna delle Grazie Hospital’, street Cattedra Ambulante, 75100 Matera, Italy.

Diwakar A, Adam RJ, Michalski AS, Tamegnon MM, Fischer AJ, Launspach JL, Horan RA, Kao SC, Chaloner K, Meyerholz DK, Stoltz DA. Sonographic evidence of abnormal tracheal cartilage ring structure in cystic fibrosis.  Laryngoscope. 2015 Oct;125(10):2398-404. doi: 10.1002/lary.25255. Epub 2015 Mar 30. [PubMed]

Fig. 23 Amit Diwaker

Tracheal cartilage ring structural abnormalities have been reported in CF mice and pigs. Whether similar findings are present in humans with CF is unknown.Tracheal cartilage ring size and shape were measured in adults with (n= 21) and without CF (n = 18).Ultrasonography was used in human subjects to noninvasively assess tracheal cartilage ring structure in both the sagittal and the transverse planes. Tracheal cartilage ring thickness was also determined from histological sections obtained from newborn non-CF and CF pigs. These values were compared with human data.Human CF tracheas had a greater width and were less circular in shape compared to non-CF subjects. CF tracheal cartilage rings had a greater midline cross-sectional area and were thicker compared to non-CF rings. Maximal tracheal cartilage ring thickness was also greater in both newborn CF pigs and human adults with CF, compared to non-CF controls.The authors’ findings demonstrate that structural differences exist in tracheal cartilage rings in adults with CF. Comparison with newborn CF pig data suggests that some of these changes may be congenital in nature.

Amit Diwacker (fig.23)   Fellowship at the Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa. Subsequently in Critical Care Medicine at Akron

Doumit M; Jaffe A. Use of the Lung Flute for sputum induction in children with cystic fibrosis: a pilot study. Pediatr Pulmonol 2015; 50(4):340-3. [PubMed]

Fig 24. Lung flute

This study aimed to assess the effectiveness of the Lung Flute (fig. 24) in obtaining a sputum sample from children with cystic fibrosis (CF) that were not productive of sputum with coughing alone. Children attending an outpatient CF clinic who were not able to provide a sample with coughing alone were eligible. Each child used the Lung Flute on two occasions at least one month apart. The primary outcome was expectoration of a sputum sample. The authors found the lung flute to be clinically useful and an easy device for sputum induction in children with CF. They suggested further research comparing its effectiveness to other sputum induction methods is  warranted.

Fig. 25 Michael Doumit UNSW Sydney

–   The lung flute is a medical device used to clear mucus from congested lungs with low-frequency sound waves. The device consists of a mouthpiece and a plastic reed which vibrates within a chamber to create sound waves in the chest cavity. These sound waves vibrate and break up mucus deposits in the lungs, allowing cilia to more easily move these deposits from the lungs to the throat.  The lung flute was granted approval by the FDA in 2010 for use in patients with chronic obstructive pulmonary disease.

Michael Doumit (fig. 25) is at Sydney Children’s Hospital, University of New South Wales, Sydney, Australia.

Driessche KV, Hens N, Tilley P, Quon BS, Chilvers MA, de Groot R, Cotton MF, Marais BJ, Speert DP, Zlosnik JE. Surgical Masks Reduce Airborne Spread of Pseudomonas  aeruginosa in Colonized Patients with Cystic Fibrosis. J Respir Crit Care Med. 2015 Oct 1;192(7):897-9. doi: 10.1164/rccm.201503-0481LE[PubMed]

Fig. 26 Keon Vanden Driessche LinkedIn.com

Extract from the letter. – “The controlled human aerosol model used in our study produced relatively precise and repeatable results despite a small sample size. Among patients with CF colonised with P. aeruginosa and producing infectious aerosol particles (55%), we demonstrated a greater than 80% reduction in infectious aerosol particle production when wearing a surgical mask while coughing.  Our data provide evidence for the new Cystic Fibrosis Foundation guideline to wear surgical masks in healthcare settings”.

Keon Vandal Driessche (fig. 26) is at the The University of British Columbia Vancouver, British Columbia, Canada. Subsequently  Infectious Diseases Specialist for Children, Antwerp University Hospital.

Dziekiewicz MA, Banaszkiewicz A, Urzykowska A, Lisowska A, Rachel M, Sands D, Walkowiak J, Radzikowski A, Albrecht P. Gastroesophageal Reflux Disease in Children with Cystic Fibrosis. Exp Med Biol. 2015 Aug 19. [Epub ahead of print][PubMed]

Fig. 27 Marcin Dziekiewicz noblemedicine.pl

Gastroesophageal reflux (GER) was diagnosed in 24/44 (54.5%) children with CF. In 14/44 patients typical GER symptoms were present. The authors confirm that the incidence of GER in children with cystic fibrosis is very high but in the majority of patients typical GER symptoms are absent. They emphasise classical pH-metry may not constitute a sufficient diagnostic method in this population because of a relatively high number of proximal reflux episodes indicating an increased risk of aspiration. The pH-impedance diagnostic measurement is advocated when suspecting GER in children with cystic fibrosis.

–   The impedance–pH-monitoring test determines if the patient’s symptoms are related either to acid reflux, to non-acid reflux, or not related to reflux of any type.

Marcin A Dziekiewicz (fig. 27) is an assistant professor at the Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, 1 Dzialdowska St., 01-184, Warsaw, Poland

Elborn JS, Bell SC, Madge SL, Burgel PR, Castellani C, Conway S, De Rijcke K, Dembski B, Drevinek P, Heijerman HG, Innes JA, Lindblad A, Marshall B, Olesen HV, Reimann AL, Solé A, Viviani L, Wagner TO, Welte T, Blasi F. Report of the European Respiratory Society/European Cystic Fibrosis Society task force on the care of adults with cystic fibrosis.  Eur Respir J. 2016 Feb; 47(2):420-8. doi: 10.1183/13993003.00592-2015. Epub 2015 Oct 9.[PubMed]
The improved survival in people with cystic fibrosis has led to an increasing number of patients reaching adulthood. This trend is likely to be maintained over the next decades, suggesting a need to increase the number of centres with expertise in the management of adult patients with cystic fibrosis. These centres should be capable of delivering multidisciplinary care addressing the complexity of the disease, in addition to addressing the psychological burden on patients and their families. Further issues that require attention are organ transplantation and end of life management.Lung disease in adults with cystic fibrosis drives most of the clinical care requirements, and major life- threatening complications, such as respiratory infection, respiratory failure, pneumothorax and haemoptysis, and the management of lung transplantation require expertise from trained respiratory physicians. The taskforce therefore strongly recommends that medical leadership in multidisciplinary adult teams should be attributed to a respiratory physician adequately trained in cystic fibrosis management.

–   The task force of distinguished CF experts  suggests the implementation of a core curriculum for trainees in adult respiratory medicine and the selection and accreditation of training centres that deliver postgraduate training to the standards of the HERMES programme.

Ellemunter H, Eder J, Fuchs S, Gappa M, Steinkamp G. Long-term improvement of lung clearance index in patients with mild cystic fibrosis lung disease: Does hypertonic saline play a role? J Cyst Fibros. 2015 Jul 16. pii: S1569-1993(15)00162-9. doi: 10.1016/j.jcf.2015.06.009. [Epub ahead of print] [PubMed]

Fig 28. Helmut Ellemunter

A study to assess effect of long-term inhalation of hypertonic saline (HS). 34 patients with mild lung disease (FEV1≥70% of predicted) had at least one LCI result before and ≥2 LCI measurements after start of hypertonic saline (HS) therapy. After a mean follow-up of 39.7 (SD 7.4) months after starting HS, LCI improved significantly from 7.89 (SD 1.35) at baseline to 6.96 (SD 1.03), and 19/34 patients had a normal LCI value at the last measurement. No decrease in mean FEV1 was observed. Thus, ventilation inhomogeneity can improve in patients with mild lung disease.

—   The authors, whilst admitting the obvious drawbacks of the study, in particular the retrospective file evaluation of longitudinal MBW and spirometry measurements, observed a statistically significant and clinically relevant improvement in LCI over three years of hypertonic saline inhalation, in parallel with stable FEV1 results. This was in sharp contrast to the one percent yearly decline in FEV1 observed before starting HS. They suggest that the deterioration of lung disease can be halted in mildly affected patients, provided that early lung disease is detected with sensitive methods and treatment is adjusted accordingly.

A number of previous publications have reported normal LCI values for children (Fuchs SI et al 2009 [PubMed]). Mean LCI (SD) on three occasions was 6.2 (0.4), 6.3 (0.4), and 6.0 (0.4) at the 1st, 2nd, and 3rd test. The upper limit of normal was 7.0 for all subjects. Within-test repeatability was 5.1%. Short-term reproducibility (1st test vs. 2nd test) was 4.2% with a mean difference of -0.13 (95% CI -0.350; 0.087). Long-term reproducibility (1st test vs. 3rd test) was 5.1%, with a mean difference of 0.017 (95% CI -0.016; 0.348).

Dr.Helmut Ellemunter (fig. 28) is Assistant Professor at the CF Centre, Medical University of Innsbruck, Austria.

Farzal Z, Kou YF, St John R, Shah GB, Mitchell RB. The role of routine hearing screening in children with cystic fibrosis on aminoglycosides: A systematic review. Laryngoscope. 2015 Jul 7. doi: 10.1002/lary.25409. [Epub ahead of print] [PubMed]

Fig. 29 Zainab Farzal scholar. google.com

Study to review the role of routine hearing screening for sensorineural hearing loss (SNHL) in children with cystic fibrosis (CF) who have been on aminoglycoside therapy.Twelve studies (1979-2014) were reviewed. The study population included 762 children (5 months-20 years). Hearing screening measures included pure-tone audiometry (PTA) at standard ± high frequency threshold (HFPTA) (12/12), distortion product otoacoustic emissions (DPOAE) (4/12), transient-evoked otoacoustic emissions (1/12), and automated auditory brainstem response (1/12).The overall prevalence of sensory neural hearing loss ranged from 0% to 29%. However, on subset analysis of children with greater than 10 courses of intravenous (IV) aminoglycosides, up to 44% had sensory neural hearing loss. Eight studies recommended hearing screening in CF children on aminoglycosides; of these, two studies recommended screening even without aminoglycoside exposure, and four studies made no recommendations. HFPTA was the most commonly recommended screening measure followed by DPOAEs.

–   This systematic review supports a recommendation for clinicians to arrange for routine hearing screening in children with CF during and after aminoglycoside exposure based on the high prevalence of sensorineural hearing loss in this population. They suggest future studies should define the optimal timing for hearing screening during and after aminoglycoside therapy in children with CF.

Zainab Farzel (fig.29) is Fellow Physician in Otolaryngology Head& Neck Surgery,Department of Otolaryngology/Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, Texas and the Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Freitas DA; Dias FA; Chaves GS; Ferreira GM; Ribeiro CT; Guerra RO; Mendonca KM. Standard (head-down tilt) versus modified (without head-down tilt) postural drainage in infants and young children with cystic fibrosis.  Cochrane Database of Systematic Reviews. 3:CD010297, 2015. [PubMed]
Postural drainage is used primarily in infants with cystic fibrosis from diagnosis up to the moment when they are mature enough to actively participate in self-administered treatments. However, there is a reported risk of gastroesophageal reflux associated with this technique. The authors eventually concluded that the use of a postural regimen with a 30 degree head-up tilt is associated with a lower number of gastroesophageal reflux episodes and fewer respiratory complications in the longterm. The 20 head-down postural drainage position was not found to be significantly different from the 20 head-up tilt modified position. Nevertheless, the fact that the majority of reflux episodes reached the upper oesophagus should make physiotherapists carefully consider their treatment strategy.

Diana Freitas et al.  Cochrane Database Syst Rev 2018 Mar9;3(3): CD01029   Standard (head-down tilt) versus modified (without head-down tilt) postural drainage in infants and young children with cystic fibrosis. Came to the same conclusions.   www.researchgate.net/scientific-contributions/Diana-Amelia-de-Freitas-2031017059

—   There have been a number of publications on the most suitable form of physiotherapy for infants and young children since Brenda Button’s first important report of the head down position causing more frequent episodes of oesophageal reflux (Button BM et al, 1997.[PubMed]). In 2008, 25 senior physiotherapists from the Association of Chartered Physiotherapists in the UK were unable to reach a consensus on the need for physiotherapy in asymptomatic CF infants (Prasad SA et al, 2008). Recent Standards from the UK CF Trust advise, “If gastro-oesophageal reflux has been identified consider using modified postural drainage avoiding a head down tilt” (Agent P, Morrison L, Prasad A, last updated 2013). (See also Topics -> Physiotherapy).              In practice experienced physiotherapists use their clinical judgment in each individual infant conscious of the fact that GO reflux is a significant contributory factor in causing chest exacerbations.

Diana Freitas is at the Department of Physical Therapy, Federal University of Rio Grande do Norte, Avenida Senador Salgado Filho, 3000, Bairro Lagoa Nova, Natal, Rio Grande do Norte, Brazil,

Geake JB, Reid DW, Currie BJ, Bell SC et al. An international multicentre evaluation and description of Burkholderia pseudomallei infection in cystic fibrosis. Pulm Med. 2015 Oct 9;15:116. doi: 10.1186/s12890-015-0109-9. Free PMC article [PubMed]

Fig. 30 James Geake
Researcher Profiles

25 culture-confirmed cases of B. pseudomallei infection were identified. The median age at acquisition was 21years, mean FEV1 % predicted was 60%, and mean BMI was 19.5kg/m(2). The location of acquisition was northern Australia or Southeast Asia for most. 19 patients (76%) developed chronic infection, which was usually associated with clinical decline.Successful eradication strategies included a minimum of two weeks of intravenous ceftazidime, followed by a consolidation phase with trimethoprim/sulfamethoxazole, and this resulted in a higher chance of success when instituted early. Three cases of lung transplantation have been recorded in the setting of chronic B. pseudomallei infection.The authors concluded chronic carriage of B. pseudomallei in patients with CF appears common after infection, in contrast to the non-CF population. This is often associated with an accelerated clinical decline.

—  An extensive review of all the published cases of Burkholderia pseudomallei, an infection which seems to be associated with people with CF visiting Thailand in the rainy season – to the extent that some would advise people with CF to avoid such visits in the rainy season.

James Geake (fig.30) is Head of Respiratory Medicine, The Lyell-McEwin Hospital, Haydown Road, Elizabeth Vale, 5112, South Australia, Australia.

Girardet A; Ishmukhametova A; Willems M; Coubes C; Hamamah S; Anahory T; Des Georges M; Claustres M. Preimplantation genetic diagnosis for cystic fibrosis: the Montpellier center’s 10-year experience.  Clin Genet 2015; 87(2):124-32, 2015 Feb.  [PubMed]

Fig 31. Anne Giradet

An overview of 10 years of experience of preimplantation genetic diagnosis (PGD) for cystic fibrosis (CF) in one center. Owing to the high allelic heterogeneity of CF transmembrane conductance regulator (CFTR) mutations in south of France, the authors set up a powerful universal test based on haplotyping eight short tandem repeats (STR) markers together with the major mutation p.Phe508del.
Of 142 couples requesting PGD for CF, 76 have been so far enrolled in the genetic work-up, and 53 had 114 PGD cycles performed. Twenty-nine cycles were canceled upon in vitro fertilization (IVF) treatment because of hyper- or hypostimulation. Of the remaining 85 cycles, a total of 493 embryos were biopsied and a genetic diagnosis was obtained in 463 (93.9%), of which 262 (without or with a single CF-causing mutation) were transferable. Twenty-eight clinical pregnancies were established, yielding a pregnancy rate per transfer of 30.8% in the group of seven couples with one member affected with CF, and 38.3% in the group of couples whose both members are carriers of a CF-causing mutation [including six couples with congenital bilateral absence of the vas deferens (CBAVD)]. So far, 25 children were born free of CF and no misdiagnosis was recorded. Our test is applicable to 98% of couples at risk of transmitting CF.

—    As the prognosis and treatment options have improved for people with CF, the decision to terminate an early pregnancy, where the fetus is found to have CF through antenatal diagnosis in the first trimester, becomes an increasingly difficult decision for both parents and professionals.  If the parents have already been identified as CF carriers through population carrier screening, by having had an affected relative or even had previous children with CF, PIGD is an ideal way to avoid having a child with CF.
The ability identify CF carriers to avoid having an affected infant, without having to terminate a pregnancy, does not seem to have received the attention it deserves since the advent of the new mutation specific treatments. Cystic fibrosis is potentially an avoidable condition using available knowledge.  The first birth of a normal girl after in vitro fertilisation and preimplantation diagnostic testing for cystic fibrosis was reported as long ago as 1992 (Handyside AH et al. N Engl J Med 1992; 327(13):905-9. [PubMed]).

Girardet A, Viart V, Plaza S, Daina G, De Rycke M, Des Georges M, Fiorentino F, Harton G, Ishmukhametova A, Navarro J, Raynal C, Renwick P, Saguet F, Schwarz M, SenGupta S, Tzetis M, Roux AF, Claustres M. The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus. Eur J Hum Genet. 2015 May 27. doi: 10.1038/ejhg.2015.99. [Epub ahead of print] (Full text available at the Eur J Hum Genet website) [PubMed]
Cystic fibrosis (CF) is one of the most common indications for preimplantation genetic diagnosis (PGD) for single gene disorders, giving couples the opportunity to conceive unaffected children without having to consider termination of pregnancy. However, there are no available standardized protocols, so that each center has to develop its own diagnostic strategies and procedures. Furthermore, reproductive decisions are complicated by the diversity of disease-causing variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the complexity of correlations between genotypes and associated phenotypes, so that attitudes and practices toward the risks for future offspring can vary greatly between countries. On behalf of the EuroGentest Network, eighteen experts in PGD and/or molecular diagnosis of CF from seven countries attended a workshop held in Montpellier, France, on 14 December 2011. Building on the best practice guidelines for amplification-based PGD established by ESHRE (European Society of Human Reproduction and Embryology), the goal of this meeting was to formulate specific guidelines for CF-PGD in order to contribute to a better harmonization of practices across Europe. Different topics were covered including variant nomenclature, inclusion criteria, genetic counseling, PGD strategy and reporting of results. The recommendations are summarized in this paper, and updated information on the clinical significance of CFTR variants and associated phenotypes is presented.

—   A very detailed paper to which many of the international experts in this area have contributed – a valuable source of information covering all aspects relating to preimplantation genetic diagnosis.

Dr. Anne Girardet (fig. 31) received her PhD in Molecular Genetics from the University Montpellier, France, in 1998. She now performs PGD in this centre where she has set up several single gene disorder protocols for PGD purposes.

Grasemann H, Gonska T, Avolio J, Klingel M, Tullis E, Ratjen F. Effect of ivacaftor therapy on exhaled nitric oxide in patients with cystic fibrosis. J Cyst Fibros. 2015 Jul 11. pii: S1569-1993(15)00163-0. doi: 10.1016/j.jcf.2015.07.001. [Epub ahead of print]  [PubMed]

Fig 32. Helmut Grasemann

Airways of patients with cystic fibrosis are deficient for nitric oxide. Low nitric oxide in cystic fibrosis has been shown to be associated

Fig 33. Tanja Gonska

with poor pulmonary function and risk of infection with certain pathogens.Fractional exhaled nitric oxide (FENO) was measured before and 4weeks after initiation of ivacaftor therapy, in patients with cystic fibrosis and a CFTR gating mutation. The effect of ivacaftor on FENO was compared to treatment with inhaled dornase alfa or hypertonic saline for 4weeks, respectively.A total of 15 patients on ivacaftor therapy were studied. Pulmonary function improved significantly and mean (±SD) FENO increased from 8.5±5.0 to 16.2±15.5ppb. The effect was more pronounced in pediatric compared to adult patients. There was no linear correlation between changes in FENO, pulmonary function or sweat chloride concentration. Neither treatment with inhaled dornase alfa (n=15) or hypertonic saline (n=16) resulted in a change in FENO.

The authors suggested therapy with ivacaftor results in an increase in nitric oxide formation in cystic fibrosis airways, while dornase alfa or hypertonic saline has no effect on airway nitric oxide. Some beneficial effects of CFTR targeting therapy in CF may result from improved airway nitric oxide production.

Dr. Helmut Grasemann (fig. 32) is a Professor in the Department of Paediatrics and Staff Respirologist at the Hospital for Sick Children, Toronto.

Tanja Gonska  (fig. 33) is a staff gastroenterologist at the Hospital for Sick Children, Toronto. She is particularly involved in paediatric pancreatology and research into in transepithelial ion and fluid transport in airway and intestine.

