Balfour-Lynn IM. Cystic fibrosis papers of the year 2009.  J R Soc Med. 2010 Jul;103 Suppl 1(Suppl 1):S6-14. Doi. 10.1258/jrsm.2010.s11003.   Free PMC article. No abstract available.   [PubMed]

      Ian Balfour-Lynn

The literature search was conducted using PubMed (www.ncbi.nlm.nih.gov/sites/entrez ), entering the search term ‘cystic fibrosis’, for the period 1 November 2008 to 15 October 2009. There were 1525 papers identified, and when limits were set for ‘clinical trial’ and ‘randomized controlled trial’ this left 40 papers. The papers selected for this review are a personal choice of studies with important or interesting clinical messages.

The free PMC article is recommended.


Albini S, Abril C, Franchini M, Hüssy D, Filioussis G. Stenotrophomonas maltophilia isolated from the airways of animals with chronic respiratory disease. Schweizer Archiv fur Tierheilkunde 2009; 151:323-328. [PubMed] Stenotrophomonas maltophilia (S. maltophilia) is frequently isolated from humans with cystic fibrosis. Seven strains of S. maltophilia isolated from animals are described, of which 5 strains were harvested from 3 horses, a dog and a cat with chronic respiratory disease. Analysis with pulsed field gel electrophoresis revealed that 2 horses, which were boarded in the same clinic but two years apart, harboured the same strain of S. maltophilia.

— In recent years S. maltophilia is more frequently isolated from people with CF and although the organism appears to be ubiquitous it is useful to know that animals are one potential source.

Sarah Albini is at the  Institute of Veterinary Bacteriology, University of Bern,

Antibiotic Treatment for Cystic Fibrosis. Report of the UK Cystic Fibrosis Trust Antibiotic Working Group. 3rd Edition. Cystic Fibrosis Trust. London. 2009. www.cysticfibrosis

 Fig 1. Alan Smyth

This group chaired by Prof. Alan Smyth produced a very detailed and liberally referenced up to date account of the current recommendations for antibiotic use in people with CF in the UK.  The recommendations differ significantly from those in N. America largely in the long established European policy of early eradication of P. aeruginosa and the recommendation to use long term prophylactic anti-staphylococcal therapy for the first three years of life. (www.cysticfibrosis.org.uk)

Alan Smyth (figure 1) is Professor of Paediatrics at Nottingham University and Director of the Nottingham Paediatric CF Centre at the Nottingham City Hospital, UK.

Bartlett JR, Friedman KJ, Ling SC, et al. Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA 2009; 302:1076-1083. [PubMed]
A subset (approximately 3%-5%) of patients with CF develops severe liver disease with portal hypertension. The objective of the study was to assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF. The authors concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF.

Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Jaclyn R Bartlett is at the Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Berk DR, Ciliberto HM, Sweet SC, Ferkol TW, Bayliss SJ. Aquagenic wrinkling of the palms in cystic fibrosis: comparison with controls and genotype-phenotype correlations. Arch Dermatol 2009; 145:1296-1299    pubmed.ncbi.nlm.nih.gov/19917960/

Fig. 2 David Berk arcutics .com

The biggest article so far on wrinkling confirms the association between aquagenic wrinkling of the palms and CF. Among patients with CF, greater AWP occurs in those who are homozygous for the DeltaF508 mutation.

Dr David R Berk (fig. 2) is at the Department of Internal Medicine and Pediatrics, Division of Dermatology, Washington University School of Medicine and St Louis Children’s Hospital,

Bernard K, Wang W, Narlawar R, Schmidt B, Kirk KL. Curcumin cross-links cystic transmembrane conductance regulator (CFTR) polypeptides and potentiates CFTR channel activity by distinct mechanisms. J Biol Chem. 2009; 284:30754-65. [PubMed]

Fig. 3 Karen Bernard. uab.edu

Curcumin has the unexpected effect of cross-linking CFTR polypeptides into SDS-resistant oligomers; both mature CFTR polypeptides at the cell surface and immature CFTR protein in the endoplasmic reticulum were cross-linked by curcumin.

The authors raise a note of caution about secondary biochemical effects of reactive compounds like curcumin in the treatment of CF. Cyclic curcumin derivatives may have better therapeutic potential in this regard. So the curcumin story continues!

Karen Bernard (fig.3)  is in the Department of Physiology and Biophysics, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama

Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, Spear SL, Michel SH, Parad RB, White TB, Farrell PM, Marshall BC, Accurso FJ. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatrics 2009; 155(6 Suppl):S73-93.pubmed.ncbi.nlm.nih.gov/19914445/

Fig. 4 Drucy Borowitz.  university at Buffalo

This consensus document states the focus of management is on maintaining health by preventing nutritional and respiratory complications. The CF Foundation convened a committee to develop recommendations based on a systematic review of the evidence and expert opinion. These guidelines encompass monitoring and treatment recommendations for infants diagnosed with CF and are intended to help guide families, primary care providers, and specialty care centers in the care of infants with CF.