Groves T, Robinson P, Wiley V, Fitzgerald DA. Long-Term Outcomes of Children with Intermediate Sweat Chloride Values in Infancy. J Pediatr. 2015 Mar 23. pii: S0022-3476(15)00099-2. doi: 10.1016/j.jpeds.2015.01.052. [Epub ahead of print][PubMed]
A retrospective review of children with intermediate sweat chloride values (raised immunoreactive trypsinogen/1 copy of p.F508del CF mutation on newborn screening (NBS)/sweat chloride value of 30-59 mmol/L) presenting to The Children’s Hospital at Westmead over 15 years. Patients with an intermediate sweat chloride evolving to a formal diagnosis of CF (termed “delayed CF”) were matched (2:1) with NBS positive patients with CF (termed “NBS positive CF”). Clinical outcomes were compared.
Fourteen of 29 (48%, 95% CI 0.3-0.66) patients with intermediate sweat chloride value evolved to a diagnosis of CF and were matched with 28 NBS positive patients with CF. Delayed CF had less pancreatic insufficiency (OR 0.06, 95% CI 0.01-0.44, P = .006), less colonization with nonmucoid Pseudomonas aeruginosa (OR 0.04, 95% CI 0.01-0.38, P = .005), milder obstructive lung disease (forced expiratory volume in 1 second/forced vital capacity ratio), and overall disease severity (Shwachman scores) at 10 years (mean difference 5.93, 95% CI 0.39-11.46, P = .04; mean difference 4.72, 95% CI 0.9-8.53, P = .015, respectively). Nutritional outcomes were better at 2 years for delayed CF but did not persist to later ages.
In this cohort, approximately one-half of infants with intermediate sweat chloride value were later diagnosed with CF. The clinical course of delayed CF was milder in some aspects compared with NBS positive CF. These results emphasize the importance of ongoing follow-up of infants with intermediate sweat chloride values.

—  A great deal of attention was given to these neonatally positive screened infants with marginal clinical findings and sweat tests. In practice, they all warrant careful follow up by clinicians who are experienced in CF care and develop a rapport with the parents. The study is useful in showing that some half of such infants eventually are shown to have CF.

Tyler Groves (fig.34) is at the Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Respiratory Medicine, The Children’s Hospital at Westmead, New South Wales, Australia.

Griesenbach U, Pytel KM, Alton EW. Cystic Fibrosis Gene Therapy in the UK and Elsewhere.  Hum Gene Ther. 2015 May; 26(5):266-75. doi: 10.1089/hum.2015.027. Free PMC Article[PubMed]

Fig. 35 Uta Griesenbach

The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first non-viral gene therapy trial designed to answer whether repeated non-viral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here.

–   A clear summary of the present situation regarding gene therapy for cystic fibrosis from the UK Gene Therapy Consortium.

Professor Uta Griesenbach (fig. 35) is one of the original and senior members of the UK Gene Therapy Consortium

Goss CH; MacNeill SJ; Quinton HB; Marshall BC; Elbert A; Knapp EA; Petren K; Gunn E; Osmond J; Bilton D. Children and young adults with CF in the USA have better lung function compared with the UK. Thorax 2015; 70(3):229-36.    [PubMed]

Fig 36. Christopher Goss

A cross-sectional study using 2010 data from patients in the US Cystic Fibrosis Foundation and the UK Cystic Fibrosis patient registries. The a priori outcome measures of interest were lung function and nutritional status. Descriptive statistics and two sample comparisons were performed. Stratification and multivariable linear regression were used to adjust for confounding.The study cohort included 13,777 children and 11,058 adults from the USA and 3968 children and 3965 adults from the UK. In children, mean body mass index centiles were similar. Lung function (FEV1 and FVC% predicted) was significantly higher in US patients ages 6-25 years of age. In a regression model adjusted for only age, FEV1% predicted was on average 3.31% of predicted (95% CI 2.65 to 3.96) higher in the USA compared with the UK. When adjusted for age, age at diagnosis, gender, pancreatic insufficiency and genotype, FEV1% predicted was on average 3.03% of predicted (95% CI 2.37 to 3.69)

higher in the USA compared with the UK. These differences persisted despite adjustment for possible confounders. Hypertonic saline and dornase alfa were much more commonly prescribed in US children.The authors concluded children and young adults with CF have better lung function in the USA compared with the UK despite similar nutritional status.

Christopher H Goss (fig. 36) is Professor, Division of Pulmonary and Critical Care Medicine and Professor of Pediatrics, University of Washington.

—   This is an important study involving international collaboration made possible using the national CF databases. The observation made by the authors, that certain preparations such a dornase alpha and hypertonic saline were much more frequently prescribed in the USA, is likely to be a major factor in the difference in respiratory function (see abstract of the editorial by Taylor-Robinson et al. below).

Taylor-Robinson D C, Schechter M, Smyth RL. Comparing cystic fibrosis outcomes across the pond. Thorax 2015; 70:203-204 Editorial. [PubMed]

This is a very interesting commentary on the study of Goss et al. (Thorax 2015; 70(3):229-36. [PubMed]).

Fig. 37 David Taylor-Robinson

The authors raise some questions concerning the conclusion that lung function of USA children is significantly better than that of UK children – a difference most marked around 6 years.
They ask if the samples are fully representative of the entire CF populations of the respective countries? The UK captures almost the entire CF population whereas the US data is for patients attending US accredited centres (an estimated 75%) containing fewer socially disadvantaged patients. However, even removing such patients from the UK data did not account for most of the difference.  Also genetic and ethnic differences were not responsible.  The data is cross sectional and may not represent true longitudinal differences and the older patients may represent only those healthier individuals who have survived. But even so, the differences in early lung function seem to be genuine albeit less than stated.
Possible reasons for the great discrepancies are the use of rhDNase and possibly nebulised hypertonic saline between young patients (<18yrs) in the UK and USA are possible reasons. For example at the time of the study use of treatments in USA vs. UK were – hypertonic saline 40.9% vs. 8.4%, any nebulised antibiotic 44 .7% vs. 42.9%, rhDNase 77.2% vs. 35.4% and macrolides 33.6% vs. 24.1%
Also all the US patients included attended recognised specialist CF Centres, which is not always the case in the UK, even though health and survival have been shown to be better with the more expert experienced care at specialist centres. Such centre care includes more frequent clinic visits, more frequent respiratory cultures and antibiotic treatments particularly at an earlier stage in milder affected patients – all factors known for generations to improve health and survival of people with CF.

— In this reviewer’s opinion, the expert care delivered at specialist centres and the great difference in the use of rhDNase are likely to be the main reasons for the discrepancy in respiratory function of the children. Also the overall coverage in the UK will certainly include more patients not attending specialist centres. It is sad that, even today, some UK paediatricians are not convinced of the benefit of referring their patients to a specialist CF centre and complain of the lack of “controlled studies”. As Sir William Osler observed “ Medicine is to be learned by experience and is not an inheritance; it cannot be revealed. Learn to see, learn to hear, learn to smell, and know that by practice alone can you become expert”

With regard to the use of rhDNase, almost every study since the treatment became available in the early Nineties has shown significant improvement in some aspect of the condition of the treated patients even amounting to improving survival. Please see Topics -> Mucolytics -> Pulmozyme (rhDNase) where I have reviewed many of the earlier publications, particularly relevant being those showing improvement even in young and mildly affected patients. These findings have encouraged the earlier use of rhDNase in infants and preschool children as soon as they were able to inhale the drug at both the Leeds and Copenhagen CF Centres.

This study highlights the great value of such comparative studies which are possible using reliable national databases such as are now established at the CF Foundation, the UK CF Trust and elsewhere.  They certainly justify the many problems we experienced in collecting and processing data the early years when the databases were started by these two national organizations.

David Taylor-Robinson (fig. 37) is Senior Clinical Lecturer in Public Health and Honorary Consultant in Public Health at the Alder Hey Children’s Hospital, Liverpool.

Hadj Fredj S; Ouali F; Siala H; Bibi A; Othmani R; Dakhlaoui B; Zouari F; Messaoud T. Prenatal diagnosis of cystic fibrosis: 10-years experience.  Pathol Biol 2015; 63(3):126-9.  [PubMed]
10 years experience in prenatal diagnosis of cystic fibrosis performed in the Tunisian population. Based on family history, 40 Tunisian couples were selected for prenatal diagnosis. Fetal DNA was isolated from amniotic fluid collected by transabdominal amniocentesis or from chronic villi by transcervical chorionic villus sampling.
Thirteen fetuses were affected, 21 were heterozygous carriers and 15 were healthy with two normal alleles of CFTR gene. Ten couples opted for therapeutic abortion. The microsatellites genotyping showed the absence of contamination of the fetal DNA by maternal DNA in 93.75%. The diagnostic strategy provides rapid and reliable prenatal diagnosis for at risk families.

—  The majority (77%) of the, presumably Muslim, couples with an affected fetus opted for termination. With the new treatment options and improving prognosis for people with CF, opting for termination of an affected fetus is an increasingly difficult decision for many couples. The availability of population carrier screening and, if indicated, preimplantation genetic diagnosis would reduce the need for taking these difficult decisions.

Sondess Hadj Fredj is Maitre assistant at the  Laboratory, Bechir Hamza Children’s hospital, Bab Saadoun, 1007 Tunis, Tunisia

Hall H; Gadhok R; Alshafi K; Bilton D; Simmonds NJ. Eradication of respiratory tract MRSA at a large adult cystic fibrosis centre. Respir Med 2015; 109(3):357-63.  [PubMed]
This is an observational cohort study from the Royal Brompton Hospital of all patients with MRSA positive sputum, 2007-2012. All eradication attempts with subsequent culture results were reviewed. Single vs. dual antibiotic regimens were compared for both new and chronic infections.37 patients (median FEV1 58.7 (27.6-111.5)% predicted) were identified, of which 67.6% (n = 25) had newly acquired MRSA. Compared with single regimens, a high proportion of dual regimens achieved MRSA eradication (84.6% vs. 50%; p = 0.1) for new infections. Rifampicin/Fusidic acid was associated with high success rates (100% vs. 60% for other dual regimens (p = 0.13)). Compared with new infections, chronic MRSA was much less likely to be eradicated (18.2%, p = 0.01).The authors concluded combined antibiotic therapy, particularly Rifampicin/Fusidic acid, is a well-tolerated and effective means of eradicating MRSA in patients with cystic fibrosis.

H Hall is at the Adult Cystic Fibrosis Centre, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.

Hayes D Jr, Kirkby S, Whitson BA, Black SM, Sheikh SI, Tobias JD, Mansour HM, Kopp BT. Mortality Risk and Pulmonary Function in Adults With Cystic Fibrosis at Time of Wait Listing for Lung Transplantation Ann Thorac Surg. 2015 Aug;100(2):474-9. doi: 10.1016/j.athoracsur.2015.04.022. Epub 2015 Jun 30. [PubMed]
Lung transplantation (LTx) benefit for survival in cystic fibrosis (CF) patients placed on the wait list is not well studied. To predict the relationship between initial forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) and the hazard ratio (HR) associated with LTx in CF patients, the United Network for Organ Sharing database was queried from 2005 to 2006 for adult patients with CF. The benefit of LTx in adults with CF was significant at a lower baseline FEV1 than expected. A threshold for baseline FVC was established below which LTx was protective.

Don Hayes Jr is at the  Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio; Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio; Section of Pulmonary Medicine, Nationwide Children’s Hospital, Columbus, Ohio.

Hayes D Jr; Warren PS; McCoy KS; Sheikh SI. Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy.  J Pediatr Gastroenterol Nutr 2015; 60(5):578-9.[PubMed]
Treatment of liver disease, including hepatic steatosis, in patients with cystic fibrosis is limited. The authors report an adolescent with CF had significant improvement in hepatic steatosis with ivacaftor treatment.

Fig. 38 A girl with steatosis that improved with adequate pancreatic replacement therapy

—   It is important to note that inadequate pancreatic enzyme replacement therapy can worsen steatosis. For example a girl with CF and gross hepatomegaly (fig. 38) was  referred to Leeds for liver biopsy; this revealed severe steatosis. She had severe undertreated intestinal malabsorption. With control of the malabsorption with adequate pancreatic replacement therapy her hepatomegaly regressed.

Heltshe SL; Mayer-Hamblett N; Burns JL; Khan U; Baines A; Ramsey BW; Rowe SM; GOAL (the G551D Observation-AL) Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015;60(5):703-12.  [PubMed]

Fig 39. Soya Heltshe

This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response. Among 151 participants prescribed ivacaftor, 29% (26/89) who were culture positive for P. aeruginosa the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected.The authors concluded Pseudomonas aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease.

An encouraging study – presumably altering the physicochemical state of the airways towards normal reduced the likelihood of P. aeruginosa colonisation/infection and/or increased the ease with which the organism was eradicated by the patient.

Sonya Heltshe (fig. 39) is Senior Biostatistician and Assistant Professor in the Center for Clinical and Translational Research, Seattle.

Hill M, Twiss P, Verhoef TI, Drury S, McKay F. Mason S, Jenkins L, Morris S, Chitty LS. Non-invasive prenatal diagnosis for cystic fibrosis: detection of paternal mutations, exploration of patient preferences and cost analysis. Prenat Diagn. 2015 Oct;35(10):950-8. doi: 10.1002/pd.4585. Epub 2015 Apr 5. [PubMed]
The authors aim to develop non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF) and determine costs and implications for implementation. A next-generation sequencing assay was developed to detect ten common CF mutations for exclusion of the paternal mutation in maternal plasma. Using uptake data from a study exploring views on NIPD for CF, total test-related costs were estimated for the current care pathway and compared with those incorporating NIPD.The assay reliably predicted mutation status in all control and maternal plasma samples. Of carrier or affected adults with CF (n = 142) surveyed, only 43.5% reported willingness to have invasive testing for CF with 94.4% saying they would have NIPD. Using these potential uptake data, the incremental costs of NIPD over invasive testing per 100 pregnancies at risk of CF are £9025 for paternal mutation exclusion, and £26 510 for direct diagnosis.The authors have developed NIPD for risk stratification in around a third of CF families. There are economic implications due to potential increased test demand to inform postnatal management rather than to inform decisions around termination of an affected pregnancy.

Hussain S; Varelogianni G; Sarndahl E; Roomans GM. N-acetylcysteine and azithromycin affect the innate immune response in cystic fibrosis bronchial epithelial cells in vitro. Lung Res 2015; 41(5):251-60. [PubMed]
The authors previously reported that N-acetylcysteine (NAC), ambroxol and azithromycin (AZM) (partially) correct the chloride efflux dysfunction in cystic fibrosis bronchial epithelial (CFBE) cells with the DF508 homozygous mutation in vitro. Here they further investigated possible immunomodulatory effects of these drugs on the regulation of the innate immune system by studying the expression of the cytosolic NOD-like receptors NLRC1 and NLRC2, and interleukin (IL)-6 production in CFBE cells. Overall, the results indicate that NAC and AZM not only can correct the chloride efflux dysfunction but also have a weakly strengthening effect on the innate immune system.

— The effect of N-acetylcysteine in CF has been the subject of numerous studies since the first publication describing a “new mucolytic agent” by  Webb et al in 1962! (see Topics -> Mucolytics). Figure 11. is from Webb ER et al. 1962

Fig 40. Purulent bronchitis sputum production – acetyl cysteine started on second day. Webb et al 1962

Despite considerable published evidence of potential benefit in CF, the drug has never been popular for treating people with CF in the UK but is used in Europe. A Cochrane review in 2013 (Tam J et al, Cochrane Database Syst Rev2013;7:CD007168) “found no evidence to recommend the use of either inhaled or oral thiol derivatives in people with cystic fibrosis. There are very few good quality trials investigating the effect of these medications in cystic fibrosis, and further research is required to investigate the potential role of these medications in improving the outcomes of people with cystic fibrosis”

Shahida Hussain is at the School of Health and Medical Sciences, Örebro University , School of Health and Medical Sciences, Örebro University , Örebro , Sweden. , Sweden.

Hutchins JL; Jacobs RA.  Thoracic paravertebral catheter placement for acute rib pain in a pregnant patient with cystic fibrosis.  A & A Case Reports. 2015; 4(3):31-2. [PubMed]
A 30-year-old woman with cystic fibrosis at 33 weeks, 4 days’ gestation sustained a rib injury during an acute pulmonary exacerbation, resulting in noncompliance with her chest wall oscillation therapy and worsening of her respiratory status with concern for inducing labor early. Insertion of an ultrasound-guided thoracic paravertebral catheter produced immediate pain relief, eliminating the need for further opioids, and she was able to tolerate her chest wall oscillation treatment. She was discharged home after 7 days and was able to deliver a healthy baby at 38 weeks via spontaneous vaginal delivery.

–   A successful practical solution to an unusual but potentially very serious problem. (See also Cutshall C, Hutchins J. A & A Case Reports 2015; 4(3):29-30. [PubMed])

Fig. 41 Liane Ioannou research.monash.edu

Ioannou L, Delatycki MB, Massie J, Hodgson J, Lewis S. “Suddenly Having two Positive People who are Carriers is a Whole New Thing”- Experiences of Couples Both Identified as Carriers of Cystic Fibrosis Through a Population-Based Carrier Screening Program in Australia. J Genet Couns. 2015 Dec;24(6):987-1000. doi: 10.1007/s10897-015-9833-9. Epub 2015 May 1. [PubMed]
A population-based CF carrier-screening program was implemented in Victoria, Australia in 2006. This study explored the experiences of couples when both partners were identified as CF carriers. Between January 2006 and December 2010, 10 carrier couples were identified and invited to undertake a semi-structured interview. Nine interviews were conducted, seven couple interviews and two individual interviews. One couple declined to participate due to the recent termination of an affected pregnancy. Interviews were analyzed using inductive content analysis.All couples experienced surprise on learning their carrier couple result. The couples who were pregnant at the time of screening chose to have prenatal diagnosis, with the majority considering it to be the “next step.” The two couples who had an affected pregnancy reported feelings of devastation and grief upon receiving their prenatal diagnosis result and terminated the pregnancy. All carrier couples were offered free genetic counseling, with only one couple declining the offer.

Couples were unprepared for a positive carrier couple result. However, all the couples changed their reproductive behavior as a result of their carrier status. The results of this study have been used to inform the program and service offered to CF carrier couples particularly with respect to genetic counseling for reproductive decision making.

Liane Ioannou (fig. 41) is senior research fellow at Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia and the Department of Medicine, Monash University, Melbourne, Australia.

Janssens S, Chokoshvilli D, Binst C, Mahieu I, Henneman L, De Paepe A, Borry P. Attitudes of cystic fibrosis patients and parents toward carrier screening and related reproductive issues. Eur J Hum Genet. 2015 Jul 29. doi: 10.1038/ejhg.2015.160. [Epub ahead of print] [PubMed]

Fig 42. Pascal Borry

A written questionnaire was administered to adult patients and parents of children with CF in Belgium with the aim to explore participants’ attitudes toward CF carrier screening and related reproductive issues. The study population was recruited from a CF patient registry in Belgium and comprised 111 participants (64 parents, 47 patients aged 16 or older). More than 80% of all participants were in favour of preconception carrier screening for CF. However, some were concerned over potential negative consequences of population-wide CF carrier screening.Regarding future reproductive intentions, 43% of the participants indicated a desire to have children. Among these, pre-implantation genetic diagnosis was found to be the most preferred reproductive option, closely followed by spontaneous pregnancy and prenatal diagnosis. Although the findings of the  study suggest that patients and parents of children with CF support a population-based carrier-screening program for CF, they also highlight some issues deserving particular attention when implementing such a program.

A number of population-based carrier screening programs are published, usually with the support of people with CF and their relatives. (See Topics-> Diagnosis-> Antenatal/Prenatal).   It is  unfortunate that the recent impressive and welcome advances in treatment have somewhat overshadowed the fact that CF is now a preventable condition and, since the availability of pre-implantation genetic diagnosis, preventable without the need for termination of any pregnancy.

Pascal Borry (fig. 42) is from the Centre for Biomedical Ethics and Law Katholieke Universiteit, Leuven and has written extensively on carrier testing.

Janssen KM, de Smit MJ, Brouwer E, de Kok FA, Kraan J, Altenburg J, Verheul MK, Trouw LA, van Winkelhoff AJ, Vissink A, Westra J. Rheumatoid arthritis-associated autoantibodies in non-rheumatoid arthritis patients with mucosal inflammation: a case-control study. Arthritis Res Ther 2015; 9;17:174. doi: 10.1186/s13075-015-0690-6.  Free PMC Article
Rheumatoid arthritis-associated autoantibodies (RA-AAB) can be present in the serum years before clinical onset of rheumatoid arthritis (RA). It has been hypothesized that initiation of RA-AAB generation occurs at inflamed mucosal surfaces, such as in the oral cavity or in the case of CF in the lungs. The aim of this study was to assess systemic presence of RA-AAB in patients without RA who had oral or lung mucosal inflammation.The non-RA patients had periodontitis (PD, n = 114), bronchiectasis (BR, n = 80) or cystic fibrosis (CF, n = 41). Serum RA-AAB levels were compared with those of periodontally healthy controls (n = 36). Patients with established RA (n = 86) served as a reference group.Although overall levels were low, RA-AAB seropositivity was associated with lung mucosal inflammation (BR and CF) and may be associated with oral mucosal inflammation (PD). To further determine whether mucosal inflammation functions as a site for induction of RA-AAB and precedes RA, longitudinal studies are necessary in which RA-AAB of specifically the IgA isotype should be assessed in inflamed mucosal tissues and/or in their inflammatory exudates.