Dr Drucy Borowitz (fig.4) at this time a leading paediatric pulmonologist and CF Centre Director at the  Women and Children’s Hospital of Buffalo, State University of New York at Buffalo, NY, USA.

Bourke SJ, Doe SJ, Gascoigne AD, Heslop K, Fields M, Reynolds D, Mannix K. An integrated model of provision of palliative care to patients with cystic fibrosis. Palliat Med 2009; 23:512-517.

Fig 6., Alistair Gascoigne

Fig 5. Stephen Bourke

Palliative care of patients with cystic fibrosis (CF) is often undertaken by CF teams rather than palliative care teams because of the specialist nature of the disease and the potential role of lung transplantation.
The Newcastle team developed an integrated model of provision of palliative care whereby most care is delivered by the CF team using palliative guidelines and pathways, with additional support available from the specialist palliative care team when needed.
They report their experience of the terminal care of 40 patients with CF with regard to the circumstances of death, lung transplantation status, specific symptoms and provision of palliative treatments. The transition from disease modifying treatments to palliative care was particularly complex. Patients had a high level of symptoms requiring palliation and most died in hospital. Palliative care is a crucial component of a CF service and requires the specialist skills of both the CF and palliative care teams.

Dr Stephen Bourke (fig.5) is a Consultant Respiratory Physician in Newcastle upon Tyne and Director of the Adult Cystic Fibrosis Centre. Dr Alistair Gascoigne (fig.6) is a Consultant Respiratory Physician also works with CF patients there; he has particular interest in intensive care medicine.

Castellani C, Southern KW, Brownlee K, Dankert Roelse J, Duff A, Farrell M, Mehta A, Munck A, Pollitt R, Sermet-Gaudelus I, Wilcken B, Ballmann M, Corbetta C, de Monestrol I, Farrell P, Feilcke M, Férec C, Gartner S, Gaskin K, Hammermann J, Kashirskaya N, Loeber G, Macek M Jr, Mehta G, Reiman A, Rizzotti P, Sammon A, Sands D, Smyth A, Sommerburg O, Torresani T, Travert G, Vernooij A, Elborn S. European best practice guidelines for cystic fibrosis neonatal screening. J Cyst Fibros 2009; 8:153-173. [PubMed]

Fig 7, Carlo Castellani

A European document full of good advice. When starting a newborn screening programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of newborn screening programmes. It is absolutely essential that early diagnosis is followed by optimal treatment.

Dr Carlo Castellani (fig. 7) is a medical geneticist from Verona, Italy who has been involved in many projects and expert committees relating to cystic fibrosis over the past twenty years. He has been particularly involved with neonatal screening and mutational analysis.

Christie LM, Ingrey AJ, Turner GM, Proos AL, Watts GE. Outcomes of a cystic fibrosis carrier testing clinic for couples. M J Australia 2009; 191:499-501 [PubMed]
To review the outcomes of offering carrier testing for cystic fibrosis to couples considering pregnancy, and to women in early pregnancy and their partners.
An after-hours clinic was established in Newcastle for discussion of issues related to prenatal testing. Couples were offered CF carrier testing by extracting DNA from a mouthwash sample. An expanded one-step model was used with both partners being tested initially for the p.F508del cystic fibrosis transmembrane conductance regulator gene (CFTR) mutation. If one partner was a p.F508del carrier, the other partner was tested for an additional 28 CFTR mutations.
Of 1000 individuals who were offered CF carrier testing, none declined. No re-collections of mouthwash samples were required, and results were available within 14 days. There were 730 individuals who had no family history of CF (73%); 27 were carriers (4%; 95% CI, 2.4%-5.3%), and there were two high-risk couples where both partners were carriers of p.F508del. There were 270 individuals who had an affected family member with CF or a child identified as a CF carrier through newborn screening; 126 were carriers (46%; 95% CI, 40.6%-52.8%), and there were two high-risk couples – one couple where both partners were carriers of p.F508del, and another couple where the woman was homozygous for p.F508del and the man was a p.F508del carrier.
The information on carrier status led the four high-risk couples to change their reproductive decisions to avoid having a child with CF.
The authors concluded that CF carrier testing for couples using an expanded one-step model will detect about 80% of high-risk couples and enables various reproductive choices. They believe that all couples considering pregnancy, and women in early pregnancy and their partners, should be offered CF carrier testing.

— There is still (in 2024) no general prenatal carrier testing for CF in the UK – only if CF in known to have occurred in other family members.  Enthusiasm for both prenatal and antenatal CF screening seems to have diminished as the outlook of people with CF improves.