—  Suggest reading the full abstract for more detail.  A study lending further support to one of the more remote effects of chronic lung inflammation in people with CF. The association between the increasing lung inflammation associated with pulmonary exacerbations and worsening of painful joints in CF is well documented (Bowler IM, Littlewood JM. Lancet 1992; 340(8813):244.  [PubMed])

Koen M J Janssen is in the Department of Oral and Maxillofacial Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Jenkins R; Wootton M; Howe R; Cooper R.  A demonstration of the susceptibility of clinical isolates obtained from cystic fibrosis patients to manuka honey. Arch Microbiol 2015; 197(4):597-601.  [PubMed] (Full article available)

Fig 43. Rowena Jenkins

Susceptibility of 56 strains of P. aeruginosa and 55 strains of Burkholderia to manuka honey, tobramycin and colistin using micro broth dilution and E strip was determined. All strains exhibited susceptibility to honey <10 % (w/v); mean susceptibility of Burkholderia (4.6 % w/v) was lower than P. aeruginosa (7.3 % w/v). Synergistic or additive combinations were found with all four strains tested. Combinations of manuka honey with antibiotics can be used to lower the MIC need to successfully inhibit both P. aeruginosa and B. cepacia. The authors suggest the use of honey as a combination agent may be possible for the management of P. aeruginosa and B. cepacia.

— There is now considerable literature on the antibacterial properties of honey including a number by Cooper R A et al from Cardiff in relation to B. cepacia (an early one abstracted in the 2000 section of this website).  More recently Rowena Jenkins (figure) has published on the subject. As yet (2023) honey has not proved to be of value in the treatment of people with CF although it has been used with success in other infections particularly involving the skin. Professor John Govan of Edinburgh had a PhD student and a chemist working on the anti-bacterial effect of honey but they were unable to identify the active component. One experienced CF physician even tried treating an adult patient with CF with nebulised solution of honey but again without obvious clinical benefit.

Dr Rowena Jenkins (fig 43) and her research group intend to investigate the activity of honey with a much larger range of bacteria and antibiotic combinations and to determine the susceptibilities of biofilms, as well as suspension cultures. Clinical studies will also be needed to determine the potential and efficacy of antibiotic and honey combinations for cystic fibrosis patients.   In 2017 Rowena moved to Swansea as Lecturer in Microbiology and Infectious Disease in the College of Medicine at Swansea University (see abstract of Roberts AEL et al 2019).

Kashirskaya NY; Kapranov NI; Sander-Struckmeier S; Kovalev V. Safety and efficacy of Creon micro in children with exocrine pancreatic insufficiency due to cystic fibrosis.  J Cyst Fibros 2015; 14(2):275-81.  [PubMed]

Fig 45. Nikolay Ivanovitch Kapranov

Fig 44. Nataliya Kashirskaya

Pancreatic enzyme replacement therapy is the foundation of nutritional management for exocrine pancreatic insufficiency (EPI). METHODS: A 3-month, open-label, multicentre study in Russia assessing safety, efficacy, and ease-of-use of Creon() Micro (5000 lipase units/spoon) in children aged 1 month to <4 years with EPI due to cystic fibrosis. Efficacy assessments included growth parameters. RESULTS: All 40 subjects (mean age 26.5 months) completed treatment. Adverse events occurred in 40% of the subjects (most commonly respiratory tract infection [15%], frequent bowel movements [8%], rhinitis, stomatitis, nasopharyngitis, and diarrhoea [all 5%]), none were serious or led to discontinuation. After 3 months, mean+/-SD increases from baseline z-scores were height/length-for-age 0.13+/-0.48, weight-for-age 0.20+/-0.39, and BMI-for-age 0.29+/-0.65. Treatment was rated ‘easy’ to administer by 95% caregivers and acceptance ‘good’/’very good’ by 90%.Creon Micro was well tolerated. Growth development parameters increased over the 3-month treatment period. Treatment was considered easy to use and acceptance was good.

Nataliya  Kashirskaya  (fig. 44) is Chief Research Officer Research Center for Medical Genetics Moscow and has published widely on various aspects of CF.

Nikolay Ivanovitch Kapranov  (fig. 45) Is based at the  Russian Academy of Medical Sciences , Research Centre of Medical Genetics Moscow.

Keenan K; Avolio J; Rueckes-Nilges C; Tullis E; Gonska T; Naehrlich L.  Nasal potential difference: Best or average result for CFTR function as diagnostic criteria for cystic fibrosis?. J Cyst Fibros 2015; 14(3):310-6.  [PubMed]
The current practice of averaging the nasal potential difference (NPD) results of right and left nostril measurements reduce inter-individual variability but may underestimate individual CFTR function.
In this study the authors found that the current practice of averaging the NPD results of right and left nostril measurements leads to an underestimation of the individual CFTR function and should be reconsidered.

Kathleen Keenan is in the Division of Paediatric Gastroenterology, Hepatology and Nutrition, University of Toronto and Physiology and Experimental Medicine, Research Institute, the Hospital for Sick Children, Toronto, Ontario, Canada.

Kellermann G, Anastasiadis AG, Dräger DL, Prall F, Hakenberg OW. Urinary Retention Due to Severe Pseudocystic Mucoid Degeneration of the Prostatic Matrix: A Rare Urologic Manifestation of Cystic Fibrosis. Urol Int. 2015 Feb 20. [Epub ahead of print]  [PubMed]
Urologic manifestations of CF include infertility and azoospermia, nephrolithiasis, and stress urinary incontinence. In this report, the authors describe a 33-year-old male, who presented with recurrent urinary retention due to prostatic enlargement despite his young age. After transurethral resection, the voiding problems resolved. Histopathological examination revealed a severe pseudocystic mucoid degeneration of the prostatic matrix as a cause of his subvesical obstruction. Although these structural changes are most probably due to his underlying disease, detailed histologic features have not been described in the literature.

G. Kellermann is at the Helios Clinic Berlin-Buch, University of Rostock, Rostock, Germany.

Kettle AJ, Turner R, Gangell CL, Harwood DT, Khalilova IS, Chapman AL, Winterbourn CC, Sly PD; AREST CF. Oxidation contributes to low glutathione in the airways of children with cystic fibrosis. Eur Respir J. 2014 ; 44(1):122-9. doi: 10.1183/09031936.00170213. Epub 2014 Mar 23[PubMed]

Fig. 46 Tony Kettle

Glutathione is an important antioxidant in the lungs but its concentration is low in the airways of patients with cystic fibrosis. Whether this deficit occurs from an early age or how oxidative stress contributes to lowering glutathione is unknown. The authors  measured glutathione, its oxidation products, myeloperoxidase, and biomarkers of hypochlorous acid in bronchoalveolar lavage from children with cystic fibrosis and disease controls using mass spectrometry and immunological techniques. 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.

Tony J Kettle (Fig. 46) is at the  Centre for Free Radical Research, Dept of Pathology, University of Otago Christchurch, Christchurch, New Zealand

Comment by Hector A et al. Oxidative stress in cystic fibrosis lung disease: an early event, but worth targeting? [Eur Respir J. 2014;44(1):17-19]     The road is paved with more than one rationale to therapeutically target neutrophil products in early CF lung disease, in order to prevent their harmful and irreversible effect on lung tissue components. The clinical implementation of these concepts is hampered by costs, drug delivery issues and optimised read-outs in this young age group, but the promises make it worth facing these challenges.

Kidd TJ, Ramsay KA, Vidmar S, Carlin JB, Bell SC, Wainwright CE, Grimwood K; ACFBAL Study Investigators. Collaborators. Pseudomonas aeruginosa genotypes acquired by children with cystic fibrosis by age 5-years. J Cyst Fibros. 2015 May;14(3):361-9. doi: 10.1016/j.jcf.2014.12.007. Epub 2015 Jan 3. [PubMed]

Fig. 47 Timothy Kidd

The authors describe Pseudomonas aeruginosa acquisitions in children with cystic fibrosis (CF) aged ≤5-years, eradication treatment efficacy, and genotypic relationships between upper and lower airway isolates and strains from non-CF sources.Of 168 CF children aged ≤5-years in a bronchoalveolar lavage (BAL)-directed therapy trial, 155 had detailed microbiological results. Overall, 201/271 (74%) P. aeruginosa isolates from BAL and oropharyngeal cultures were available for genotyping, including those collected before and after eradication therapy.Eighty-two (53%) subjects acquired P. aeruginosa, of which most were unique strains. Initial eradication success rate was 90%, but 36 (44%) reacquired P. aeruginosa, with genotypic substitutions more common in BAL (12/14) than oropharyngeal (3/11) cultures. Moreover, oropharyngeal cultures did not predict BAL genotypes reliably.The authors concluded CF children acquire environmental P. aeruginosa strains frequently. However, discordance between BAL and oropharyngeal strains raises questions over upper airway reservoirs and how to best determine eradication in non-expectorating children.

— Impressive early eradication rate and confirmation of the fact that first infections are usually unique strains acquired from the environment.

Timothy Kidd (fig. 47) is Adjunct Senior Fellow at the Queensland Children’s Medical Research Institute, Royal Children’s Hospital, The University of Queensland, Herston, QLD 4029, Australia

Khanna AR, Coumans JV. Spontaneous Improvement of Chiari I Malformation and Syringomyelia in a Patient With Cystic Fibrosis. Neurosurgery 2015 Aug 24. [Epub ahead of print] [PubMed]

Fig. 48 Arjun R Khanna
US News Health

A report of a patient with cystic fibrosis who presented during an exacerbation of bronchiectasis and was found to have a Chiari I malformation with associated syringomyelia. Eight months later, when the patient had returned to baseline pulmonary status, repeat imaging showed interval improvement in both the size of the syrinx and descent of cerebellar tonsils.
This rare case of spontaneous improvement of syringomyelia and Chiari I malformation attributable to relief from chronic cough offers interesting insight into the mechanism of these disorders.

Arjun R Khanna (fig. 48) is in the Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts.

Knudsen KB, Mathiesen ER, Eriksen V, Skov M, Nielsen KG, Johannesen J, Pressler T. The development of diabetes among Danish cystic fibrosis patients over the last two decades. Pediatr Diabetes. 2015 May;16(3):219-26. doi: 10.1111/pedi.12143. Epub 2014 Jun 1[PubMed]
Cystic fibrosis (CF)-related diabetes (CFRD) is correlated with age and has been associated with a decline in body mass index (BMI), pulmonary function, and survival. Over the last two decades, the focus has been on the early diagnosis and treatment of diabetes; therefore, in this study, we evaluated the status of the current clinical condition and survival in our CF population. In addition, we also aimed to investigate the incidence of diabetes among adolescence over time and to identify characteristics associated with early diabetes onset.

A retrospective chart review of a birth cohort consisting of 161 CF patients born between 1975 and 1994 and followed until 2011.Over two decades, the incidence of CFRD among 11- to 16-year-old children remained unchanged at 12-14%, while the proportion of children with chronic pulmonary infection at age 10 declined from 31 to 8% (p B Knudsen0.001). Severe CF-mutation, i.e., group I and II mutations, were associated with diabetes (p = 0.003). Female gender was borderline associated with diabetes among adolescents (p = 0.06). No significant worsening in pulmonary function, BMI or survival was identified when comparing CFRD patients to CF patients without CFRD.The incidence of diabetes among adolescence with CF in the Copenhagen clinic has not changed over the last two decades. Severe CF mutations are a risk factor for CFRD, and female gender is borderline associated with CFRD among adolescents. Pulmonary function, BMI and survival were comparable regardless of the onset

Karin B Knudsen is at the Cystic Fibrosis Centre, Rigshospitalet, Copenhagen, 2100, Denmark.

Konstan MW; Plant BJ; Elborn JS; Rodriguez S; Munck A; Ahrens R; Johnson C.  Efficacy response in CF patients treated with ivacaftor: post-hoc analysis.  Pediatr Pulmonol 2015; 50(5):447-55.  [PubMed]
Clinical studies in patients with cystic fibrosis and G551D-CFTR showed that the group treated with ivacaftor had improved clinical outcomes. To better understand the effect of ivacaftor therapy across the distribution of individual FEV(1) responses, data from Phase 3 studies (STRIVE/ENVISION) were re-examined. In this post-hoc analysis of patients (n=209) who received 48 weeks of ivacaftor or placebo, patients were assigned to tertiles according to FEV(1) response. Across all tertiles, numerical improvements in FEV(1), sweat chloride, CFQ-R and the frequency of pulmonary exacerbations were observed in ivacaftor-treated patients: the treatment difference versus placebo was statistically significant for all outcomes in the upper tertile and for some outcomes in the lower and middle tertiles. The number needed to treat for a >5% improvement in % predicted FEV(1) was 1.90, for a >5% body weight increase was 5.74, and to prevent a pulmonary exacerbation was 3.85.The authors concluded that this analysis suggests that the majority of patients with clinical characteristics similar to STRIVE/ENVISION patients have the potential to benefit from ivacaftor therapy.

—   Further confirmation of the remarkable effect of ivacaftor in all genetically appropriate patients – as expected, response was better in the less severely affected patients.

(Tertile: Any of the two points that divide an ordered distribution into three parts, each containing a third of the population).

Kopp BT, Nicholson L, Paul G, Tobias J, Ramanathan C, Hayes D Jr. Geographic variations in cystic fibrosis: An analysis of the U.S. CF Foundation Registry. Pediatr Pulmonol. 2015 Mar 30. doi: 10.1002/ppul.23185. [Epub ahead of print]  pubmed.ncbi.nlm.nih.gov/25825016/

Fig. 49 Benjamin T Kopp pedsresearch.org

Emerging evidence suggests that the prevalence of pathogens common in cystic fibrosis (CF) may be unevenly distributed across the United States (U.S.). Data were analyzed from the 30,896 subjects in the U.S. CF Foundation Patient Registry during the years 2007-2012, via geographical grouping of states based upon the Nationwide Inpatient Sample classification.
Significant differences in racial distribution were seen, including half of the total U.S. African-American CFulation residing in the South. Both African-Americans and Hispanics had increased Medicaid usage (52.2%, 41.8%, respectively). Culture-reported pathogens were markedly different across the U.S., with the highest percentage of patients with Methicillin-resistant Staphylococcus aureus (41.9%), Pseudomonas aeruginosa (71.2%), and non-tuberculous mycobacterium (10.0%) in the South. The South region also had the lowest mean body mass index and forced expiratory volume in one second. Chronic medication usage such as inhaled tobramycin or macrolides followed P. aeruginosa distribution, while inhaled dornase alfa was most used in the West (84.7%). Co-morbid conditions varied, with the highest percentage of depressed subjects in the Midwest (18.3%). Mean regional mortality rates were not statistically different among regions, although highest in each age grouping of the South.
The authors concluded the U.S. has significant regional variations in CF demographics, insurance, pathogens, medication usage, and co-morbidities, without an overall impact on regional mortality. They suggest that regional variations in care practices should be studied further based on the findings.

Benjamin T Kopp  (fig. 49)   is Associate Professor of Pediaitrics in the Section of Pulmonary Medicine, Nationwide Children’s Hospital, Columbus, Ohio. and the Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio.

Krzyżanowska P, Pogorzelski A, Skorupa W, Moczko J, Grebowiec P, Walkowiak J. Exogenous and endogenous determinants of vitamin K status in cystic fibrosis. Sci Rep. 2015 Jul 10;5:12000. doi: 10.1038/srep12000. Free PMC article [PubMed]

Fig. 50 Jaroslaw Walkowiak

Cystic fibrosis (CF) patients are at high risk for vitamin K deficiency. The effects of vitamin K supplementation are very ambiguous. Therefore, the authors aimed to define the determinants of vitamin K deficiency in a large cohort of supplemented – 146 (86.9%) and non-supplemented – 22 (13.1%) CF patients. Vitamin K status was assessed using prothrombin inducted by vitamin K absence (PIVKA-II) and undercarboxylated osteocalcin (u-OC). The pathological PIVKA-II concentration (≥ 2 ng/ml) and abnormal percentage of osteocalcin (≥ 20%) were found in 72 (42.8%) and 60 (35.7%) subjects, respectively. Liver involvement, diabetes, and glucocorticoid therapy were potential risk factors for vitamin K deficiency. Pathological concentrations of PIVKA-II occurred more frequently in patients with pancreatic insufficiency and those who have two severe mutations in both alleles of the CFTR gene. Pathological percentage of u-OC was found more frequently in adult CF patients and those not receiving vitamin K. However, it seems that there are no good predictive factors of vitamin K deficiency in CF patients in everyday clinical care.Early vitamin K supplementation in CF patients seems to be warranted. It is impossible to clearly determine the supplementation dose. Therefore, constant monitoring of vitamin K status seems to be justified.

–    It seems clear that there is a variable need for extra vitamin K in people with CF to avoid depletion and the recommendation of these authors seems to be sound advice.

Patrycja Krzyżanowska is in the department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland.

Jaroslaw Walkowiak (fig.50) is Head of Department; Director of Institute  of Poznan University of Medical Sciences, Poznań, Poland.

Lenherr N, Lurà M, Trachsel D, Latzin P, Hammer J. Ivacaftor in a young boy with the rare gating mutation S549R – use of lung clearance index to track progress: a case report. BMC Pulm Med. 2015 Oct 16;15:123. doi: 10.1186/s12890-015-0120-1. Free PMC article [PubMed]

Fig. 51  Nina Lenherr

S549R is a rare gating mutation considered to be less sensitive to potentiators such as ivacaftor than all other gating mutations.  An 8-year-old boy with the rare S549R gating mutation treated with ivacaftor had subjective clinical improvements, the sweat chloride level and the lung clearance index decreased impressively within a few weeks of treatment while forced expiratory volume in the first and second values remained in normal range.

The authors emphasise the value of measuring small airway function by lung clearance index as an outcome measure for new interventions targeting the correction of the CFTR defect at an age before traditional lung function parameters start to deteriorate.

Nina Lenherr (fig.51)  is in the Division of Intensive Care and Pulmonology, University Children’s Hospital Basel (UKBB), University of Basel, Spitalstrasse 33, CH-4056, Basel, Switzerland.

Mainz JG, Gerber A, Lorenz M, Michl R, Hentschel J, Nader A, Beck JF, Pletz MW, Mueller AH. Pseudomonas aeruginosa Acquisition in Cystic Fibrosis Patients in Context of Otorhinolaryngological Surgery or Dentist Attendance: Case Series and Discussion of Preventive Concepts. Case Rep Infect Dis 2015;2015:438517. doi: 10.1155/2015/438517. Epub 2015 Mar 18 [PubMed]

Fig. 51 Jochen Mainz ResearchGate

For their almost regular sinonasal involvement, CF patients often require otorhinolaryngological (ORL) attendance. Despite some fields around ORL-procedures with comparable risk for acquisition of P. aeruginosa as dental procedures, such CF cases have not yet been reported. The authors present four CF patients, who primarily acquired P. aeruginosa around ORL surgery, and one around dentist treatment. Perils include contact to pathogen-carriers in waiting rooms, instrumentation, suction, drilling, and flushing fluid, when droplets containing pathogens can be nebulized. Postsurgery mucosal damage and debridement impair sinonasal mucociliary clearance, facilitating pathogen proliferation and infestation.
They suggest that sinonasal surgery and dentist treatment of CF patients without chronic P. aeruginosa colonisation must be linked to repeated microbiological assessment. Further studies must elaborate whether all CF patients undergoing ORL-surgery require anti-pseudomonal prophylaxis, including nasal lavages containing antibiotics. Altogether, this underestimated risk requires structured prevention protocols.

—    There is increasing interest in the upper respiratory tract and its relation to lower airways infection, in particular as a source of infection.The risks from dental equipment have been known for many years first from Copenhagen (Jensen ET et al. J Hosp Infect 1997; 36(2): 117-122. [PubMed] but the the possibility of other upper respiratory tract procedures determining the onset of P. aeruginosa infection is obviously important.

Jochen Mainz (Fig.51)  is professor at the  Cystic Fibrosis Center, Pediatric Pneumology, Jena University Hospital, 07740 Jena, Germany.