Louise M Christie is at  Hunter Genetics, Newcastle, NSW, Australia

Coates AJ, Crofton PM, Marshall T. Evaluation of salt supplementation in CF infants.[PubMed]

Fig 8. Allan Coates author’s photo

CF infants are at increased risk of sodium depletion which may lead to impaired growth. The objective of this study was to evaluate their sodium supplementation requirements. Ten CF infants had serial measurements of weight and plasma/urine sodium and creatinine. Sodium supplementation was adjusted with the aim of maintaining fractional excretion (FENa) between 0.5% and 1.5% and urinary sodium > 10 mmol/L. The urine sodium:creatinine (UNa:Cr) ratio strongly correlated with FENa [UNa:Cr (mmol/mmol)=35.0 x FENa (r=0.99)]. The FENa target range corresponded to UNa:Cr 17-52 mmol/mmol.

All infants required sodium supplementation to achieve UNa:Cr. > 17 mmol/mmol. Sodium supplement requirements (mean+/-SD) at ages 0-3, 3-6, 6-9 and 9-12 months were 1.9+/-0.5, 1.8+/-0.8, 1.9+/-0.9 and 0.8+/-0.4 mmol/kg/d. No infant required calorie supplementation to achieve expected weight gain.The authors concluded that using current UK CF Trust and European CFS guidelines many cases of sodium depletion may be overlooked. Some infants require more than the recommended 1-2 mmol/kg/d. The UNa:Cr ratio is a useful non-invasive measure to monitor sodium supplementation

— This is a particularly useful paper as most infants are diagnosed after neonatal screening and the advice in the UK and European CF Society consensus documents suggested that routine sodium supplementation was unnecessary. However, salt supplementation is certainly necessary in hot climates where pseudo-Bartter’s syndrome is a relatively frequent occurrence.

Prof. Allan Coates (fig. 8) is Senior Scientist Emeritus in 2023 and a leading CF researcher at the Hospital for Sick Children Toronto.

Cohen-Cymberknoh M, Blau H, Shoseyov D, Mei-Zahav M, Efrati O, Armoni S, Kerem E. Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros 2009; 8:253-257. [PubMed]

Fig. 9 Malena Cohen-Cymberknoh LinkedIn

Nine patients with CF and allergic bronchopulmonary aspergillosis (ABPA) (4 male, 5 female, ages 7-36 years) received high dose intravenous methyl prednisolone (HDIVPM) (10-15 mg/kg/d), for 3 days per month, and itraconazole, until clinical and laboratory resolution of their ABPA.   All patients showed clinical and laboratory improvement, (FEV(1) increase, serum IgE levels and total eosinophil counts decrease) and treatment was discontinued after 6-10 pulses. Adverse effects were minor and disappeared shortly after each IV pulse therapy. The authors suggest that high-dose IV-pulse methylprednisolone is an effective treatment for ABPA in CF with minor side effects.

This appears to be an effective way of avoiding unwelcome side effects of prolonged courses of oral corticosteroids (prednisolone) which are often severe during treatment of ABPA – particularly the altered facial features distress patients when repeat or prolonged courses are required.

Malena Cohen-Cymberknoh (fig.9) is Associate Professor at the CF Centers of Hadassah Medical Center, Mount Scopus, Jerusalem, Israel.

Dauletbaev N, Fischer P, Aulbach B, Gross J, Kusche W, Thyroff-Friesinger U, Wagner TO, Bargon J. A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis. Euro J Med Res 2009; 14:352-358. [PubMed]

Fig. 10 Joachim Bargon rotfreuzkliniken.de

A single-centre, randomised, double-blinded, placebo-controlled phase II clinical study to test safety and efficacy of a 12-week therapy with low-dose (700 mg/daily) or high-dose (2800 mg/daily) of N-acetylcysteine (NAC). High-dose NAC was a well-tolerated and safe medication but did not alter clinical or inflammatory parameters. However, extracellular glutathione in induced sputum tended to increase on high-dose NAC.
The authors concluded that high-dose NAC is a well-tolerated and safe medication for a prolonged therapy of patients with CF with a potential to increase extracellular glutathione in CF airways.

—  This study confirms the generally perceived lack of clinical effect of N-acetylcysteine on the respiratory function and inflammatory parameters but the increase in extracellular glutathione may be of some benefit.
It is difficult to reconcile the lack of clinical effect with some of the early reports showing marked increase in the volume of sputum; also the clinical experience suggesting some benefit. The effects are complicated – even more recently it has been reported that that NAC causes a significant efflux of Cl from CF bronchial epithelial cells (Vereloqianni G et al. The effect of N-acetylcysteine on chloride efflux from airway epithelial cells. Cell Biol Int 2010; 34:245-252. [PubMed]).
So reports on NAC in CF have continued  to appear, the most recent being that of Guerini et al, in 2022 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879903/] wherein was concluded, “it is possible to establish that this molecule opens great hope in the treatment of this disease. However, there is still a lack of many in vivo studies on which to base this hypothesis”.  

Prof. Joachim Bargon (fig. 10) of University of Frankfurt is the corresponding author.

Dequeker E, Stuhrmann M, Morris MA, Casals T, Castellani C, Claustres M, et al. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders – updated European recommendations. Eur J Hum Genet 2009; 17:51-65. pubmed.ncbi.nlm.nih.gov/18685558/

Fig. 11 Els Dequeker LinkedIn Belgium

An increasing number of laboratories offering molecular genetic analysis of the CFTR gene and the growing use of commercial kits strengthen the need for an update of previous best practice guidelines (published in 2000). The importance of organizing regional or national laboratory networks, to provide both primary and comprehensive CFTR mutation screening, is stressed. Current guidelines focus on strategies for dealing with increasingly complex situations of CFTR testing. Diagnostic flow charts now include testing in CFTR-related disorders and in fetal bowel anomalies. Emphasis is also placed on the need to consider ethnic or geographic origins of patients and individuals, on basic principles of risk calculation and on the importance of providing accurate laboratory reports. Finally, classification of CFTR mutations is reviewed, with regard to their relevance to pathogenicity and to genetic counselling.

Dr Els Dequeker (fig.11) is at the Center for Human Genetics, Campus Gasthuisberg, KULeuven, Belgium.

 Flume PA, Ciolino J, Gray S, Lester MK. Patient-reported pain and impaired sleep quality in adult patients with cystic fibrosis. J Cyst Fibros 2009; 8:321-325. [PubMed]

Fig 12 Patrick Flume CF Foundation

Sleep impairment has been described in patients with cystic fibrosis (CF). Pain is a known cause of sleep disturbance and as pain is commonly reported in patients with CF, the authors sought to find an association between impaired sleep quality and pain. Fifty adult CF patients completed surveys of pain and sleep quality. Pain and poor sleep quality were reported in a majority of adult CF patients and there was a strong correlation between the two. This will have important clinical implications in the evaluation and treatment of adult patients.There are more reports and attention paid to chronic pain which is very common in people with CF. In this study from the USA the pain was contributing significantly to sleep disturbance in many patients.

Flume PA, Robinson KA, O’Sullivan B, Finder JD, Vender RL, Willey-Courand DB, White TB, Marshall BC. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Clinical Practice Guidelines for Pulmonary Therapies Committee. Respiratory Care 2009; 54:522-537.[PubMed]
A CF Foundation committee found no evidence that one method of airway clearance was superior to the others and although the evidence for benefit was not strong, recommended daily airway clearance be performed and regular exercise taken by all patients.A most studies have failed to show one method of airway clearance is significantly better than the others; however, other studies have confirmed that regular physiotherapy is definitely better than no physiotherapy.

In the UK The Association of Chartered Physiotherapists in Cystic Fibrosis published their “Standards of Care and Good Clinical Practice for Physiotherapy Management of Children and Adults with Cystic Fibrosis” edited by Penney Argent, Lisa Morrison and Ammani Prasad in 2011; it is an excellent review of the subject.

Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC. Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Resp Crit Car 2009; 180:802-808.[PubMed]
The Cystic Fibrosis Foundation established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians.

Dr Patrick Flume (fig.12) is a pulmonologist in Charlestown South Carolina.  He oversees a rapidly growing CF Center, including the largest adult CF program in South Carolina. He has served on numerous CF Foundation committees including as founding co-chair of the Pulmonary Practice Guidelines Committee, and his active research interests include CF, bronchiectasis and non-tuberculous mycobacteria.

Fuchs SI, Eder J, Ellemunter H, Gappa M. Lung clearance index: normal values, repeatability, and reproducibility in healthy children and adolescents. Pediatr Pulmonol 2009; 44:1180-1185. [PubMed]
The aim of this prospective study was to assess within-test repeatability, short term reproducibility and long term reproducibility, and to establish normal values for the LCI in healthy children and adolescents using the sidestream ultrasonic flow sensor (EasyOne Pro, MBW Module, ndd Medical Technologies, Switzerland).
The study confirms the reliability and robustness of equipment, protocol and analysis and the reliability of the MBW technique in general. The present data will help to interpret the effect of therapeutic interventions and interpretation of longitudinal data in patients with pulmonary diseases.
Further evidence that this test does seem to be an extremely useful and is also applicable to young children with CF.

Dr Susanne I Fuchs is in the Department of Paediatric Pulmonology and Neonatology, Medizinische Hochschule Hannover, Hannover, Germany.