Merlo CA; Clark SC; Arnaoutakis GJ; Yonan N; Thomas D; Simon A; Thompson R; Thomas H; Orens J; Shah AS.  National Healthcare Delivery Systems Influence Lung Transplant Outcomes for Cystic Fibrosis. Am J Transplant 2015; 15(7):1948-57.  [PubMed]
Successful lung transplantation (LTx) depends on multiple components of healthcare delivery and performance. The authors conducted an international registry analysis to compare post-LTx outcomes for cystic fibrosis (CF) patients using the UNOS registry in the United States and the National Health Service (NHS) Transplant Registry in the United Kingdom.

—   Both the United States and United Kingdom have similar early survival outcomes, suggesting important dissemination of best practices internationally. However, patients using US Medicare/Medicaid insurance had significantly worse survival after lung transplant.

Matthes E, Goepp J, Carlile GW, Luo Y, Dejgaard K, Billet A, Robert R, Thomas DY, Hanrahan JW. Low free drug concentration prevents inhibition of F508del CFTR functional expression by the potentiator VX-770 (ivacaftor). Br J Pharmacol. 2015 Oct 22. doi: 10.1111/bph.13365.   [PubMed]

Fig. 52 Elizabeth Matthes

The most common cystic fibrosis (CF) mutation F508del inhibits the gating and surface expression of CFTR (CF Transmembrane conductance Regulator), a plasma membrane anion channel, therefore optimal pharmacotherapies will likely require both a “potentiator” to increase channel open probability and a “corrector” that improves folding and trafficking of the mutant protein and its stability at the cell surface. Interaction between CF drugs has been reported but remains poorly understood. CFTR.

The authors concluded chronic exposure to clinically relevant concentrations of VX-770 does not reduce F508del CFTR function when assayed at those concentrations. Therapeutic benefit of VX-770 + VX-809 (Orkambi) is probably limited by the efficacy of VX-809 rather than by an inhibitory effect of VX-770.

Elizabeth Matthes (fig. 52) is a researcher technician in the Department of Physiology, McGill University, Montréal, QC, Canada.  Subsequently undergraduate  Teaching Lab Coordinator at McGill University.

Maleth J; Balazs A; Pallagi P; Balla Z; Kui B; Katona M; Judak L; Nemeth I; Kemeny LV; Rakonczay Z Jr; Venglovecz V; Foldesi I; Peto Z; Somoracz A; Borka K; Perdomo D; Lukacs GL; Gray MA; Monterisi S; Zaccolo M; Sendler M; Mayerle J; Kuhn JP; Lerch MM; Sahin-Toth M; Hegyi P.  Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis. Gastroenterol 2015; 148(2):427-39.e16.  [PubMed]

Fig. 53 Jozsef Malek

Excessive consumption of ethanol is one of the most common causes of acute and chronic pancreatitis. Alterations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) also cause pancreatitis. However, little is known about the role of CFTR in the pathogenesis of alcohol-induced pancreatitis. Based on studies of human, mouse, and guinea pig pancreas, the authors found that alcohol disrupts expression and localisation of the CFTR. This appears to contribute to development of pancreatitis.The authors suggest strategies to increase CFTR levels or function might be used to treat alcohol-associated pancreatitis.

Jozsef Maleth (fig. 53) is in the First Department of Medicine, University of Szeged, Szeged, Hungary.

Massie J, Castellani C, Grody WW.  Carrier screening for cystic fibrosis in the new era of medications that restore CFTR function.Lancet. 2014 Mar 8;383(9920):923-5. doi: 10.1016/S0140-6736(13)61092-2. Epub 2013 Aug 30. Review. No abstract available.  PMID: [PubMed

Fig 54. John Massie ResearchGate

A timely and very interesting review. Unfortunately there is no abstract available so a summary by this reviewer of the main messages follows –

Although the introduction of carrier screening has resulted in a reported reduction in live CF births by 50%, the authors note that its widespread introduction has been limited by several issues including variable phenotype of patients with the same genotype, the numerous mutations associated with cystic fibrosis, low public awareness of the disease, infrastructure for preconception and prenatal care, genetic counseling resources, and health economic considerations. Resolution of these issues has been slow.

Furthermore, a new issue has emerged — namely, the development of CFTR restorative therapy that challenges the idea that cystic fibrosis is not curable. In this article the authors discuss the implications of “CFTR restorative therapy” on carrier screening for cystic fibrosis. These recent developments include a CFTR suppressor that promotes ribosomal read through for patients with nonsense class 1 mutations (ataluren), a CFTR potentiator that promotes chloride channel gating (ivacaftor) and two CFTR correctors that promote trafficking (lumacaftor and VX-661). The licensing of ivacaftor for the treatment of people with the GF551D (Gly551Asp) mutation undoubtedly represents a new era for the treatment of CF. The availability, and dramatic results of ivacaftor treatment for people with one or two Gly551Asp mutations are likely to influence some decisions about whether to terminate an affected pregnancy. If the drugs are shown to work from infancy, some may argue carrier screening in no longer justified; others would consider carrier screening would still be justified so parents could consider their ability to look after a child with CF or alternatively prepare them for the task.

Unfortunately even if treatment is started soon after birth there is already definite evidence, in both human and animal CF newborns, of there already being significant structural changes. These include meconium ileus, pancreatic structural changes, absence of the vas deferens and structural airway abnormalities. So then the question arises whether pregnant women could safely take CFTR potentiators, correctors or suppressors to prevent these intrauterine complications. Even if the new drugs were proved safe during pregnancy, preconception population carrier screening would still be needed with prenatal testing to establish the diagnosis so appropriate treatment could be started. Even further speculation into the future would consider the need to included only mutations that were associated with severe disease in any screening programme.

Finally, the very high annual cost of ivacaftor (US$270,000) and of presumably other new CFTR therapies still to come, tend to shift the balance in favour of screening.  The authors note an ethical dilemma that “inclusion of the cost of ivacaftor in cost-effectiveness studies is likely to shift the balance substantially in favour of carrier screening while at the same time, an effective but costly therapy is on offer”.

Noting there is still much information needed and no changes to present carrier programmes are needed, the authors consider the information given to at-risk couples about the Gly551Asp will need to change.

—   This reviewer’s additional comments.  While discussing these issues one should not loose sight of the fact that, with present knowledge accumulated over many years of research, it is possible for all couples identified as prospective carrier parents to choose an infant unaffected by CF without the need to terminate any pregnancy at any stage by using preimplantation genetic diagnosis. Cystic fibrosis is now a preventable condition that most parents would wish their child to avoid if at all possible.

John Massie (fig. 54) is Honorary Clinical Associate Professor din the Department of Paedaitrics University of Melbourne and a Research fellow at the Murdoch Children’s Research Institute, Melbourne.  John Massie has published extensively on this subject.

Mayer-Hamblett N, Kloster M, Rosenfeld M, Gibson RL, Retsch-Bogart GZ, Emerson J, Thompson V, Ramsey BW. Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis. Clin Infect Dis. 2015 Sep 1;61(5):707-15. doi: 10.1093/cid/civ377. Epub 2015 May 13.pubmed.ncbi.nlm.nih.gov/25972024/

Fig 55 Nicole Mayer Hamblett
Cystic Fibrosis Foundation

Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the airways in individuals with cystic fibrosis. A key question is whether children with newly acquired Pa infection who are able to achieve sustained eradication after early anti-pseudomonal therapy demonstrate improved long-term health outcomes compared with those who are unable to achieve a sustained microbiologic response.This cohort study utilized observational follow-up data on children participating in the Early Pseudomonas Infection Control trial who received standardised therapy for newly acquired Pa. Sustained eradicators were defined as those who maintained Pa-negative cultures for 12 months after initial anti-pseudomonal therapy. Associations between eradication status and outcomes were assessed.
Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17-.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25-.73) compared with non-sustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with non-sustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline.This is the first study to quantify the long-term durability of microbiological response associated with early anti-pseudomonal therapy, demonstrating the critical importance of optimizing anti-pseudomonal therapies during early Pa infection. The clinical impact of failure to achieve sustained Pa eradication remains unclear, however, and may be confounded by anti-Pa antibiotic usage.

Editorial Commentary: Pseudomonas aeruginosa Eradication: How Do We Measure Success? [Clin Infect Dis. 2015]PMID: 25972024 [PubMed – in process] PMCID: PMC4626753 [Available on 2016-09-01]

Nicole Mayer-Hamblett (fig. 55) is at the Department of Pediatrics Department of Biostatistics, University of Washington Department of Seattle Children’s Hospital, Washington;

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 Thorac Soc. 2014 Feb;11(2):198-204. doi: 10.1513/AnnalsATS.201208-068OC. Free PMC article [PubMed]

Fig. 56 Laura A McCauley

This study assessed associations between vitamin D and % predicted lung function, pulmonary exacerbations, and first Pseudomonas aeruginosa infection in children with CF. The authors hypothesised that children with CF who have 25-hydroxy vitamin D (25-OHD) levels less than 30 μg/L would have worse lung function and more pulmonary exacerbations than those with 25-OHD greater than or equal to 30 μg/L.This 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 μg/L), insufficient (20-29 μg/L), and deficient (<20 μg/L). Longitudinal models followed individuals’ changing vitamin D groups over time to compare numbers of pulmonary exacerbations (defined by hospitalization), 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 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-year.

–   This study showed that 25OHD level less than or equal to 20ug/L in children with CF was associated with three times higher rate of pulmonary exacerbations than those sufficient in vitamin D. The cause and effect was a matter of conjecture. The obvious suggestion is that the vitamin D deficiency levels were a reflection of a more general suboptimal standard of care.

Laura A McCauley (fig.56) is at the Department of Pediatrics, Marshfield Clinic, Marshfield, Wisconsin

Mazumdar M, Christiani DC, Biswas SK, Ibne-Hasan OS, Kapur K, Hug C. Elevated sweat chloride levels due to arsenic toxicity. N Engl J Med. 2015 Feb 5;372(6):582-4. doi: 10.1056/NEJMc1413312 Full text of the letter available. [PubMed]

Fig. 57 Maitreyi Mazumdar

None of 11 participants in Bangladesh with sweat chloride levels of 60 mmol per liter or higher had a genetic diagnosis of cystic fibrosis.  Current arsenic levels in water were higher for the 40 participants with abnormal sweat conductivity (>60 mmol per liter) than for participants with normal or intermediate sweat conductivity (median, 11.9 μg per liter vs. 2.7 μg per liter; P=0.01). The same pattern was seen with current arsenic levels in fingernails (median, 5.64 μg per gram vs. 1.39 μg per gram; P=0.008). Adjusted models revealed no significant confounding according to age, sex, smoking status, or body-mass index. There was no relationship between sweat chloride level and scores on lung-function tests or pulmonary symptoms.

The authors conclude their study shows that elevated sweat chloride levels are found among persons exposed to arsenic in the absence of a genetic diagnosis of cystic fibrosis.

— Yet another reason for an abnormal sweat test.

Maitreyi Mazumdar  is Staff Physician, Pediatric Neurology at Boston Children’s Hospital, Boston, MA

Morton A; Wolfe S. Enteral tube feeding for cystic fibrosis.  Cochrane Database of Systematic Reviews. 4:CD001198, 2015.  [PubMed]

Fig. 58 Alison Morton & Fig. 59 Sue Wolfe
author’s photo

The authors identified 38 trials; however, they considered none were eligible for inclusion in this review. Reported use of enteral tube feeding suggests that it does result in nutritional and respiratory improvement; but, the efficacy has not been fully assessed by randomised controlled trials. They do acknowledge, however, that performing a randomised controlled trial would be difficult due to the ethics of withholding an intervention in a group of patients whose nutritional status necessitates it.

This review by two very experienced Leeds dietitians, Sue Wolfe and Alison Morton, notes that, although there are no controlled trials, reports do support the use of enteral tube feeding.  Fortunately, the authors do not make the frequent closing plea of many Systematic Reviewers for more controlled trials! They consider a controlled trial of enteral feeding would be unethical – so, quite correctly, clinical judgment of the professional carers, and discussion with the patient/parents, should determine who requires and who receives this nutritional treatment.

Alison Morton (fig.58) and Sue Wolfe (Fig.59) are Consultant Dietitians for Adult and Paediatric Cystic Fibrosis Units respectively in the Leeds Regional CF Centres.

Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC, Higgins M; VX11-770-110 (KONDUCT) Study Group. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015 Jul;3(7):524-33. doi: 10.1016/S2213-2600(15)00201-5. Epub 2015 Jun 9. [PubMed]

Fig. 60  Richard Moss
Author’s photo

Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. The authors assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation.They did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV1) of at least 40. They randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11, 12-17, and ≥18 years) and % predicted FEV1 (<70, ≥70 to ≤90, and >90).The primary outcome was the absolute change from baseline in % predicted FEV1 through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores.
An open-label extension enrolled 65 of the patients after washout; after 12 weeks, they did an interim analysis.After 24 weeks, the treatment difference in mean absolute change in % predicted FEV1 between ivacaftor (n=34) and placebo (n=35) was 2·1 percentage points (95% CI -1·13 to 5·35; p=0·20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24·0 mmol/L, 95% CI -28·01 to -19·93; p<0·0001) and CFQ-R respiratory domain (8·4, 2·17 to 14·61; p=0·009). In prespecified subgroup analyses, % predicted FEV1 significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5·0 percentage points, 95% CI 1·15 to 8·78; p=0·01), but not in patients aged 6-11 years (-6·3 percentage points, -11·96 to -0·71; p=0·03).In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV1 improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5·0 percentage points [p=0·0005]; ivacaftor-to-ivacaftor, 6·0 percentage points [p=0·006]). There were no new safety concerns
Although this study did not show a significant improvement in % predicted FEV1, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease.

Richard B Moss (fig. 60)  is former chief of the Pediatric Pulmonary and Allergy Divisions, and allergy-immunology and pulmonary fellowship training programs director, at Stanford University. at Stanford University School of Medicine, Palo Alto, CA, USA

Munck A, Mayell SJ, Winters V, Shawcross A, Derichs N, Parad R, Barben J, Southern KW. Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening. J Cyst Fibros. 2015 Nov;14(6):706-13. doi: 10.1016/j.jcf.2015.01.001. Epub 2015 Jan 24. [PubMed]

Fig. 60a Anne Munck

Newborn screening (NBS) for cystic fibrosis (CF) results in the recognition of a number of infants with a positive NBS result, but an inconclusive diagnosis. Varied practice exists with respect to the management of these infants.A Delphi consensus approach was used to determine agreement on statements generated by a core group of specialists.  Infants were divided into group A (normal sweat chloride and two CFTR mutations, at least one of which has unclear phenotypic consequences) and group B (intermediate sweat chloride and one or no CFTR mutations). 32 statements were produced for Round 1 and 24 achieved consensus. After Round 1, a designation exercise was undertaken and the term “CF Screen Positive, Inconclusive Diagnosis (CFSPID)” was suggested for Round 2. Agreement was achieved for this statement and for all other statements aside from the need for routine respiratory culture, on which there was divided opinion. The core group advocated local practice for this issue. A sensitivity analysis demonstrated that consensus for Round 2 was achieved by change in opinion rather than attrition.The authors note their exercise had generated a new designation and statements to guide the management of infants with CFSPID through a robust international Delphi process. These statements will be a valuable tool for CF teams and will improve the consistency of management of these infants.

–   The detailed suggestions on the management of the two groups of infants are very helpful and supported by a large group of experienced professionals. The central recommendation common to both groups is that a paediatrician expert in cystic fibrosis should follow them all up for as long as necessary.

Anne Munck (fig. 60a) is a paediatrician at Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant, Paris, France; Assistance publique-Hôpitaux de Paris, Hôpital Robert Debré, CF Center, Université Paris 7, Paris, France.

Nadal M; Laudier B; Malinge MC; Binois R; Esteve E.  [Aquagenic palmar keratoderma in a patient heterozygous for the mutation c.3197G>C in the CFTR gene]. [French]  Annal Dermat Venereol 2015; 142(3):201-5. [PubMed]
The first case of aquagenic keratoderma associated with a new mutation in the CFTR gene. An 18-year-old patient with no particular history was referred for a painful rash on both palms occurring whenever she showered, and which had been ongoing for several months. The clinical examination was normal except for an appearance of moderate palmar hyperhidrosis. Following a test in which both hands were immersed in cold water for 5 minutes, the patient presented itching, burning and pain localised to the hands. The palms were wrinkled and oedematous with white, translucent and confluent papules. A clinical diagnosis of aquagenic palmar keratoderma was made. A genetic study revealed the presence of a new mutation in the CFTR gene for cystic fibrosis in the heterozygous state inherited from her mother: c.3197G>C or p.Arg1066.Pro and a heterozygous polypyrimidic 5T variant inherited from her father.

–   Several studies have shown association of acquagenic keratoderma with the CFTR gene for heterozygotes (carriers without cystic fibrosis), for patients with cystic fibrosis and for a patient with CFTRopathy and pancreatitis.

Navarro S.  [Historical compilation of cystic fibrosis].  Gastroenterol Hepatol. 2015 Jun 9. pii: S0210-5705(15)00115-6. doi: 10.1016/j.gastrohep.2015.04.012. [Epub ahead of print] [Article in Spanish] [PubMed]

Fig. 60b Salvador Navarro
Parc Tauli

Cystic fibrosis is the most common life-shortening recessively inherited disorder in the Caucasian population. The genetic mutation that most frequently provokes cystic fibrosis (ΔF508) appeared at least 53,000years ago. For many centuries, the disease was thought to be related to witchcraft and the “evil eye” and it was only in 1938 that Dorothy H. Andersen characterized this disorder and suspected its genetic origin. The present article reviews briefly some of the pathological discoveries and diagnostic and therapeutic advances made in the last 75 years. The review ends with some considerations for the future. (Fig. 4 in the article is of Karl Landsteiner not Sydney Farber).

Salvadore Navarro (fig. 60b)  is Consultor sénior jubilado, Servicio de Gastroenterología, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, España.

Nishida K, Smith Z, Rana D, Palmer J, Gallicano GI. Cystic fibrosis: A look into the future of prenatal screening and therapy. Birth Defects Res C Embryo Today. 2015 Mar;105(1):73-80. doi: 10.1002/bdrc.21091. [PubMed]

Fig. 61 Kevin Nishida

Despite recent guidelines suggesting prenatal screening for carriers of cystic fibrosis (CF) mutations, many physicians do not offer patients this service or even counseling. Some argue that the risks of miscarriage associated with prenatal diagnostic techniques outweigh the benefit of added insight, but with the advent of newer, noninvasive techniques, risks of miscarriage may be significantly lowered. Prenatal diagnosis provides parents the time to prepare for raising a child with CF, and soon, could provide treatment options in utero that could improve quality of life.Here, the authors describe two of the most promising gene therapy approaches: lentivirus and adenoassociated virus (AAV)-mediated gene transduction. Thus, prenatal detection and treatment is in a most crucial stage for care of patients with CF.

–   It is of some concern that intra uterine gene therapy treatment of a CF fetus is increasingly mentioned in the literature as a possibilty when the birth of such a fetus could be avoided by carrier indentification and preimplantation genetic diagnosis.   Although scientifically interesting, it is unlikely that anyone would be prepared to undertake intrauterine gene therapy for a human fetus affected by CF in the foreseeable future. However, there have been previous suggestions that fetal gene therapy would be necessary (Larson et al, 1997; Cohen & Larson, 2006 above) although the work on which these suggestions were based was not repeatable in a careful UK study (Buckley et al, 2008 below). Also it is very unlikely that fetal gene therapy would ever be advisable or indeed approved by the regulatory authorities.

It is unfortunate that there seems to be a lessening of interest in both antenatal screening and diagnosis and population screening for CF mutations – these aspects of prevention being overshadowed by the dramatic developments in specific mutational therapy. In this reviewer’s opinion this is unfortunate for the detection of a CF mutation in each of a couple proposing to have children can, by the use of preimplantation genetic diagnosis, allow them to have a healthy child unaffected by CF.

Kevin Nishida (fig. 61) Georgetown University School of Medicine, Georgetown University Special Master’s Program in Physiology, NW, Med/Dent NE, Washington, DC.