Goubau C, Wilschanski M, Skalicka V, Lebecque P, Southern KW, Sermet I, Munck A, Derichs N, Middleton PG, Hjelte L, Padoan R, Vasar M, De Boeck K. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax 2009; 64:683-691. [PubMed]
Patients with intermediate sweat chloride values in whom either additional CF diagnostic test was abnormal were compared with subjects in whom this was not the case and patients with classic CF.
The phenotypic features of four groups were compared: 59 patients with CFTR dysfunction, 46 with an intermediate sweat chloride concentration but no evidence of CFTR dysfunction (CF unlikely), 103 patients with CF and pancreatic sufficiency (CF-PS) and 62 with CF and pancreatic insufficiency (CF-PI).The CFTR dysfunction group had more lower respiratory tract infections (p = 0.01), more isolation of CF pathogens (p<0.001) and clubbing (p = 0.001) than the CF unlikely group, but less frequent respiratory tract infections with CF pathogens than the CF-PS group (p = 0.05).
Patients in the CF-PS group had a milder phenotype than those with PI. Many features showed stepwise changes through the patient groups. The authors concluded that patients with intermediate sweat chloride values and two CFTR mutations or an abnormal NPD measurement have a CF-like phenotype compatible with CFTR dysfunction and, as a group, differ phenotypically from patients with intermediate sweat chloride values in whom further CF diagnostic tests are normal as well as from CF-PS and CF-PI patients.

— Although these conclusions seem obvious and confirm previous observations, they are helpful when considering patients with a dubious diagnosis. Long term expert follow-up may be required for some years at a CF Centre and is definitely advisable.

Dr C Goubau is in the Department of Paediatrics, Paediatric Pulmonology, University Hospital of Leuven, Herestraat 49, 3000 Leuven, Belgium.

Guilbault C, Wojewodka G, Saeed Z, Hajduch M, Matouk E, De Sanctis JB, Radzioch D. Cystic fibrosis fatty acid imbalance is linked to ceramide deficiency and corrected by fenretinide. Am J Respir Cell Mol Biol. 2009; 41:100-106.[PubMed]

Fig. 13 Claudine Guilbault Researchgate

Patients with cystic fibrosis (CF) and Cftr-knockout mice (CF mice) display an imbalance in fatty acids, with high arachidonic acid (AA) and low docosahexaenoic acid (DHA) concentrations. The authors’ recent studies demonstrated defects in another class of lipids, ceramides, in patients with CF and in CF mice. This study investigates the relationship between ceramide, AA, DHA, and the correction of lipid imbalances in CF mice after treatment with fenretinide.

Concentrations of AA, DHA, and ceramide were assessed in plasma from 58 adult patients with CF and 72 healthy control subjects. After 28 days of treatment with fenretinide, the same analysis was performed in wild-type and CF mice from plasma and organs (lung, ileum, pancreas, and liver).Low ceramide levels were associated with high AA and low DHA concentrations in patients with CF. No correlation was observed in healthy control subjects. Greater deficiencies were seen in patients with CF who were diagnosed before the age of 18, specifically with statistically significant higher levels of AA. Treatment with fenretinide (N-(4-hydroxyphenyl)retinamide; 4-HPR) normalized high levels of AA and low levels of ceramide, and increased the levels of DHA in CF mice. As in patients with CF, low ceramide levels correlated with higher AA and lower DHA levels in plasma of CF mice. Lipid abnormalities correlated with ceramide deficiencies in patients with CF and CF mice.
The authors showed that fenretinide treatment normalizes the fatty acid imbalance in CF mice with reducing AA to WT levels and increasing DHA. They propose that fenretinide treatment might improve this pathological phenotype in patients with CF.

— These findings are mentioned in some detail as they seem to link the fatty acid abnormalities (Freedman SD et al. 1999 [PubMed] with the ceramide accumulation described in CF (Teichgraber V et al. 2008. [PubMed] above) and even suggest a potential treatment.

Dr Claudine Guilbault (fig.13) is in the Department of Medicine, McGill University, Montreal, Quebec, Canada.

Heijerman H, Westerman E, Conway S, Döring G. Consensus working group. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: A European consensus. J Cyst Fibros 2009; 8:295-315[PubMed]

Fig. 14 Harry Heijerman A PaediatriciansLife

In this European consensus document the authors review the current status of inhaled medication in CF, including the mechanisms of action of the various drugs, their modes of administration and indications, their effects on lung function, exacerbation rates, survival and quality of life, as well as side effects.   A detailed consensus document with no less than 249 referencesProf

Harry Heijerman, (fig.14) is Pulmonologist, at Haga Teaching Hospital, Department of Pulmonology, The Hague. He is a leading European pulmonologist and founding editor of the Journal of Cystic Fibrosis.

Huffmyer JL, Littlewood KE, Nemergut EC. Perioperative management of the adult with cystic fibrosis. Anesth Analg 2009; 109:1949-1961.     pubmed.ncbi.nlm.nih.gov/19923526/

Fig. 15 Julie L Huffmyer UVA School of Medicine

A helpful review article on the optimal perioperative management of patients with CF requires an understanding of the relevant pathophysiology and the unique challenges presented by these patients.
The authors reviewed these concepts, including special considerations such as liver and lung transplantation and pregnancy.
These are particularly important as not infrequently a person with CF is admitted to a surgical unit where there is limited knowledge of CF – for example postoperatively enzymes may be omitted leading to DIOS and serious unnecessary complications.