Ooi CY, Castellani C, Keenan K, Avolio J, Volpi S, Boland M, Kovesi T, Bjornson C, Chilvers MA, Morgan L, van Wylick R, Kent S, Price A, Solomon M, Tam K, Taylor L, Malitt KA, Ratjen F, Durie PR, Gonska T. Inconclusive diagnosis of cystic fibrosis after newborn screening. Share on Pediatrics. 2015 Jun;135(6):e1377-85. doi: 10.1542/peds.2014-2081. Epub 2015 May 11[PubMed]

Fig. 62 Keith Chee Ooi research.unsw.edu.au

To prospectively study infants with an inconclusive diagnosis of cystic fibrosis (CF) identified by newborn screening (NBS; “CF screen positive, inconclusive diagnosis” [CFSPID]) for disease manifestations.prospectively evaluated and monitored. Genotype, phenotype, repeat sweat test, serum trypsinogen, and microbiology data were compared between subjects with CF and CFSPID and between subjects with CFSPID who did (CFSPID→CF) and did not (CFSPID→CFSPID) fulfill the criteria for CF during the first 3 years of life.Eighty-two subjects with CFSPID and 80 subjects with CF were enrolled. The ratio of CFSPID to CF ranged from 1:1.4 to 1:2.9 in different centers. CFTR mutation rates did not differ between groups; 96% of subjects with CFSPID and 93% of subjects with CF had 2 mutations. Subjects with CFSPID had significantly lower NBS immunoreactive trypsinogen (median [interquartile range]:77 [61-106] vs 144 [105-199] μg/L; P < .0001) than did subjects with CF. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were isolated in 12% and 5%, respectively, of subjects with CFSPID. CF was diagnosed in 9 of 82 (11%) subjects with CFSPID (genotype and abnormal sweat chloride = 3; genotype alone = 4; abnormal sweat chloride only = 2). Sweat chloride was abnormal in CFSPID→CF patients at a mean (SD) age of 21.3 (13.8) months. CFSPID→CF patients had significantly higher serial sweat chloride (P < .0001) and serum trypsinogen (P = .009) levels than did CFSPID→CFSPID patients.A proportion of infants with CFSPID will be diagnosed with CF within the first 3 years. These findings underscore the need for clinical monitoring, repeat sweat testing at age 2 to 3 years, and extensive genotyping.

–    This report is rather confusing. The fact that 96% of subjects with “CF positive screen but inconclusive diagnosis (CFSPID)” had two CF mutations surely indicates they had cystic fibrosis and would eventually develop overt clinical signs if not already present in mild degree?  It is important to follow such infants carefully in the long term at a CF centre rather than at their local hospital to treat the very earliest signs of malabsorption or chest involvement.  The days of “not bad enough to refer to a CF centre” are over!  Many UK paediatricians would start long term flucloxacillin and vitamin supplements in the infants with two CF mutations and carefully assess their need for pancreatic enzymes as “normal weight” may also represent suboptimal weight gain for a particular infant.

Keith Chee Ooi (Fig 62) is Professor at Discipline of Pediatrics, School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, Australia; Sydney Children’s Hospital Randwick, Sydney, Australia; Division of Gastroenterology, Hepatology, and Nutrition.

Uc A; Olivier AK; Griffin MA; Meyerholz DK; Yao J; Abu-El-Haija M; Buchanan KM; Vanegas Calderon OG; Abu-El-Haija M; Pezzulo AA; Reznikov LR; Hoegger MJ; Rector MV; Ostedgaard LS; Taft PJ; Gansemer ND; Ludwig PS; Hornick EE; Stoltz DA; Ode KL; Welsh MJ; Engelhardt JF; Norris AW.  Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass.  Clinical Science 2015; 128(2):131-42.[PubMed]
Glycaemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycaemia developed over time. It is interesting that functional changes in CF pig pancreas were not associated with a decline in islet cell mass. The results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.

Olivier AK; Gibson-Corley KN; Meyerholz DK. Animal models of gastrointestinal and liver diseases. Animal models of cystic fibrosis: gastrointestinal, pancreatic, and hepatobiliary disease and pathophysiology. [Review] Am J Physiol – Gastr L 2015; 308(6):G459-71.  [PubMed]

Fig 63. Alicia Oliver

Multiple organ systems, including the gastrointestinal tract, pancreas, and hepatobiliary systems, are affected by cystic fibrosis. Many of these changes begin early in life and are difficult to study in young CF patients. Recent development of novel CF animal models has expanded opportunities in the field to  better understand CF pathogenesis and evaluate traditional and innovative therapeutics. In this review, the authors discuss manifestations of CF disease in gastrointestinal, pancreatic, and hepatobiliary systems of humans and animal models. They also compare the similarities and limitations of animal models and discuss future direction for modeling CF.

Alicia K Olivier (fig.63) is Director of the Comparative Pathology Laboratory, University of Iowa where a great deal of the CF animal work is carried out.

O’Neill K; Bradley JM; Johnston E; McGrath S; McIlreavey L; Rowan S; Reid A; Bradbury I; Einarsson G; Elborn JS; Tunney MM.  Reduced bacterial colony count of anaerobic bacteria is associated with a worsening in lung clearance index and inflammation in cystic fibrosis. ONE [Electronic Resource]. 10(5):e0126980, 2015. Free PMC article [PubMed]

Fig. 64 Katherine O’Neill

Anaerobic bacteria have been identified in abundance in the airways of cystic fibrosis subjects. The aim of this study was to investigate the relationship between the colony count of aerobic and anaerobic bacteria, lung clearance index (LCI), spirometry and C-Reactive Protein (CRP) in patients with CF.The authors observed an inverse correlation between colony count of aerobic bacteria (n = 41, r = -0.35; p = 0.02), anaerobic bacteria (n = 41, r = -0.44, p = 0.004) and LCI was observed. There was an inverse correlation between colony count of anaerobic bacteria and CRP (n = 25, r = -0.44, p = 0.03) only.The authors consider the results of this study demonstrate that a lower colony count of aerobic and anaerobic bacteria correlated with a worse lung clearance index. A lower colony count of anaerobic bacteria also correlated with higher CRP levels. They suggest these results indicate that lower abundance of aerobic and anaerobic bacteria may reflect microbiota disruption and disease progression in the CF lung.

–   These findings are difficult to understand.  It is advised the reader looks at the full article which is available.

Katherine O’Neill (fig. 63) is at CF and Airways Microbiology Research Group, Queen’s University Belfast, Belfast, United Kingdom; Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom.

Park IK; Olivier KN.  Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis. Respir Crit Care Med 2015; 36(2):217-24. 25826589  K N [PubMed]

Fig 64. Kenneth Oliver

Increasing numbers of CF and non-CF bronchiectasis patients are affected by pulmonary nontuberculous mycobacteria (NTM) infection worldwide. Two species of NTM account for up to 95% of the pulmonary NTM infections: Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC). Diagnosis of pulmonary NTM infection is based on criteria specified in the 2007 American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) guidelines.While many initial positive cultures do not progress to active NTM disease, even a single positive NTM sputum culture obtained from higher risk groups such as classic CF or older women with bronchiectasis and very low body mass index should be closely monitored for progressive disease.Macrolides remain the most effective agents available against MAC and MABSC. Infection with MABSC may be associated with worse clinical outcomes, as more than half of MABSC isolates have inducible macrolide resistance conferred by an active erm(41) gene.

Of growing concern in CF is that MABSC is becoming more common than MAC, seems to target younger patients with classic CF, and is more difficult to manage, often requiring prolonged courses of intravenous antibiotics. Recurrence rates of NTM after initial successful treatment remain high, likely due to non-modifiable risk factors raising the question of whether secondary prophylaxis is feasible. More rapid and readily available methods for detecting inducible macrolide resistance and better in vitro susceptibility testing methods for other drugs that correlate with clinical responses are needed. This is crucial to identify more effective regimens of existing drugs and for development of novel drugs for NTM infection

A timely article on an increasing problem in people with CF by experts in this area.

Kenneth Olivier (fig. 64) is a pulmonologist in Bethesda, Maryland and is affiliated with National Institutes of Health Clinical Center.

Patel S, Sinha IP, Dwan K, Echevarria C, Schechter M, Southern KW. Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis. Cochrane Database Syst Rev. 2015 Mar 26;3:CD009841. doi: 10.1002/14651858.CD009841.pub2. [PubMed]
To evaluate te effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis.(please see PubMed for detail)
Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the ΔF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing.

Sanjay Patel is at the Department of Women’s and Children’s Health, University of Liverpool, Alder Hey Children’s NHS Foundation Trust, Eaton Road, Liverpool, Merseyside, UK, L12 2AP.

Patil N, Marco A, Montales MT, Bhaskar N, Mittadodla P, Mukasa LN. Pulmonary Tuberculosis in a Patient with Cystic Fibrosis. N Am J Med Sci. 2015 May;7(5):233-5. doi: 10.4103/1947-2714.157494. [PubMed]   Free PMC Article

Fig. 65 Naveen Patil

A 24-year-old CF patient had fever, cough, hemoptysis, and weight loss of 1week duration prior to admission. Past sputum cultures grew methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. The patient was treated with broad spectrum antibiotics based on previous culture data, but failed to improve. Chest radiograph and computed tomography (CT) chest revealed chronic collapse of the anterior sub segment of right upper lobe and multiple bilateral cavitary lesions which were worse compared to prior films. Mycobacterium tuberculosis (MTB) was suspected and was confirmed by positive acid-fast bacilli (AFB) smears and cultures. After receiving first-line anti-tuberculous drugs, the patient’s condition markedly improved.

MTB is an infrequent finding, but considered a potential pathogen in CF patients, and may lead to serious pulmonary complications if there is a delay in diagnosis and treatment. The same group from Arkansas report a 26 year old pregnant CF patient who had recurreent MTB infection (Marco A et al. Respir Med case Rep 2015; 16;57-9).[PubMed]

Naveen Patil (fig.65) is in Department of Health, Arkansas, United States ; University of Arkansas for Medical Sciences, Arkansas, United States.

Peckham D, Williams K, Wynne S, Denton M, Pollard K, Barton R. Fungal contamination of nebuliser devices used by people with cystic fibrosis. J Cyst Fibros. 2015 Jun 20. pii: S1569-1993(15)00153-8. doi: 10.1016/j.jcf.2015.06.004. [Epub ahead of print] [PubMed

Fig 66. Daniel Peckham

A total of 170 nebulisers from 149 subjects were screened by wetting a sterile cotton swab with sterile water and swabbing each drug chamber. The swab was then plated out on Sabouraud and on Scel+agar and incubated at 27°C for up to 2weeks.Fungal cultures were positive in 86 (57.7%) patient’s devices. In 28/149 (18.8%), 39/149 (26.2%), 47/149 (31.5%) and 20/149 (13.4%) of subjects Aspergillus species, yeasts, moulds and both yeasts and moulds were isolated respectively. There was no difference in contamination rates between different devices.Nebuliser devices are frequently contaminated by moulds and yeasts and emphasis should be placed on ensuring adequate nebuliser hygiene.

Peckham D, Whitaker P, White H. Research in progress-electronic patient records: a new era. Thorax 2015 May; 70(5):473-5. doi: 10.1136/thoraxjnl-2014-206573. Epub 2014 Dec 10. [PubMed]
Clinical information systems and electronic records are starting to appear in secondary care and herald new potentials for improving health provision and capturing high quality data. In 2006, the authors set up a program to develop electronic patient records (EPR) for chronic disease using Cystic Fibrosis (CF) as their initial model. Seven years on they are now exploring the real time clinical data to identify risks, trends and outcomes in chronic disease management. The authors are also working to establish new models of integration and to connect information between the client and all areas of health care.

Professor Daniel Peckham (fig. 66) is Director of the Regional CF Centre for adults at St James’s University Hospital in Leeds has pioneered the use of electronic records. His unit now is mostly without paper records.

Principi N; Blasi F; Esposito S.  Azithromycin use in patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis 2015; 34(6):1071-9[PubMed]
Long-term treatment with azithromycin (Az) is included in the current guidelines for CF patients aged >6 years. Az has microbiological, immunomodulatory and anti-inflammatory properties that can reduce some of the biological problems that are among the causes of the progressive lung damage associated with CF. Moreover, although it is not active against Pseudomonas aeruginosa, sub-inhibitory concentrations can reduce their pathogenic role by interfering with some bacterial activities and increasing their susceptibility to antibiotics. Azithromycin also has anti-viral activity that limits the risk of the bacterial pulmonary exacerbations that frequently occur after apparently mild viral infections.

The available data seem to indicate that it is effective during its first year of administration, but the impact of longer treatment is debated. Other still undefined aspects of the use of Az include the possible emergence of antibiotic resistance in the other bacterial pathogens that usually colonise CF patients, the real incidence of adverse events and the drug’s potential interference with other routine therapies.

Nicola Principi –   A review from Milan on the present use and actions of azithromycin in CF. In the USA a median of 67.3% of eligible individuals 6 years and older are receiving longterm azithromycin – considerably more than in the UK.

Prayle AP, Jain K, Touw DJ, Koch BC, Knox AJ, Watson A, Smyth AR. The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison. J Cyst Fibros. 2015 Aug 15. pii:S1569-1993(15)00174-5.doi: 10.1016/j.jcf.2015.07.012. [Epub ahead of print] Full text available [PubMed]

Fig 67 Andrew Prayle cf.cochrane.org

A study to investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission.Eighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 (a biomarker of renal toxicity) was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%).Renal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels.

The full text is available and interesting. The authors discuss the relatively new KIM-1 marker of nephrotoxicity. Before suggesting evening dosing is definitely more toxic they advise a more extensive trial.

Andrew Prayle (fig.67) is a Clinical Assistant Professor, Faculty of Medicine and Sciences, Nottingham.

Quittner A, Suthoff E, Rendas-Baum R, Bayliss MS, Sermet-Gaudelus I, Castiglione B, Vera-Llonch M. Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation: patient-reported outcomes in the STRIVE randomized, controlled trial. Health Qual Life Outcomes. 2015 Jul 2; 13:93. doi: 10.1186/s12955-015-0293-6.[PubMed] Free full text
The authors evaluated how ivacaftor treatment affected CF symptoms, functioning, and well-being, as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a widely-used patient-reported outcome (PRO) measure.The results illustrate broad benefits of ivacaftor treatment across many domains: respiratory symptoms, physical and social functioning, health perceptions, and vitality, as measured by the CFQ-R. The breadth of improvements reflects the systemic mechanism of action of ivacaftor compared to other therapies.

Findings support the patient-reported value of ivacaftor treatment in this patient population.

Quon BS; Schaeffer MR; Molgat-Seon Y; Wilkie SS; Wilcox PG; Guenette JA.  Physiological mechanisms of dyspnoea relief following ivacaftor in cystic fibrosis : a case report.  Resp Physiol Neurobiol 2015; 205:105-8. [PubMed

Fig 68. Bradley Quon

The authors performed detailed cardiopulmonary exercise testing pre- and post-initiation of ivacaftor in a 27-year old male with CF (CFTR genotype F508del/G551D) and chronic airflow  obstruction (FEV1/FVC=0.44). An improvement of FEV1 (by 16%) following ivacaftor was accompanied by clinically significant improvements in exercise capacity (by 14%) and exertional dyspnea (by up to 5 Borg scale units). These improvements were attributable, at least in part, to favourable alterations in the ventilatory response to exercise, including improvements in breathing patterns (e.g., increased tidal volume and reduced breathing frequency) and dynamic operating lung volumes (e.g., increased inspiratory reserve volume and inspiratory capacity) and decreases in dynamic mechanical ventilatory constraints.

Bradley S Quon (fig.68) is Assistant Professor of Medicine University of British Columbia and Research Director of the St Paul’s Hospital Adult CF Clinic.

Qvist T, Gilljam M, Jönsson B, Taylor-Robinson D, Jensen-Fangel S, Wang M, Svahn A, Kötz K, Hansson L, Hollsing A, Hansen CR, Finstad PL, Pressler T, Høiby N, Katzenstein TL; Scandinavian Cystic Fibrosis Study Consortium (SCFSC).  Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia.  J Cyst Fibros. 2015; 14(1):46-52. doi: 10.1016/j.jcf.2014.08.002. Epub 2014 Aug 30. [PubMed]
Data from Danish, Swedish and Norwegian CF centres between 2000 and 2012 identified 11% (157/1270) patients with at least one positive NTM culture during this period. Higher rates of NTM were detected in the  larger centres.

Fig. 69 Tvas Qvist
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Qvist T, Taylor-Robinson D, Waldmann E, Olesen HV, Hansen CR, Mathiesen IH, Høiby N, Katzenstein TL, Smyth RL, Diggle PJ, Pressler T. Comparing the harmful effects of nontuberculous mycobacteria and Gram negative bacteria on lung function in patients with cystic fibrosis. J Cyst Fibros. 2015 Oct 5. pii: S1569-1993(15)00215-5. doi: 10.1016/j.jcf.2015.09.007. [Epub ahead of print] [PubMed]
Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. Infections with a significant impact on rate of decline in % FEV1 were Mycobacterium abscessus complex with -2.22% points per year (95% CI -3.21 to -1.23), Burkholderia cepacia complex -1.95% (95% CI -2.51 to -1.39), Achromobacter xylosoxidans -1.55% (95% CI -2.21 to -0.90), and Pseudomonas aeruginosa -0.95% (95% CI -1.24 to -0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope.

–  A helpful record of extensive experience over a considerable time from Copenhagen confirming the more serious consequences of M. abscessus.

Tavas Qvist (fig.69) is an infectious disease physician at the Copenhagen CF Center.

Radhakrishna N, Morton J. Burkholderia pseudomallei in cystic fibrosis and treatment complications. Respirol Case Rep. 2015 Mar;3(1):1-2. doi: 10.1002/rcr2.86. Epub 2014 Nov 30. [PubMed] Full article available.

Fig. 70 Naghmeh Radhadkrishna

A healthy 29-year-old Australian man with cystic fibrosis (CF) grew Burkholderia pseudomallei on a routine sputum culture 1 month after returning from holiday in Thailand. He underwent a 12-month treatment regime with multiple antibiotics resulting in a number of adverse events. Sputum cultures were cleared of the pathogen and remain negative 8 years post-treatment. There were no clinical sequelae and no deterioration in lung function. Few reports have been published to date on melioidosis in CF patients. The proposed management for this infection includes multiple antibiotics regimens for prolonged periods of time, which may result in adverse events. Optimal treatment and length of treatment are currently determined on an individual basis.

Naghmeh Radhakrishna  (fig.70) is the respiratory registrar at the Monash Medical Centre Melbourne, Victoria, Australia ; Alfred Hospital Melbourne, Victoria, Australia.

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; 190(10):1111-6. doi: 10.1164/rccm.201407-1277OC. [PubMed]

Fig. 71 Kathryn Ramsey Telethon Kids Institute

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. They determined which clinical outcomes (pulmonary inflammation, infection, structural lung disease, respiratory hospitalisations, 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 pro-inflammatory bacterial pathogens 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.

—  More evidence that intervention against infection must be very early in CF infants if the decline in respiratory function is to be minimised or hopefully even avoided.  The UK CF Trust Antibiotic Working Group’s recommendation of longterm flucloxacillin for CF infants from birth for at least the first 3 years seems to be supported by recent studies of this type.

Kathryn A Ramsey (fig. 71) is at the Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia.

Reichman G, De Boe V, Braeckman J, Michielsen D. Urinary incontinence in patients with cystic fibrosis. Scand J Urol. 2015 Oct 19:1-4. [Epub ahead of print]   [PubMed]

Fig. 72 Gina Reichman 

Questionnaires were used to determine the prevalence of incontinence in patients of the Cystic Fibrosis Clinic of the University Hospital in Brussels. Questionnaires were completed by 122 participants aged 6-59 years, showing an overall prevalence of 27% for urinary incontinence. Mainly adults reported urinary incontinence, with a prevalence of 11% in men and 68% in women aged 12 and above. The amount of urinary leakage was usually only a few drops and coughing mainly triggered it. Many of the participants had never mentioned this symptom to anyone.

— As in previous studies, the problem was particularly frequent in women with CF. It is relevant that a quarter of this study population refrained from coughing up phlegm and from physiotherapy. This may adversely affect their respiratory condition. So it is important to actively question and inform about this problem, to enable its detection and treatment.

Gina Reichman (fig.72) is a urologist at the Department of Urology, University Hospital – Free University of Brussels (VUB) , Brussels , Belgium.

Ren CL, Fink AK, Petren K, Borowitz DS, McColley SA, Sanders DB, Rosenfeld M, Marshall BC. Outcomes of infants with indeterminate diagnosis detected by cystic fibrosis newborn screening. Pediatrics. 2015 Jun;135(6):e1386-92. doi: 10.1542/peds.2014-3698. Epub 2015 May 11. [PubMed]

Fig. 73 Clement L Ren CHOP Research Institute

Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) describes asymptomatic infants with a positive cystic fibrosis (CF) newborn screen (NBS) but inconclusive diagnostic testing for CF. Little is known about the epidemiology and outcomes of CRMS. The goal of this study was to determine the prevalence, clinical features, and short-term outcomes of infants with CRMS.The authors analyzed data from the US CF Foundation Patient Registry (CFFPR) from 2010 to 2012. They compared demographic, diagnostic, anthropometric, health care utilization, microbiology, and treatment characteristics between infants with CF and infants with CRMS.There were 1983 infants diagnosed via NBS between 2010 and 2012 reported to the CFFPR. By using the CF Foundation guideline definitions, 1540 and 309 infants met the criteria for CF and CRMS, respectively (CF:CRMS ratio = 5.0:1.0). Of note, 40.8% of infants with CRMS were entered into the registry with a clinical diagnosis of CF. Infants with CRMS tended to have normal nutritional indices. However, 11% of infants with CRMS had a positive Pseudomonas aeruginosa respiratory tract culture in the first year of life.CRMS is a common outcome of CF NBS, and some infants with CRMS may develop features concerning for CF disease. A substantial proportion of infants with CRMS were assigned a clinical diagnosis of CF, which may reflect misclassification or clinical features not collected in the CFFPR.

–   It is no surprise that many of the “cystic fibrosis transmembrane conductance regulator related metabolic syndrome” (CRMS) were eventually classified as having cystic fibrosis.

Clement L Ren (fig.73) is in the Division of Pediatric Pulmonology, Department of Pediatrics, University of Rochester, Rochester, New York;

Ridderberg W, Andersen C, Væth M, Bregnballe V, Nørskov-Lauritsen N, Schiøtz PO. . Lack of evidence of increased risk of bacterial transmission during cystic fibrosis educational programmes. J Cyst Fibros. 2015 May 20. pii: S1569-1993(15)00115-0. doi: 10.1016/j.jcf.2015.04.007. [Epub ahead of print]  [PubMed]

Fig. 74 Winnie Riddersberg

Educational and rehabilitation programmes increase the quality-of-life of patients with cystic fibrosis, but patients are discouraged to participate because of the risk of cross-infections.    Isolates of Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae cultured one year before to one year after attendance were investigated by pulsed field gel electrophoresis, multilocus sequence typing and/or spa-typing.   The authors typed 984 bacterial isolates cultured from 46 patients aged 5-18years attending educational programmes at Aarhus University Hospital during 2009-2011. There were no cross-infections with P. aeruginosa. Six cases of S. aureus or H. influenzae strain replacement with a new strain-type shared with a fellow attendee were found. However, the probability of acquiring a shared strain of S. aureus or H. influenzae was not increased for patients attending educational programmes.Transmission of P. aeruginosa, S. aureus and H. influenzae related to attendance to the investigated educational programmes could not be documented.

— This reviewer  considers this abstract is seriously misleading and suggests readers consult the full text.  The full text states that “CF patients infected with Burkholderia cepacia complex, methicillin-resistant S. aureus, Pandorea sp., multiresistant Achromobacter sp., or multiresistant P. aeruginosa were excluded from participation in educational programmes. The attendees were not segregated according to P. aeruginosa carrier status, but patients with respiratory cultures of P. aeruginosa six months prior to attendance (n = 13) were treated with oral ciprofloxacin and inhaled tobramycin the evening before and on the morning of educational programme days in order to minimise the risk of transmission. Children with respiratory cultures of Achromobacter sp. six months prior to attendance (n = 1) were treated with inhaled colistin the evening before and on the morning of educational programme days in order to minimise the risk of transmission”.

Few clinicians would allow their patients to attend these programmes the danger being that a highly resistant P. aeruginosa may spread to a number of other patients before it was recognised as has been reported from other clinics with tragic results. 

Winnie Riddersberg (fig.74) is Senior scientist at QIAGEN Aaathus Denmark

Robertson SM; Luo X; Dubey N; Li C; Chavan AB; Gilmartin GS; Higgins M; Mahnke L.  Clinical drug-drug interaction assessment of ivacaftor as a potentialitor of cytochrome P450 and P-glycoprotein.  J Clin Pharmacol 2015; 55(1):56-62.  [PubMed]

Fig. 75 Sarah Robertson

A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect inhib of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients.

The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6.Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

Sarah M Robertson (fig. 75) is strategic cross-functional leader at Vertex Pharmaceuticals Incorporated, Boston, MA,, USA.

Roberts R; Speight L; Lee J; George L; Ketchell RI; Lau D; Duckers J.  Retinal screening of patients with cystic fibrosis-related diabetes in Wales – a real eye opener.  J Cyst Fibros 2015; 14(2):282-4. [PubMed]
In the UK the National Screening Committee recommends annual retinal screening for all diabetic patients over the age of twelve years. Currently, patients on insulin therapy for Cystic Fibrosis-Related Diabetes Mellitus (CFRD) at the All Wales Adult Cystic Fibrosis Service, UK are invited for annual screening.  67 of the 228 (29%) patients attending the CF centre were receiving insulin therapy. Of the 43 who had retinal scans, 18 (42%) had evidence of retinopathy. Patients with retinopathy had a higher mean HbA1c (p=0.04), mean duration of diabetes and mean duration on insulin (p<0.001).Almost half of the patients screened had evidence of retinopathy but over a third of the patients with CFRD did not attend screening appointments. Improving patient uptake of retinal scans will become increasingly important in an ageing CF population.

—    A disappointing proportion of eligible patients attended for retinal screening particularly in view of the high percentage of retinopathy in those who did attend.

From the All Wales Adult Cystic Fibrosis Centre, University Hospital Llandough, Cardiff, CF64 2XX, United Kingdom.

Roux AL, Catherinot E, Soismier N, Heym B, Bellis G, Lemonnier L, Chiron R, Fauroux B, Le Bourgeois M, Munck A, Pin I, Sermet I, Gutierrez C, Véziris N, Jarlier V, Cambau E, Herrmann JL, Guillemot D, Gaillard JL; OMA group.  Comparing Mycobacterium massiliense and Mycobacterium abscessus lung infections in cystic fibrosis patients. J Cyst Fibros. 2015; 14(1):63-9. doi: 10.1016/j.jcf.2014.07.004. Epub 2014 Jul 30. [PubMed]
This data from a national French survey, show a particular link between M. massiliense and malnutrition specifically in CF patients. Unlike M. abscessus, the bacteriological response of M. massiliense to combination antibiotic therapies containing clarithromycin was excellent. Distinguishing between M. massiliense and M. abscessus has major clinical implications for CF patients.

Rowland M, Gallagher C, Gallagher CG, Laoide RÓ, Canny G, Broderick AM, Drummond J, Greally P, Slattery D, Daly L, McElvaney NG, Bourke B. Outcome in patients with cystic fibrosis liver disease. J Cyst Fibros. 2015 Jan;14(1):120-6. doi: 10.1016/j.jcf.2014.05.013. Epub 2014 Jun 7 [PubMed]

Fig 76. Marion Rowland

Irish children with CF liver disease (CFLD), and their age and gender matched controls were enrolled at baseline and reviewed after 10 years to determine which characteristics predict mortality.72/84 (85.71%) of participants were followed, (mean age Cases 21.71yrs SD 6.5, CF controls 23.62 SD 5.6, 22 (61%) males), with no difference in duration of follow-up. Nineteen participants (26.4%) died,  38.9% (14/36) with CFLD and 13.89% (5/36) CF controls (Odds Ratio (OR) 3.94 95% CI:1.23-12.56 p=0.005).   In logistic regression, liver disease (OR 4.28 95% CI 1.07-17.16) female gender (OR 12.25 95% CI 2.37-63.24), reduced pulmonary function, (OR 5.11 95% CI 1.09-23.81) were each independent risk factors for mortality in CF.  zzzThe authors concluded liver disease is an independent risk factor for mortality in CF

Marion Rowland (fig.76)  is Lecturer in Clinical Research, School of Medicine Dublin. She has had extensive international experience and for the past 15 years has been a Clinical Epidemiologist with a special interest in paediatric gastrointestinal diseases.

Sawicki GS, McKone EF, Pasta DJ, Millar SJ, Wagener JS,, Johnson CA, Konstan MW. Sustained Benefit from Ivacaftor Demonstrated by Combining Clinical Trial and Cystic Fibrosis Patient Registry Data. Am J Respir Crit Care Med. 2015 Oct 1;192(7):836-42. doi: 10.1164/rccm.201503-0578OC. [PubMed]

Fig. 77 Gregory S Sawacki childrenshospital.org

A study to examine, over a 3-year period, whether ivacaftor therapy affects pulmonary function and nutritional measures in patients with CF with a G551D mutation compared with patients with CF who are homozygous for the F508del mutation.A propensity score was used to match patients with CF greater than or equal to 6 years of age who have a G551D mutation and received ivacaftor in clinical trials for up to 144 weeks with data from patients in the U.S. Cystic Fibrosis Foundation Patient Registry who are homozygous for the F508del mutation.The rate of lung function decline in G551D ivacaftor-treated patients was slower by nearly half. Moreover, treatment with ivacaftor is shown to improve body mass index and weight-for-age z scores for G551D patients over the 3-year analysis period. The authors conclude these findings suggest that ivacaftor is a disease-modifying therapy for the treatment of cystic fibrosis.

—    Few would question the authors’ conclusions that ivacaftor is a disease modifying therapy for the treatment of CF. However, the study does show that the benefits are sustained.

Gregory S Sawacki (fig. 77) is Professor Director of the CF centre at the Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.

Sanders B, Emerson J, Ren CL, Schechter MS, Gibson RL, Morgan W, Rosenfeld M; EPIC Study Group. Early Childhood Risk Factors for Decreased FEV1 at Age Six to Seven Years in Young Children with Cystic Fibrosis. Ann Am Thorac Soc. 2015; 12(8):1170-6. doi: 10.1513/AnnalsATS.201504-198OC.

Fig. 78 Don B Sanders Indiana School of medicine

To evaluate early childhood predictors of lung function at age 6-7 in a large U.S. CF cohort in the current era of widespread early eradication therapy for P. aeruginosa.   Participants were children with CF enrolled before age 4 in the Early Pseudomonas Infection Control (EPIC) Observational Study, a multicenter, longitudinal study that enrolled P. aeruginosa-negative children not exceeding 12 years of age. Linear regression was used to estimate the association between potential early childhood risk factors and the best FEV1% predicted at age 6-7 years.Four hundred and eighty-four children (of 1,797 enrolled in the EPIC Observational Study) met the eligibility criteria for this analysis. Mean (SD) age at enrolment was 2.0 (1.3) years.In a multivariable model adjusted for age at enrolment, the following risk factors were significantly associated with lower mean (95% confidence interval) FEV1% predicted at age 6-7: weight percentile less than 10% during the year of enrolment (-5.3 [-9.1, -1.5]), P. aeruginosa positive during the year of enrolment (-2.8 [-5.7, 0.0]), crackles or wheeze during the year of enrolment (-5.7 [-9.4, -1.9]), mother’s education of high school or less (-4.2 [-7.3, -1.2]), and mother smoked during pregnancy (-4.4 [-8.8, 0.1]).In this large U.S. cohort, the authors identified several early childhood risk factors for lower FEV1 at age 6-7 years, most of which are modifiable

—  Most of the factors identified are predictable, obvious  and familiar to most experienced clinicians and have been suggested in previous studies but it is good to have them clearly documented in such a large population.

Don B Sanders (fig.78) is at the Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Sawicki GS, Chou W, Raimundo K, Trzaskoma B, Konstan MW. Randomized trial of efficacy and safety of dornase alfa delivered by eRapid nebulizer in cystic fibrosis patients. J Cyst Fibros. 2015 Nov;14(6):777-83. doi: 10.1016/j.jcf.2015.04.003. Epub 2015 Apr 25. [PubMed]
Efficacy and safety of dornase alfa via an electronic nebulizer with vibrating membrane technology have not been formally assessed in randomized clinical trials.   87 CF patients (≥6years) were randomized in a crossover study to receive dornase alfa 2.5mg/d in 2-week periods with the Pari eRapid and Pari LC Plus jet nebulizers. The primary end point was comparison of forced expiratory volume in the first second. Safety, quality of life, and treatment satisfaction/preference were also compared between devices.Lung function was equivalent between nebulizers. Most domain scores from the Cystic Fibrosis Questionnaire-Revised and Treatment Satisfaction Questionnaire for Medication instruments were similar but patients strongly preferred the eRapid. Mean patient-reported administration times were shorter with the eRapid vs the LC Plus (2.7 vs 10.2min). Adverse events were similar between devices.

Administration of dornase alfa via the eRapid nebulizer resulted in comparable efficacy and safety, shorter nebulization times, and higher patient preference.

Gregory S Sawacki (fig. 77) is Professor Director of the CF centre at the Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.

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

Fig 80. Susanna McColley

Fig 79.  Adrienne Savant

In this article, the authors review cystic fibrosis research published in Pediatric Pulmonology during 2014, as well as related articles published in other journals. This is a very interesting, comprehensive well referenced (100 references) account of progress during 2014 and is recommended reading for all those responsible for any aspect of CF care.

Susanna McColley (fig.80) is Associate Director, Cystic Fibrosis Center Division of Pulmonary Medicine Ann & H. Lurie Robert Children’s Hospital of Chicago;
Adrienne Savant (fig. 79) is Attending Physician, Pulmonary Medicine; Co-Director, Cystic Fibrosis Center Northwestern University Feinberg School of Medicine.

Safi KH, Filbrun AG, Nasr SZ. Hypervitaminosis A causing hypercalcemia in cystic fibrosis. Case report and focused review. Am Thorac Soc 2014; 11(8):1244-7. doi: 10.1513/AnnalsATS.201404-170BC.[PubMed]
Hypercalcemia is a rare complication of hypervitaminosis A. The authors report a 4-year old child with cystic fibrosis (CF) and pancreatic insufficiency who was found to have hypervitaminosis A causing hypercalcemia, complicated by nephrocalcinosis and renal impairment. She was managed by withholding vitamin A supplements, aggressive diuresis, and prednisolone.The authors emphasise the importance of regular vitamin A monitoring in patients with CF. There is a wide variability for the lowest intake of vitamin A required to cause toxicity.

— It is disappointing to read that there are still children with CF who do not have their fat soluble vitamin  levels monitored on a regular basis – a practice recommended in some centres for over 30 years!

Khalid H Safi is in the Department of Pediatric Pulmonology, University of Michigan, Ann Arbor, Michigan.

Schall JI, Mascarenhas MR, Maqbool A, Dougherty KA, Elci O, Wang DJ, Altes TA, Hommel KA, Shaw W, Moore J, Stallings VA. Choline Supplementation with a Structured Lipid in Children with Cystic Fibrosis: A Randomized Placebo-Controlled Trial. J Pediatr Gastroenterol Nutr. 2015 Oct 9. [Epub ahead of print] [PubMed]
Choline depletion is seen in cystic fibrosis (CF) and pancreatic insufficiency (PI) in spite of enzyme treatment and may result in liver, fatty acid and muscle abnormalities. This study evaluated the efficacy and safety of an easily absorbed choline-rich structured lipid (LYM-X-SORB [LXS]) to improve choline status.Children with CF and PI were randomised to LXS or placebo in a 12-month double blind trial. 110 subjects were enrolled (age 10.4 ± 3.0 years). LXS had improved choline intake, plasma choline status and muscle choline stores, compared with placebo. The choline-rich supplement was safe, accepted by participants and improved choline status in children with CF.

–  The metabolism and significance of choline in CF and other conditions has been reviewed recently (Hollebeck CB. Cent Nerv Syst Agents Med Cham 2012; 12(2):100-13. [PubMed]. In the present study there is no mention that there was any change in the clinical condition commensurate with the improved choline status.>

Schechter MS; Regelmann WE; Sawicki GS; Rasouliyan L; VanDevanter DR; Rosenfeld M; Pasta D; Morgan W; Konstan MW. Antibiotic treatment of signs and symptoms of pulmonary exacerbations: a comparison by care site. Pulmonology 2015; 50(5):431-40.325 a href=”http://pmid.us/25530325″>[PubMed] Pediatric care sites enrolled in the Epidemiologic Study of Cystic Fibrosis (ESCF) were ranked by median FEV1 % predicted of the children they followed. Those sites in the highest quartile for FEV(1) were more likely to prescribe antibiotics when patients presented with either mild or overt evidence of a pulmonary exacerbation (PEx). While this may not be the only reason that their patients have superior median FEV(1), it is likely an important contributor.

–   An interesting study confirming the importance of early treatment of even mild new symptoms and signs – one of the most important principles of CF care. A new cough needs treatment whatever the other signs and symptoms!

Sheikh SI; Long FR; McCoy KS; Johnson T; Ryan-Wenger NA; Hayes D Jr.  Ivacaftor improves appearance of sinus disease on computerised tomography in cystic fibrosis patients with G551D mutation. Clin Otolaryngol 2015; 40(1):16-21[PubMed]
Twelve patients with a G551D-CFTR mutation were monitored for at least one year before and after starting ivacaftor. Patients with CF and G551D mutation, within 6 months of starting ivacaftor had significant improvements in weight, BMI and mean % FEV1. Significant lessening of underlying sinus disease measured by CT scan was noted, suggesting a disease modifying effect.

Sheikh SI; Long FR; McCoy KS; Johnson T; Ryan-Wenger NA; Hayes D Jr. Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation. J Cyst Fibros 2015; 14(1):84-9.  [PubMed]

Fig. 81 Shahid I Sheikh nationwidechildrens.org

A single-center study was performed in CF patients receiving ivacaftor to evaluate the usefulness of high resolution computed tomography (HRCT) of the chest as a way to gauge response to ivacaftor therapy.
Ten patients with CF were enrolled for at least one year before and after starting ivacaftor. At time of enrolment, mean age was 20.9 +/- 10.8 (range 10-44) years. There were significant improvements from baseline to 6 months in mean %FVC (93 +/- 16 to 99 +/- 16) and %FEV1 (79 +/- 26 to 87 +/- 28) but reverted to baseline at one year. Mean sweat chloride levels decreased significantly from baseline to one year. Mean weight and BMI improved at 6 months. Weight continued to improve with stabilisation of BMI at one year.Chest HRCT showed significant improvement at one year in mean modified Brody scores for bronchiectasis, mucous plugging, airway wall thickness, and total Brody scores. Elevated bronchiectasis and airway wall thickness scores correlated significantly with lower %FEV1, while higher airway wall thickness and mucus plugging scores correlated with more pulmonary exacerbations requiring IV and oral antibiotics respectively.The authors concluded that, based on their findings, HRCT imaging is a useful tool in monitoring response to ivacaftor therapy.

Dr S I Sheikh (fig.81) is in the Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA

Skov M; Pressler T; Lykkesfeldt J; Poulsen HE; Jensen PO; Johansen HK; Qvist T; Kraemer D; Hoiby N; Ciofu O. The effect of short-term, high-dose oral N-acetylcysteine treatment on oxidative stress markers in cystic fibrosis patients with chronic P. aeruginosa infection — a pilot study.  J Cyst Fibros 2015; 14(2):211-8.  [PubMed]
Supplementation with anti-oxidants is potentially beneficial for CF patients. The effect of 4 weeks of oral N-acetylcysteine (NAC) treatment (2400 mg/day divided into two doses) on biochemical parameters of oxidative stress was investigated in an open-label, controlled, randomised trial on 21 patients; 11 patients in the NAC group and 10 in the control group. Biochemical parameters of oxidative burden and plasma levels of antioxidants were assessed at the end of the study and compared to the baseline values in the two groups.
A significant increase in the plasma levels of the antioxidant ascorbic acid (p=0.037) and a significant decrease in the levels of the oxidized form of ascorbic acid (dehydroascorbate) (p=0.004) compared to baseline were achieved after NAC treatment. No significant differences were observed in the control group. The parameters of oxidative burden did not change significantly compared to baseline in either of the groups.
A better lung function was observed in the NAC treated group with a mean (SD) change compared to baseline of FEV1% predicted of 2.11 (4.6), while a decrease was observed in the control group (change -1.4 (4.6)), though not statistically significant.   The authors concluded that  treatment with N-acetylcysteine 1200 mg x 2/day for 30 days significantly decreased the level of oxidised vitamin C and increased the level of vitamin C (primary end-points) and a non statistically significant improvement of lung function was observed in this group of patients.

—   Further modest evidence that N-acetylcysteine had a significant effect on the antioxidant status of people with CF.  (Some past papers from as far back as 1962 are reviewed in Topics -> Mucolytics -> N-acetylcysteine).

Marianne Skov  is at the Copenhagen Cystic Fibrosis Center, University Hospital Rigshospitalet, Copenhagen, Denmark.

Salinas DB, Sosnay PR, Azen C, Young S, Raraigh KS, Keens TG, Kharrazi M. Benign outcome among positive cystic fibrosis newborn screen children with non-CF-causing variants. J Cyst Fibros. 2015 Mar 28. pii: S1569-1993(15)00061-2. doi: 10.1016/j.jcf.2015.03.006. [Epub ahead of print]

Fig.82 Danieli Salinas

The authors analyzed CF disease-defining variables over 2-6 years in two groups of California CF screen- positive neonates born from 2007 to 2011: (1) children with two CF-causing variants and (2) children with one CF-causing and one non-CF-causing variant, as defined by CFTR2.
Children carrying non-CF-causing variants had significantly higher birth weight, lower immunoreactive trypsinogen and sweat chloride values, higher first year growth curves, and a lower rate of persistent Pseudomonas aeruginosa colonization compared to children with two CF-causing variants.
The outcomes in children 2-6 years of age with the L997F, G576A, R1162L, V754M, R668C, R31C, and S1235R variants are consistent with the CFTR2 non-CF-causing classification.