Julie L Huffmyer (fig.15)  is in the Department of Anaesthesiology, University of Virginia Health System, Charlottesville, VA

Horsley A. Lung clearance index in the assessment of airways disease. Respir Med 2009; 103:793-799.  Free article

     Fig 16. Alex Horsley ResearchGate

In the last few years there has been a growing interest in lung clearance index (LCI), a measure of lung physiology derived from multiple breath washout tests. This resurgence of interest was initially driven by the recognition that such assessments were capable of detecting early airways disease in children, and are more sensitive and easier to perform in this population than conventional lung function tests (Aurora P, Kozlowska W, Stocks J. Gas mixing efficiency from birth to adulthood measured by multiple-breath washout. Respir Physiol Neurobiol, 2005;148(1-2):125-139.). With an appreciation of the importance of earlier identification of airways dysfunction, and prevention of irreversible structural airway changes, methods of following airways disease in these “silent years” are especially important.Lung clearance Index has now been reported in studies involving all age groups, from infants to adults (Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. Thorax, 2007;62:341-7.[PubMed]; Horsley AR, Gustafsson PM, Macleod K, Saunders CJ, Greening AP, Porteous D, et al. Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax, 2008;63:135-40. [PubMed]) and has a narrow range of normal over this wide age range, making it especially suitable for long-term follow-up studies. In cystic fibrosis (CF) particularly, there is a pressing need for sensitive and repeatable clinical endpoints for therapeutic interventions (Rosenfeld M. An overview of endpoints for cystic fibrosis clinical trials: one size does not fit all. Proc Am Thorac Soc, 2007;4(4):299-301. [PubMed]), and LCI has been proposed as an outcome measure in future CF gene therapy studies (Davies JC, Cunningham S, Alton EW, Innes JA. Lung clearance index in CF: a sensitive marker of lung disease severity. Thorax, 2008;63:96-97[PubMed]).

This review considers how LCI is derived, how it differs from conventional lung function testing, and its applications and limitations.This is a good review of lung clearance index with many useful references so the abstract has been included in full. Does seem to be an important advance in respiratory function testing particularly for young children.

Dr Alex Horsley (fig.16) is a Clinical Senior Lecturer and Honorary Consultant at the Manchester Adult Cystic Fibrosis Centre, based at University Hospitals South Manchester NHS Foundation Trust. He is involved in several aspects of CF research but has a special interest in lung clearance index as a measure of early airways disease, and in the role of airway mucins in the pathophysiology of CF. (This paper written while in Dept. Respiratory Medicine Edinburgh)

Hubert D, Le Roux E, Lavrut T, Wallaert B, Scheid P, Manach D, Grenet D, Sermet-Gaudelus I, Ramel S, Cracowski C, Sardet A, Wizla N, Deneuville E, Garraffo R. Continuous versus intermittent infusions of ceftazidime for treating exacerbation of cystic fibrosis. Antimicrob Agents Ch 2009; 53:3650-3656. [PubMed]

Fig. 17 Dominique Hubert       ecom-cf

Patients with chronic Pseudomonas aeruginosa infection received two successive courses of intravenous tobramycin and ceftazidime (200 mg/kg of body weight/day) for pulmonary exacerbation administered as thrice-daily short infusions or as a continuous infusion. The continuous infusion of ceftazidime appeared to be as efficient as short infusions in patients with cystic fibrosis as a whole, but it gave better results in patients harbouring resistant isolates of P. aeruginosa.   Ideally a steady blood level of ceftazidime should be maintained during treatment in contrast to aminoglycosides where peak levels are ideal.

— Previous studies have shown continuous infusion of CZ to be more satisfactory and are recommend for maximum effect – for example when attempting to eradicate Pseudomonas when standard eradication treatment has failed. It is interesting that better result were obtained in the present study when treating resistant bacteria.

Dominique Hubert (fig. 17)  is at the Centre de Ressources et de Compétences pour la Mucoviscidose, Service de Pneumologie, Hôpital Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.

Hull JH, Garrod R, Ho TB, Knight RK, Cockcroft JR, Shale DJ. Bolton CE. Increased augmentation index in patients with cystic fibrosis. Eur Resp J 2009; 34:1322-1328. [PubMed]
Increased large artery stiffness occurs in a range of inflammatory conditions indicating an ageing of the vasculature and additionally being an independent risk factor for cardiovascular events. Augmentation index (AIx) is increased in adults with CF, in the presence of a normal blood pressure and independent of diabetic status. AIx was related to the systemic inflammatory status.

These findings have implications for management and require further exploration so that cardiovascular health can be maintained. As more adults are studied new findings arise. This contrasts with a previous report that there was a reduction in atheroma in patients with CF. It is perhaps reasurring that when the hearts of the CF patients receiving a heart-lung transplant was used succesfully for non-CF persons requiring a heart transplant there seemed to be reasonable function.

J H Hull is at the Faculty of Health and Social Care Sciences, Kingston University and St George’s, London, UK.

Löhr JM, Hummel FM, Pirilis KT, Steinkamp G, Körner A, Henniges F. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol Hepatol 2009; 21:1024-1031. [PubMed]

Fig. 18 Matthias Löhr acarepro.abbott.com

Measurements of size, surface, acid resistance, release of enzymes, pharmacokinetics and batch consistency were undertaken. Available pancreatin preparations vary widely with respect to investigated parameters, which may have consequences for facilitating optimal digestion.

Prof. Johannes-Matthias Löhr (fig.18) is at Gastrocentrum, Department of Surgical Gastroenterology, Karolinska Institute University Hospital, Huddinge, SE-141 86 Stockholm, Sweden.

Lebecque P, Leonard A, De Boeck K, De Baets F, Malfroot A, Casimir G, Desager K, Godding V, Leal T. Early referral to cystic fibrosis specialist centre impacts on respiratory outcome. J Cyst Fibros 2009; 8:26-30. [PubMed]

Fig.19  Patrick Lebecque

Published studies concerning the impact of specialist care on lung disease in cystic fibrosis remain limited and most are either biased due to comparison with historical controls and/or underpowered. In this retrospective multicentric study, data from all CF children fulfilling the following criteria were collected: 1) Age 6yr and less than 18 yrs at the end of 2003; 2) diagnosed before 8 yrs; 3) follow-up in an accredited  Belgian CF centre; 4) at least 1 spirometry and respiratory culture available for 2003. Group A included children referred 2 yrs or more after the diagnosis. Patients from Group A were then matched with a single early referred patient on the basis of 2 criteria: same centre, as closest age as possible (Group B). Data from 217 children were collected (Group A: 67). Late referred patients had a lower FEV1 (77.2%+/-22.4 vs 86.7% +/-19.4, p=0.01) and a higher prevalence of P. aeruginosa (38.6 vs 17.5%, p<0.05).So in this population of CF children, a delay of 6.1 yr (vs 0.1 y) between diagnosis and referral to a specialist clinic resulted in poorer respiratory outcome at age 13 years.

Most experienced CF clinicians (including this reviewer, are convinced that CF centre care is the ideal from diagnosis – which, with neonatal screening, should now be from a few weeks – but unfortunately by no means all paediatricians agree.

Patrick Lebecque (fig 19) wrote a detailed article full of sound advice and available on the internet – Patrick Lebecque (2012). The Prognosis of Cystic Fibrosis – A Clinician’s Perspective, Cystic Fibrosis – Renewed Hopes Through Research, Dr. Dinesh Sriramulu (Ed.), ISBN: 978-953-51-0287-8, InTech, Available from: http://www.intechopen.com/books/cystic-fibrosis-renewed-hopes-through-research/the-prognosis-of- cystic-fibrosis-a-clinician-s-perspective

Lubamba B, Lebacq J, Lebecque P, Vanbever R, Leonard A, Wallemacq P, Leal T. Airway delivery of low-dose miglustat normalizes nasal potential difference in F508del cystic fibrosis mice. Am J Respir Crit Care 2009; 179:1022-1028. pubmed.ncbi.nlm.nih.gov/19299496/

Fig. 20 Bob Lubamba scibioxconsulting.com

N-butyldeoxynojyrimicin (NB-DNJ, miglustat [Zavesca]) an approved drug for treating Gaucher disease, was reported to be able to correct the defective trafficking of the F508del-CFTR protein. The authors consider their results provide clear evidence that nasal delivery of miglustat, at picomolar doses, normalizes sodium and Cftr-dependent chloride transport in F508del transgenic mice; they highlight the potential of topical miglustat as a therapy for CF.

One of a number of publications describing the effect of miglustat in CF cells and mice since the first report in 2006 (Norez C et al. [PubMed]).

Bob Lubamba (fig. 20) is at the Department of Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium. Subsequently Chief Scientist at Scibiox Consulting.

Joo NS, Wine JJ, Cuthbert AW. Lubiprostone stimulates secretion from tracheal submucosal glands of sheep, pigs, and humans. Am J Physiol – Lung C 2009; 296:L811-24. [PubMed]
Lubiprostone, a putative ClC-2 chloride channel opener, has been investigated for its effects on airway epithelia (tracheas). Lubiprostone is shown to increase submucosal gland secretion in pigs, sheep, and humans and to increase short-circuit current (SCC) in the surface epithelium of pigs and sheep. Use of appropriate blocking agents and ion-substitution experiments shows anion secretion is the driving force for fluid formation in both glands and surface epithelium. From SCC concentration-response relations, it is shown that for apical lubiprostone K(d) = 10.5 nM with a Hill slope of 1.08, suggesting a single type of binding site and, from the speed of the response, close to the apical surface, confirmed the rapid blockade by Cd ions. Responses to lubiprostone were reversible and repeatable, responses being significantly larger with ventral compared with dorsal epithelium. Submucosal gland secretion rates following basolateral lubiprostone were, respectively, 0.2, 0.5, and 0.8 nl gl(-1) min(-1) in humans, sheep, and pigs. These rates dwarf any contribution surface secretion adds to the accumulation of surface liquid under the influence of lubiprostone. Lubiprostone stimulated gland secretion in two out of four human cystic fibrosis (CF) tissues and in two of three disease controls, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (COPD/IPF), but in neither type of tissue was the increase significant. Lubiprostone was able to increase gland secretion rates in normal human tissue in the continuing presence of a high forskolin concentration.Lubiprostone had no spasmogenic activity on trachealis muscle, making it a potential agent for increasing airway secretion that may have therapeutic utility.