— These results would be expected. The information regarding the specific mutations is valuable.

Danieli Barino Salinas is a pediatric pulmonologist at Pediatrics-Pediatric Pulmonology, Keck School of Medicine, Children’s Hospital Los Angeles, University of Southern California (USC), 4650 Sunset Boulevard, MS 83, Los Angeles, CA 90027,

Schultz A, Stick S. Early pulmonary inflammation and lung damage in children with cystic fibrosis. Respirology 2015 Mar 30. doi: 10.1111/resp.12521. [Epub ahead of print]

Fig 83  Andre Schultz

Individuals with cystic fibrosis (CF) suffer progressive airway inflammation, infection and lung damage. Airway inflammation and infection are present from early in life, often before children are symptomatic. CF gene mutations cause changes in the CF transmembrane regulator protein that result in an aberrant airway microenvironment including airway surface liquid (ASL) dehydration, reduced ASL acidity, altered airway mucin and a dysregulated inflammatory response. This review discusses how an altered microenvironment drives CF lung disease before overt airway infection, the response of the CF airway to early infection, and methods to prevent inflammation and early lung disease.

Andre Schultz (fig. 83) is a Paediatrician and Respiratory Physician at the Princess Margaret Hospital for Children, a Raine Medical Research Foundation Clinical Research Fellow and a Clinical Senior Lecturer at the School of Paediatrics and Child Health, University of Western Australia.

–     Already there are a number of significant structural changes in the CF infant by the time of birth as evidenced by the often severe pancreatic changes (figure: neonatal CF pancreas). These changes permitted Dorothy Andersen to recognise CF as a distinct entity among the many marasmic infants that came to postmortem in New York during the Thirties. These changes are likely to be irreversible as may also be the case with the prenatal changes in the lung where early structural and inflammatory changes, even in the fetus, have been described and reviewed (Verhaeghe C et al. J Cyst Fibros 2007; 6:304-308. [PubMed] Full text of an interesting review), the possibility of inflammatory changes being related to ion channel abnormalities was suggested.

Stankovic Stojanovic K, Hubert D, Leroy S, Dominique S, Grenet D, Colombat M, Clement A, Fayon M, Grateau G.  25054230″> Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network.  Amyloid 2014; 21(4):231-7. doi: 10.3109/13506129.2014.943834. Epub 2014 Jul 23. [PubMed]
Nine cases of AA amyloidosis were identified (CF prevalence in France is approximately 6000 patients) 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. Organ involvement included kidney disease in all cases (proteinuria, with a median age at onset of 24 years, 4 cases with nephrotic syndrome, 5 with renal failure); gastrointestinal (4 cases with duodenal ulcer); thyroid (2 cases); and hepatobiliary system (3 cases). The median age at diagnosis of CF was 6.5 years. Five patients had pancreatic insufficiency. All patients had chronic respiratory infections requiring intravenous antibiotics several times a year. Five patients have died, at a median age of 29 years and a median duration of 6 years after the onset of proteinuria.

–    AA amyloidosis is a rare but important complication of CF. As in these patients, renal involvement is predominant.

Stecenko AA, Moran A. Update on cystic fibrosis-related diabetes. Curr Opin Pulm Med. 2010 Nov;16(6):611-5. doi: 10.1097/MCP.0b013e32833e8700.[PubMed]

Fig.84 Arlene A Stecenko

The aim of this articis to provide a detailed review of recent publications on cystic fibrosis-related diabetes (CFRD) with a particular focus on the interplay between cystic fibrosis (CF) lung disease and diabetes.
CFRD is a form of diabetes that is distinct from type 1 or type 2 diabetes. CFRD remains very common and increases in prevalence with increasing age so that one in two middle-aged CF persons have CFRD. People with CFRD have lower lung function, worse nutrition, more frequent hospitalization, and worse mortality than CF people without diabetes. The excess mortality previously noted in women with CFRD compared with CF women without diabetes or CF men is much less apparent.
CFRD is due to insulin deficiency and peripheral insulin resistance is much less a factor. Genetic susceptibility and oxidant stress are key risk factors for developing CFRD. The lung is the prime end organ target in CFRD and mortality is due to respiratory failure, not vascular complications. Insulin is the mainstay of therapy and early recognition and institution of therapy appear to improve health outcomes.

CFRD remains one of the most important co-morbidities in CF. Early recognition of the disease and therapeutic intervention may diminish the negative impact that diabetes has on lung health in CF. Although a clearer understanding of the role of oxidant stress and genetics in the pathogenesis of CFRD is being elucidated, much needs to be learned before more targeted, specific therapies can be developed for this distinct form of diabetes.

Arlene Audrey Stecenko (fig. 84) is Associate Professor at the Department of Pediatrics, Emory University, 2015 Uppergate Drive, Atlanta, GA 30322, USA.

Subbarao P; Milla C; Aurora P; Davies JC; Davis SD; Hall GL; Heltshe S; Latzin P; Lindblad A; Pittman JE; Robinson PD; Rosenfeld M; Singer F; Starner TD; Ratjen F; Morgan W.  Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report.  Ann Amer Thorac Soc 2015; 12(6):932-9.   [PubMed]

Fig 85. Padmaja Subbarao

This workshop, of distinguished attendees, concluded that the Multiple Brehttp://www.sickkids.ca/images/Staff%20profiles/9748-011549.jpgath Washout (MBW) test is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients  with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardisation across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, they concluded there are insufficient data to support the use of Lung Clearance Index or MBW parameters in the routine clinical management of patients with CF.This attractive, non-invasive, test has received considerable attention and evaluation in recent years, particularly as a measure of respiratory function in young children. It is likely to gain general acceptance as a measure of respiratory function in young patients and represents a major advance.

Padmaja Subbarao (fig. 85) is Staff Respirologist at the Hospital for Sick Children, Toronto

Sonneveld N, Stanojevic S, Amin R, Aurora P, Davies J, Elborn JS, Horsley A, Latzin P, O’Neill K, Robinson P, Scrase E, Selvadurai H, Subbarao P, Welsh L, Yammine S, Ratjen F. Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations. Eur Respir J. 2015 Oct; 46(4):1055-64. doi: 10.1183/09031936.00211914. Epub 2015 Jul 9.[PubMed]

Fig 86 Nicole Sonneveld ResearchGate

Fig. 87 Sanja Stanojevic medicine.dal.ca

A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI −0.60– −0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: −0.9%, 95% CI −1.0– −0.4%).LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.A retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations in CF and to understand factors explaining the heterogeneous response.
The study confirms that LCI does decrease significantly in patients with CF treated for a pulmonary exacerbation. However the overall effect size was smaller for LCI than for FEV1, and there was discordance between FEV1 and LCI.

The authors suggest future studies should assess how treatment response assessed by LCI is linked to the subsequent course of lung disease as well as long-term outcomes.

Nicole Sonneveld (fig. 86) is in the Division of Respiratory Medicine, Hospital for Sick Children, Toronto, ON, Canada.
Sanja Stanojevic (fig. 87) of the Division of Respiratory Medicine, Hospital for Sick Children, Toronto, ON, Canada Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, ON,

Taylor-Cousar J, Niknian M, Gilmartin G, Pilewski JM; for the VX11-770-901 investigators. Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States. J Cyst Fibros. 2015 Feb 11. pii: S1569-1993(15)00010-7. doi: 10.1016/j.jcf.2015.01.008. [Epub ahead of print] [PubMed]

Fig. 88 Jennifer Taylor-Cousar som.cuanschutz.edu

Patients with severe lung disease were excluded from the randomized Phase 3 trials of ivacaftor. This open-label study was designed to provide ivacaftor to patients in critical medical need prior to commercial product availability.   CF patients aged ≥6years with a G551D-CFTR mutation and FEV1≤40% predicted or listed for lung transplant received ivacaftor 150mg every 12h. The primary endpoint was safety as determined by adverse events. Secondary endpoints included assessment of lung function and weight.The rate of serious adverse events was consistent with disease severity. At 24weeks of treatment with ivacaftor, there was a mean absolute increase predicted FEV1% of 5.5 percentage points and a 3.3kg mean absolute increase in weight from baseline.So in patients with severe lung disease, ivacaftor was well tolerated and was associated with improved lung function and weight gain.

Taylor-Cousar JL; Wiley C; Felton LA; St Clair C; Jones M; Curran-Everett D; Poch K; Nichols DP; Solomon GM; Saavedra MT; Accurso FJ; Nick JA.  Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease.  J Cyst Fibros 2015; 14(2):228-36.  [PubMed]
Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks.  Twenty subjects completed the study. Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. The drug was safe and decreased sputum elastase activity. The authors suggested further study of sildenafil as an anti-inflammatory in cystic fibrosis.See also Topics -> Drug modulation, New drugs -> phosphodiesterase inhibitors. Also sildenafil is mentioned in various contexts in this History (pulmonary hypertension, activation of chloride transport)and these can be found via ‘Site Search’ in the Main Menu.

Jennifer L Taylor-Cousar (fig. 88) is Associate Director, Adult CF Program National Jewish Health, Denver, and Assistant Professor in the University of Colorado in Pulmonology and Pediatrics.

Thaker V; Haagensen AL; Carter B; Fedorowicz Z; Houston BW. Recombinant growth hormone therapy for cystic fibrosis in children and young adults.[Update of Cochrane Database Syst Rev. 2013;6:CD008901;[PubMed] Cochrane Database of Systematic Reviews. 5:CD008901, 2015. [PubMed]

Fig 89. Vidu Thaker

Four controlled trials were included in this review (with 161 participants in total), each with an unclear risk of bias. There was no consistent benefit in lung function across all studies. Little evidence was found for improvement in quality of life. An improvement in fasting blood glucose levels was reported when comparing recombinant human growth hormone (rhGH) to placebo only. Exercise capacity improved in participants receiving standard dose recombinant growth hormone versus no treatment, but not for any other comparison.

The authors concluded recombinant growth hormone therapy is effective in improving the intermediate outcomes in height, weight and lean tissue mass when compared with no treatment. One measure of pulmonary function test showed moderate improvement at a single time point, but no consistent benefit was seen across all studies. No significant changes in quality of life, clinical status or side-effects were observed in this review. Long-term, well-designed randomised controlled trials of recombinant growth hormone therapy in people with CF are required prior to evaluation of human growth hormone treatment for routine use.

–   There are now a number publications concerning growth hormone therapy in CF (see Topics -> Endocrinology – > Human growth hormone). At this time of increasing treatment possibilities and improving nutritional management, it seems unlikely there would be great enthusiasm for yet another “long-term, well designed randomised controlled trial of growth hormone therapy” as suggested by these reviewers. Treatment is expensive (up to £15,000 per year) and requires numerous injections and is very unlikely to come into “routine use”. However, the relationship between suboptimal intrauterine and postnatal growth and reduced insulin-like growth factor 1 levels is receiving increasing attention.

Vidhu Thaker (fig. 89) is a Fellow in Endocrinology at Boston Children’s Hospital.

Tiddens HA; De Boeck K; Clancy JP; Fayon M; H G M A; Bresnik M; Derchak A; Lewis SA; Oermann CM; ALPINE study investigators.  Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study. J Cyst Fibros 2015; 14(1):111-9.   [PubMed]

Fig. 90 Harm Tiddens
Erasmus MC

A single-arm, open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study was conducted to evaluate the safety and efficacy of a 28-day treatment course of AZLI to eradicate newly acquired Pa infection in pediatric CF patients.CF patients (3 months to <18 years) with new onset Pa infection were treated with AZLI 75 mg 3 times daily for 28 days. New onset Pa infection was defined as first lifetime Pa-positive respiratory tract culture (throat swab, sputum) or Pa-positive culture after a >2-year history of Pa-negative cultures (> 2 cultures/year). Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. Primary endpoint was the percentage of patients with cultures negative for Pa at all post-treatment time points.A total of 105 pediatric CF patients enrolled (3 months to <2 years, n=24; 2 to <6 years, n=25; 6 to <18 years, n=56). Of the 101 patients who completed treatment, 89.1% (n=90) were free of Pa at the end of treatment and 75.2% (n=76) were free of Pa 4 weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of Pa at all post-treatment time points.So AZLI was effective and well tolerated in eradicating Pa from newly infected pediatric patients with CF. These eradication rates are consistent with success rates reported in the literature for various antibiotic regimens, including other inhaled antibiotics studied for eradication.

Harm Tiddens (fig.90) is professor at  Erasmus MC-Sophia, University Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands.

Turillazzi E, Frati P, Busardò FP, Gulino M, Fineschi V. The European Court legitimates access of Italian couples to assisted reproductive techniques and to pre-implantation genetic diagnosis Med Sci Law. 2015 Jul;55(3):194-200. doi: 10.1177/0025802414532245. Epub 2014 Apr 28. [PubMed]
On 28 August 2012, the European Court of Human Rights (ECHR) issued a judgment regarding the requirements for the legitimate access of couples to assisted reproductive techniques (ART) and to pre-implantation genetic diagnosis (PGD).This judgment concerns the case of an Italian couple who found out after their first child was born with cystic fibrosis that they were healthy carriers of the disease. When the woman became pregnant again in 2010 and underwent fetal screening, it was found that the unborn child also had cystic fibrosis, whereupon she had the pregnancy terminated on medical grounds. In order to have the embryo genetically screened prior to implantation under the procedure of PGD, the couple sought to use in vitro fertilisation to have another child. Since article 1 of the Italian law strictly limits access to ART to sterile/infertile couples or those in which the man has a sexually transmissible disease, the couple appealed to the European court, raising the question of the violation of articles 8 and 14 of the European Convention on Human Rights. The applicants lodged a complaint that they were not allowed legitimate access to ART and to PGD to select an embryo not affected by the disease.

The European Court affirmed that the prohibition imposed by Italian law violated article 8 of the European Convention on Human Rights. Focusing on important regulatory and legal differences among EU Nations in providing ART treatments and PGD, the authors derived some important similarities and differences.

Ulph F, Cullinan T, Qureshi N, Kai J. Parents’ responses to receiving sickle cell or cystic fibrosis carrier results for their child following newborn screening. Eur J Hum Genet. 2015 Apr;23(4):459-65. doi: 10.1038/ejhg.2014.126. Epub 2014 Jul 9.[PubMed]

Fig 91. Fiona Ulph

Universal newborn screening for sickle cell disorders and cystic fibrosis aims to enable the early identification and treatment of affected babies. Screening can also identify infants who are healthy carriers, with carrier results being the commonest outcome for parents and professionals to discuss in practice. However it is unclear what the effect will be on parents on being informed of their baby’s carrier result.Semi-structured face-to-face interviews were conducted with a purposeful sample of 67 family members (49 mothers, 16 fathers, 2 grandparents) of 51 infants identified by universal newborn screening as carriers of cystic fibrosis (n=27) and sickle cell (n=24), across all health regions in England. Data were analysed by thematic analysis with subsequent respondent validation. Untoward anxiety or distress among parents appeared influenced by how results were conveyed, rather than the carrier result per se. Parents who had more prior awareness of carrier status or the possibility of a carrier result assimilated the information more readily. Being left in an information vacuum while awaiting results, or before seeing a professional, led some parents to fear that their child had a serious health condition. Parental distress and anxiety appeared mostly transient, subsiding with understanding of carrier status and communication with a professional. Parents regarded carrier results as valuable information and sought to share this with their families and to inform their children in the future. However parents needed greater support after communication of results in considering and accessing cascade testing, and negotiating further communication within their families.It is good that parents welcomed being informed of their infant’s carrier status as others have found, provided they receive adequate information, may regard as an opportunity for future prevention.

Fiona Ulph (fig.91)  is Senior Lecturer in Qualitative Methods, School of Psychological Sciences in the University of Manchester. Her research interests focus on children’s roles in health care; professional-parent-child communications; and advances in genetics and screening.

Vanstone MB; Egan ME; Zhang JH; Carpenter TO.  Association between serum 25-hydroxyvitamin D level and pulmonary exacerbations in cystic fibrosis. Pulmonology 2015; 50(5):441-6.  [PubMed]

Fig 92 Michelle Vanstone

The annual number of pulmonary exacerbations in pediatric CF patients was found to be significantly associated with 25-OHD levels and gender, raising the consideration that maintaining vitamin D sufficiency may lead to decreased incidence of pulmonary exacerbations and hospitalisations requiringantibiotic therapy.

Dr. Michelle Vanstone, (fig. 92) is a pediatric endocrinologist in Saint Louis, Missouri. This paper is from Dept. of Pediatrics, Yale University School of Medicine.

—   It is surprising that there are still reports of children with CF who have suboptimal vitamin D levels despite the fact that the tendency to low fat soluble vitamin levels and the need for adequate monitoring and appropriate supplementation has been known for over 30 years! It could be that in the group with increased pulmonary exacerbations and low levels of vitamin D, both were a reflection of the care the patients received?

Visca A; Bishop CT; Hilton S; Hudson VM.  Oral reduced L-glutathione improves growth in pediatric cystic fibrosis patients. J Pediatr Gastroenterol Nutr 2015; 60(6):802-10.[PubMed]
The aim of the study was to determine whether oral GSH could improve growth in CF. Subjects were treated with oral GSH or placebo (calcium citrate), each 65 mg kg day divided into 3 doses per day at mealtimes, and administered daily for 6 months. The GSH treatment group gained an average of 0.67 standard deviation (SD) in weight-for-age-and sex z score (wfaszs), (19.1 weight percentile points) during the course of 6 months, with no adverse effects (vs placebo with an increase of 0.1 SD in wfaszs [2.1 weight percentile points], P < 0.0001). Fecal calprotectin improved, GSH -52.0 vs placebo 0.5), also BMI for GSH improved 0.69 SD BMI-adjusted-for-age-and-sex z score versus placebo 0.22 SD (BMI percentile 21.7 GSH vs 5.2 placebo), and height 0.2 SD in height-for-age-and-sex z score (hfaszs) GSH versus -0.06 SD hfaszs placebo [height percentile 7.0 GSH vs -2.6 placebo], all P < 0.0001). Secondary outcomes improved significantly, as well. The authors concluded that oral reduced L-GSH significantly improves measures of growth status and gut inflammation in CF. — Glutathione just won’t go away!!!  Despite the lack of interest in acetyl cysteine and glutathione in the UK, some published work does seem to demonstrate some beneficial effect in people with CF (see Topics -> mucolytics -> N-acetyl cysteine).

Vreede CL; Berkhout MC; Sprij AJ; Fokkens WJ; Heijerman HG.  Ivacaftor and sinonasal pathology in a cystic fibrosis patient with genotype deltaF508/S1215N. J Cyst Fibros 2015; 14(3):412-3. [PubMed]

Fig. 93 Charlotte Vreede

A report of a positive favourable effect of ivacaftor on the sinonasal pathology in a 17 year old patient with CF. Although there were some adverse reports of the effect of ivacaftor on the upper respiratory tract, after 5 months of ivacaftor use in this patient, the CT-sinus showed complete resolution of the opacification of the paranasal sinuses and a decrease in symptoms of sinonasal disease.

Dr C L Verde is in the Department of Pulmonology, Haga Teaching Hospital, Leyweg 275, 2545 CH The Hague, The Netherlands.

Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP; TRAFFIC Study Group; TRANSPORT Study Group. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220-31. doi: 10.1056/NEJMoa1409547. Epub 2015 May 17[PubMed]

Fig. 94 Claire Wainwright
author’s photo

Two phase 3, randomized, double-blind, placebo-controlled studies were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo.

These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.

Claire Wainwright (Fig.94) is Professor at Queensland Children’s Medical Research Institute, Royal Children’s Hospital, Lady Cilento Children’s Hospital, and University of Queensland School of Medicine, Brisbane, Australia (C.E.W.)

Waters V, Chiang J, Sonneveld N, Kukkar R, Tullis E, Ratjen F. Prolongation of antibiotic treatment for cystic fibrosis pulmonary exacerbations. J Cyst Fibros. 2015 Nov;14(6):770-6. doi: 10.1016/j.jcf.2015.07.010. Epub 2015 Aug 9. [Epub ahead of print]. [PubMed]

Fig.95 Valerie Waters

A retrospective cohort study, using the Toronto CFDATABASE from 1997 to 2012, of CF individuals with pulmonary exacerbations requiring intravenous antibiotic treatment. A total of 538 pulmonary exacerbations in 253 patients were used for these analysis; 39% of these exacerbations fully recovered lung function at follow-up. Exacerbations were more frequently treated with >14days of antibiotics in older patients with lower FEV1 at exacerbation and higher rates of B. cepacia complex infections.   Subjects with exacerbations treated for >14days had a significantly greater increase in FEV1  from day 14 to follow up compared to those with ≤14days (p<0.001).
This study confirms that in the treatment of pulmonary exacerbations, maximum lung function is not achieved within 14 days in all patients, and that there is continued improvement beyond this period.Text Box:

Valerie Waters (fig. 95) is staff physician in the Division of Infectious Disease, Hospital for Sick Children, Toronto. The focus of her research with regards to CF is the epidemiology, diagnosis and management of multi-drug resistant bacterial pathogens

Willis J, Michael DD, Boyer H, Misono S. Prevalence and Severity of Dysphonia in Patients with Cystic Fibrosis: A Pilot Study. Otolaryngol Head Neck Surg. 2015 Jul;153(1):88-93. doi: 10.1177/0194599815581832. Epub 2015 Apr 27. [PubMed]
A study to assess the prevalence and severity of dysphonia in patients with cystic fibrosis sinusitis.  Cystic fibrosis sinusitis appeared to be associated with worse vocal function as measured by patient self-report as well as auditory-perceptual evaluation of voice compared with patients with non-CF sinusitis and healthy controls.

John Willis is at the Lions Voice Clinic, Department of Otolaryngology, Head and Neck Surgery, University of Minnesota, Minneapolis, Minnesota, USA.

Wilcock MJ, Ruddick A, Gyi KM, Hodson ME. Renal diseases in adults with cystic fibrosis: a 40 year single centre experience. J Nephrol. 2015 Oct;28(5):585-91. doi: 10.1007/s40620-015-0179-z. Epub 2015 Feb 25. [PubMed]
In this study the authors report for the first time on the prevalence of all forms of renal disease in a cystic fibrosis population using a retrospective review of adult patients attending the Adult Cystic Fibrosis Department at the Royal Brompton Hospital.The prevalence of all renal diseases in their population was 5.1%. The most commonly identified problem was renal stones. At 2.0% the prevalence of renal stones in adult patients with cystic fibrosis was comparable to the general population. A range of other renal diseases were identified, the next most common being drug-induced acute kidney injury.

M J Wilcox is with the Department of Cystic Fibrosis, Royal Brompton Hospital, London, UK. and the Oxford Kidney Unit, Churchill Hospital Oxford UK

Wilder-Smith EP.  Stimulated skin wrinkling as an indicator of limb sympathetic function. Clin Neurophysiol 2015; 126(1):10-6.[PubMed]

Fig 96. Einar Wilder-Smith

Skin wrinkling upon water immersion has been used as an indicator of limb nerve function for more than 80 years. Until recently, a poor understanding of the physiology and lack of standardisation have hampered routine use of the test. The process underlying stimulated skin wrinkling has been recently identified as dependent on digital vasoconstriction mediated via sympathetic nerve fibres. Vasoconstriction is postulated to drive wrinkling through loss of digit volume, which induces a negative pressure in the digit pulp and exerts a downward pull on the overlying skin and ultimately results in wrinkles. Improved test standardisation has been achieved through substituting water with EMLA for inducing skin wrinkling. This has made testing much easier and has helped implement stimulated skin wrinkling as a practical routine clinical bedside test. A literature search identified 10 studies of sufficient quality for evaluating stimulated skin wrinkling as a diagnostic test of sympathetic under or over function. Seven studies provide level 1 or 2 evidence as a diagnostic test of small fibre neuropathy and three provide level 1 or 2 evidence for cystic fibrosis. There is reasonable evidence allowing the test to be employed as a simple and effective marker for small fibre neuropathy and cystic fibrosis

Einar Wilder-Smith (fig. 96) is Professor and Senior Consultant Neurologist, Yong Loo Lin School of Medicine, National University of Singapore. His research concerns peripheral nerve disorders.

—  The first description of finger wrinkling in cystic fibrosis by Prof. Robert (Bob) Elliott in 1974 excited considerable interest as the basic defect was still totally obscure. Since then there have been a number of publications describing various aspects of the phenomenon (see Elliott RB 1974 in Seventies section).

Williams SN, Nussbaum E, Chin TW, Do PC, Singh KE, Randhawa I. Diagnosis of cystic fibrosis in the kindred of an infant with CFTR-related metabolic syndrome: importance of follow-up that includes monitoring sweat chloride concentrations over time. Pediatr Pulmonol. 2014 Mar;49(3):E103-8. doi: 10.1002/ppul.22918. Epub 2013 Nov 4. [PubMed]

Fig 97  Sophia N Williams

Newly implemented newborn screening (NBS) programs in California have resulted in a large subset of patients in whom at least two cystic fibrosis transmembrane conductance regulator (CFTR) mutations are identified, but subsequent sweat chloride analysis reveals normal or indeterminate values. These patients are diagnosed with CFTR-Related Metabolic Syndrome (CRMS). However, the natural progression and management of these patients are not clearly understood and frequently after the age of 1-year these patients are lost to follow-up with Cystic Fibrosis (CF) Centers.
We present the first case of an infant who was referred to Miller Children’s Hospital for a NBS positive for CF and subsequent discovery of identical mutations in six of his seven older brothers. Several siblings had positive sweat chloride results on repeat testing after the age of 3 years.The authors wisely suggest the need for continued follow-up of CRMS in a CF center with diagnostic evaluation including repeat sweat chloride testing, beyond the currently recommended period.

–   Such follow-up is absolutely essential and should be at a CF Center. It is very sad that many of the CRMS infants are being lost to follow-up.

Sophie N Williams (fig.97) is a pediatric pulmonologist at Pediatric Pulmonology/Allergy/Immunology, Miller Children’s Hospital, Long Beach, University of California, Irvine.

Woestenenk JW, van der Ent CK, Houwen RH. Pancreatic Enzyme Replacement Therapy and Coefficient of Fat Absorption in Children and Adolescents with Cystic Fibrosis. J Pediatr Gastroenterol Nutr. 2015 Mar 11. [Epub ahead of print] [PubMed]

Fig 98. Janna W Woestenenk

There are few details of the daily practice regarding PERT and the resulting coefficient of fat absorption (CFA) are known. The authors therefore recorded the PERT and CFA in a large cohort of pancreatic insufficient pediatric CF patients. 1,719 completed 3-day dietary food records, including the pancreatic enzyme intake registrations, and 1,373 CFA assessments of 224 CF patients, aged 0 – 17 years. The clinical characteristics, PERT, expressed as an intake of lipase unit (LU)/g fat/day and LU/kg/day, and the CFA were described for the group as a whole, and separately for those on enteral tube feeding. Cross-sectional relationship between the CFA and the LU/g fat/day and LU/kg/day were determined for each year of age. The authors also addressed the effect of the interventions done in patients with CFA outcomes <85%.

The LU/g fat/day was relatively stable throughout the age groups, while the LU/kg/day fell markedly with age. The median CFA in the 17 age groups varied between 86% and 91%, however, with a CFA below 85% in 325/1,373 (24%) of the measurements.No relationship was found between PERT and CFA. The patients with persistent CFA <85% had significant lower z-scores weight-for-age, and weight-for-height (p 0.01) than those with CFA ≥85%.
In this study population, no correlation between an enzyme dosage and the degree of fat malabsorption was found. However a CFA below 85% was found in 24% of the measurement

This data appears to be from Dr Woestenenk’s Thesis, University of Utrecht, “Dietary Intake and body growth in cystic fibrosis”. The findings confirm previous work in this area that many children and adolescents had an energy intake below that traditionally recommended although higher than healthy cintrols. It seems to be more prudent to advise calorie intake slightly above age specific intake with individual adjustments as necessary. There was an enormous variation in the need for pancreatic enzyme therapy with no clear correlation between the coefficient of fat absorption and pancreatic enzyme dosages. The advise to consider each patient individually is very sound and confirmed by this very interesting and extensive study (Dietary Intake and body growth in cystic firbosis. J W Woestenenk. The full version of the thesis is available on the internet)

Woestenenk JW, Broos N, Stellato RK, Arets HG, van der Ent CK, Houwen RH. Vitamin E intake, α-tocopherol levels and pulmonary function in children and adolescents with cystic fibrosis. Br J Nutr. 2015 Apr 14;113(7):1096-101. doi: 10.1017/S0007114515000215. Epub 2015 Mar 12. [PubMed]
It has been suggested that higher serum α-tocopherol levels could have protective effects on pulmonary function (PF) in patients with CF. Whether current recommendations are indeed optimal for preventing deficiency and whether vitamin E has therapeutic benefits are subjects of debate. Therefore, the authors studied vitamin E intake as well as the long-term effects of vitamin E intake in the present large sample of children and adolescents with CF.Vitamin E intake was lower than recommended, but serum α-tocopherol deficiency was rare. They found no evidence that higher serum α-tocopherol levels had protective effects on pulmonary function. Adjustment of the recommendations to the real-life intake of these patients may be considered.

Woestenenk JW; Broos N; Stellato RK; Arets HG; van der Ent CK; Houwen RH. Serum retinol levels and pulmonary function in children and adolescents with cystic fibrosis. J Cyst Fibros 2015; 14(3):392-7. [PubMed]It has been suggested that higher serum retinol levels could have protective effects on pulmonary function (PF) in patients with cystic fibrosis (CF). However, serum retinol levels will be transiently decreased during pulmonary exacerbation. Therefore, the extent of chronic pulmonary inflammation should be included when describing the association between PF and serum retinol. The authors studied the longitudinal relation between serum retinol, immunoglobulin G (IgG) and PF in paediatric CF patients.  They measured the serum retinol, IgG and forced expiratory volumes in one second (FEV1% pred.) of 228 CF patients during a seven-year follow up period. The cross-sectional and longitudinal relations between these variables were assessed.Serum retinol, with medians levels between 1.2 and 1.4 mumol/l, were relatively stable, while median serum IgG gradually increased during the age years. The FEV1% pred. was longitudinally inversely associated with serum IgG and age, but not with serum retinol. Each g/l increase in serum IgG level was associated with an accelerated yearly decline in FEV1% pred. of 0.5% (95% CI -0.8 to -0.1, p=0.008), and each year increase in age was associated with a 1.7% (95% CI -2.1 to -1.3, p=0.000) decline in FEV1% pred. This effect was not observed with respect to serum retinol levels (95% CI -1.9 to 2.2, p=0.570).

In this retrospective study the authors found no evidence that higher serum retinol levels had protective effects on pulmonary function. The well-known association between a rising IgG and declining FEV1% pred. was confirmed.

Janna W (Willie) Woestenenk (fig. 98) is a Senior Nutrition Scientist, Paediatric Care & Metabolics, Danone Nutricia Research ,Utrecht.

Wormser B. 50 Years Ago in The Journal of Pediatrics: Cor Pulmonale in Cystic Fibrosis of the Pancreas. J Pediatrics 2015; 167(5):1080.  Discussing – Moss AJ, Harper WH, Dooley RR, Murray JF, Mack JF. J Pediatr 1965;67:797-807)
Moss et al published their work 19years after the medical community first recognised the phenomenon of pulmonary hypertension in patients with cystic fibrosis. This squeeze of the pulmonary vasculature had been attributed to hypoxaemia and cor pulmonale, its sequelae, had been recognised as a major cause of death for patients with cystic fibrosis.This study aimed to improve the ability to detect pulmonary hypertension and cor pulmonale for prognostic purposes. This included an evaluation of the noninvasive technology available at the time. Their study of 21 stable patients with cystic fibrosis indicated that none of the available techniques (which included electrocardiogram, vectorcardiogram, chest radiograph, and vital capacity) could reliably predict the presence of cor pulmonale. This left only cardiac catheterization, the gold standard both then and now.Over the next 50 years, our understanding of pulmonary hypertension in cystic fibrosis and other chronic pulmonary diseases has progressed, yielding an understanding of the chronic systemic inflammation and pulmonary vascular bed remodelling that occurs in these patients to create the phenomenon of pulmonary hypertension. We have created new means of examining our patients’ hearts with noninvasive techniques such as Doppler echocardiography and cardiac magnetic resonance imaging. Our treatment goals have evolved with our diagnostic technology and today, our studies of pulmonary hypertension in cystic fibrosis reflect that shift. Current research focuses on the outcomes of patients with pulmonary hypertension following lung transplantation. Recent analyses of the United Network for Organ Sharing registry modernized our knowledge by demonstrating that patients with severe pulmonary hypertension still have lower survival rates than those with mild hypertension, but that the existence of pulmonary hypertension does not affect post-transplant survival. 
In the next 50years, the success of gene therapy and new medications already being tested will aim to make the discussion of pulmonary hypertension in patients with cystic fibrosis a vestige of medical history. ( Belle-van Meerkerk G., Cramer M.J., Kwakkel-van Erp J.M., Nugroho M.A., Tahri S., de Valk H.W., et al: Pulmonary hypertension is a mild comorbidity in end-stage cystic fibrosis patients. J Heart Lung Transplant 2013; 32: pp. 609-6142. Hayes D., Tobias J.D., Mansour H.M., Kirkby S.,.  McCoy K.S., Daniels C.J., et al: Pulmonary hypertension in cystic fibrosis with advanced lung disease. Am J Respir Crit Care Med 2014; 190: pp. 895- 905.

Ben Wormser.  Pediatric Residency Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.

— An interesting review of the changing approach to pulmonary hypertension in people with CF.

Yan Z; Stewart ZA; Sinn PL; Olsen JC; Hu J; McCray PB Jr; Engelhardt JF.  Ferret and pig models of cystic fibrosis: prospects and promise for gene therapy.  Hum Gene Ther 2015; 26(1):38-4. [PubMed]

Fig 99  Ziying Yan medicine.uiowa.edu

The disease phenotypes in the ferret and pig models is more reflective of human CF disease than mouse models. The ferret and pig CF models also provide unique opportunities to develop and assess the effectiveness of gene and cell therapies to treat affected organs. In this review, the authors examine the organ disease phenotypes in these new CF models and the opportunities to test gene therapies at various stages of disease progression in affected organs. They discuss the progress in developing recombinant replication-defective adenoviral, adeno-associated viral, and lentiviral vectors to target genes to the lung and pancreas in ferrets and pigs, the two most affected organs in CF. Through this review, they hope to convey the potential of these new animal models for developing CF gene and cell therapies.

Ziying Yan (fig.99) Research Professor at the Department of Anatomy and Cell Biology, University of Iowa School of Medicine , Iowa City, IA 52242.

Yousef S, Solomon GM, Brody A, Rowe SM, Colin AA. Improved clinical and radiographic outcomes after treatment with ivacaftor in a young adult with cystic fibrosis with the P67L CFTR mutation. Chest 2015; 147(3):e79-82. doi: 10.1378/chest.14-1198. [PubMed]
Originally approved for the G511D CFTR mutation, ivacaftor is now approved for eight additional alleles exhibiting gating defects and has also been tested in R117H, a CFTR mutation with residual function that exhibits abnormal gating.P67L is a class 4 conductance (non-gating) mutation exhibiting residual CFTR function. The authors report marked clinical improvement, normalisation of spirometry, and dramatic reduction in radiographic structural airway changes after >1 year of treatment with ivacaftor in a young adult with the compound heterozygous genotype P67L/F508del CFTR. The case suggests that ivacaftor may have a potential benefit for patients with CF with non-gating mutations.

Shatha Youssef is a paediatric pulmonologist in the Division of Pediatric Pulmonology, Miller School of Medicine, University of Miami, Miami, FL.

Zemanick ET, Emerson J, Thompson V, McNamara S, Morgan W, Gibson RL, Rosenfeld M; EPIC Study Group. Clinical outcomes after initial pseudomonas acquisition in cystic fibrosis. Pediatr Pulmonol. 2015 Jan;50(1):42-8. doi: 10.1002/ppul.23036. Epub 2014 Mar 18.[PubMed]

Fig. 100 Edith Zemanick childrenscolorado.org

To evaluate clinical outcomes associated with initial isolation of Pseudomonas aeruginosa (Pa) in a large U.S. cystic fibrosis (CF) cohort in the current era of widespread early Pa eradication therapy.Participants were children with CF enrolled in the Early Pseudomonas Infection Control (EPIC) Observational Study who had no isolation of Pa from respiratory cultures prior to enrollment. Population-averaged regression models using generalized estimating equation methods were used to estimate the effect of Pa acquisition on endpoints including lung function, growth, pulmonary exacerbation rate, respiratory signs and symptoms, and respiratory cultures.Eight hundred thirty-eight subjects were observed for a mean 4.6 (SD 1.2) years during which 431 (51%) acquired Pa. There was no statistically significant effect of Pa acquisition on the slopes of FEV1 % predicted or growth parameters. Pulmonary exacerbation rate was statistically significantly greater after Pa acquisition (incident rate ratio 1.40, 95% CI 1.07, 1.84) as were odds of crackles or wheeze on physical exam (OR 1.23, 95% CI 1.00, 1.52). Odds of isolation of MRSA (OR 1.86, 95% CI 1.38, 2.49) and S. maltophilia (OR 2.11, 95% CI 1.49, 2.98) increased after Pa acquisition, while the odds of H. influenzae (OR 0.54, 95% CI 0.46, 0.64) decreased.In this large U.S. cohort, the authors did not detect an association between acquisition of Pa and deterioration in lung function or nutrition. Pa acquisition was associated with significantly increased pulmonary exacerbation rate and odds of crackles or wheeze. Pa infection may be the cause of these outcomes or a marker of more severe disease.Thi study was rather short term to detect significant disadvantages of acquiring Pseudomonas infection.Also presumably the infection was treated. It has been shown in the case of screened CF infants that early adverse experience may be minimised for years by adequate treatment – but significantly more treatment is required. The presence of crackles or wheeze in young CF children is alarming.See also commentary by Zemanick ET and Laguna TA. Clin Infect Dis 2015; 61(5):716-718. Where the subject is discussed and editorial is available in full.

Dr. Edith Zemanick (fig. 100) is a pediatric pulmonologist in Aurora, Colorado and is affiliated with multiple hospitals in the area, including Associate Director of the Pediatric CF Center, Children’s Hospital Colorado and Memorial Hospital.

Zlotogora J, Grotto I, Kaliner E, Gamzu R. The Israeli national population program of genetic carrier screening for reproductive purposes.   Genet Med. 2015 Apr 16. doi: 10.1038/gim.2015.55. [Epub ahead of print] [PubMed]

Fig 101. Joel Zlotogora

The Israeli population genetic screening program for reproductive purposes, launched in January 2013, includes all known, nationally frequent severe diseases (carrier frequency 1:60 and/or disease frequency 1 in 15,000 live births). The carrier screening program is free of charge and includes  testing for cystic fibrosisData on the tests performed over a 12-month period were collected from laboratories nationwide.  More than 62,000 individuals were tested. The carrier frequency was within the expected range for most of the diseases. The national population genetic carrier screening is aimed toward providing couples with knowledge of the existing options for the prevention of serious genetic conditions when it is relevant for them. It is still too early to determine whether this aim has been achieved.It is encouraging that this service is now available in Israel. The take up by young people before becoming pregnant will be interesting for previous studies have shown only a modest interest amongst non-relatives and non-pregnant individuals.

Joel Zlotogora (fig. 101) is Associate Professor of Human Genetics, Hebrew University of Jerusalem

Zuckerman JB, Clock SA, Prato BS, McDevitt JJ, Zhou JJ, Leclair LW, Lucas FL, Saiman L. Air contamination with bacteria in cystic fibrosis clinics: implications for prevention strategies. Am J Respir Crit Care Med. 2015 Mar 1;191(5):598-601. doi: 10.1164/rccm.201410-1877LE[PubMed]

Fig. 102 Jonathan B Zuckerman mainehealth.org

The authors concluded air contamination with CF respiratory pathogens during clinic visits was infrequent, and use of surgical masks did not reduce contamination in examination  rooms. They found that the air of spirometry rooms was more likely to be contaminated than that of exam rooms, presumably as a result of the generation of contaminated aerosols during forced expiratory manoeuvres and cough. Contamination in spirometry rooms cleared by 30 minutes and was not associated with age, signs and symptoms, air exchange rates, or specific CF pathogens.The findings provide the basis for the recommendation in the updated Infection Prevention and Control Guideline for CF to allow 30 minutes to elapse between patients with CF during performance of spirometry (unless high-efficiency particulate absolute filtration or negative pressure ventilation is used). Mask use by patients with CF is not advised in examination rooms but is recommended in common areas such as waiting rooms and clinic corridors.

Jonathan B Zuckerma (fig.102)  is Clinical Associate Professor, Tufts University School of Medicine. Director, Adult Cystic Fibrosis Program at Maine Medical Center.

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Vidhu Thaker