Subsequently there have been a number of publications (30)  concerning CF and lubiprostone – Musch MW, Wang Y, Claud EC, Chang EB .Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig Dis Sci. 2013; 58:668-77. [PubMed]

Dr N S Joo was working at the Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, UK.

Lisowska A, Wójtowicz J, Walkowiak J. Small intestine bacterial overgrowth is frequent in cystic fibrosis: combined hydrogen and methane measurements are required for its detection.Acta Biochim Pol. 2009;56(4):631-4[PubMed]

Fig. 21 Aleksandra Lisowska

From the Department of Pediatric Gastroenterology and Metabolism, Poznań University of Medical Sciences, Poznań, Poland.  Hydrogen breath test (BT) is commonly used as a diagnostic tool for the detection of small intestine bacterial overgrowth (SIBO). It was reported that colonic methane production is far more frequent in cystic fibrosis (CF) patients than in other subjects. Therefore, measuring exclusively hydrogen in the diagnostic breath test for diagnosing SIBO might be of limited value.
The authors aimed to assess the usefulness of combined measurement of hydrogen and methane expiration for the diagnosis of SIBO in CF.
The study comprised 62 CF patients aged 5 to 18 years. Three-hundred-ninety subjects assessed due to gastrointestinal symptoms for the presence of SIBO served as a comparative group. In all subjects hydrogen/methane BT using glucose was performed. A positive BT was defined as fasting hydrogen > or = 20 ppm or fasting methane > or = 10 ppm or a rise of > or = 12 ppm hydrogen or > or = 6 ppm methane over baseline during the test.
In 23 (37.1%) CF patients and in 52 (13.3%) subjects from the comparative group abnormal BT results were found. In seven (11.3%) CF patients and 29 (7.4%) of the other subjects studied methane measurement allowed diagnosis of SIBO.

— Small intestine bacterial overgrowth is frequent in cystic fibrosis. For its detection in cystic fibrosis and other gastrointestinal patients, combined hydrogen and methane measurement instead of hydrogen breath test should be applied. Without the additional measurement of methane a significant percentage of SIBO will be missed

Dr Aleksandra Lisowska (fig.21)  is at the Department of Pediatric Gastroenterology and Metabolism, Poznań University of Medical Sciences, Poznań, Poland.

Massie J, Petrou V, Forbes R, Curnow L, Ioannou L, Dusart D, Bankier A, Delatycki M. Populations based carrier screening for cystic fibrosis in Victoria: the first three years experience. Aus NZ J Obstet Gynecol 2009; 49:484-489.[PubMed]

Fig. 22 John Massie. ResearchGate

CF carrier screening was offered to 3020 women and couples planning a pregnancy, or in early pregnancy, through obstetricians and general practitioners in Victoria, Australia from January 2006 to December 2008. Of the nine carrier couples, six were pregnant at the time of screening (five natural conception and one in vitro fertilisation) and all had CVS (mean gestation 12.5 weeks). Two fetuses were affected, three were carriers and one was not a carrier. Termination of pregnancy was undertaken for the affected fetuses.
The authors concluded that carrier screening for CF by obstetricians and general practitioners by cheek swab sample can be successfully undertaken prior to pregnancy or in the early stages of pregnancy.

— Carrier screening was pioneered by David Brock in Edinburgh but abandoned there apparently as a result of the introduction of neonatal screening becoming available; also the improving prognosis was a factor. However, antenatal screening was recommended by a UK Health Technology Assessment report and even by the UK National Screening Committee but has not been implemented in the UK (by 2024) on the grounds of expense. Indeed, it certainly seems to be an approach which should be available to future parents should they wish it.   A downward trend in the incidence of CF has been noted in North Eastern Italy where antenatal screening is available (Castellani et al. [PubMed]) and also in Edinburgh.

Dr John Massie (fig. 22) is at the Department of Respiratory Medicine, Murdoch Children’s Research Institute Unit, Royal Children’s Hospital, Melbourne, Victoria 3052, Australia

Mayell SJ, Munck A, Craig JV, Sermet I, Brownlee KG, Schwarz MJ, Castellani C, Southern KW. European Cystic Fibrosis Society Neonatal Screening Working Group. A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis. J Cyst Fibros 2009; 8:71-78. [PubMed].

Fig. 23 Sarah Mayell Welsh Paediatric Soc.

Current screening protocols result in recognition of infants with an equivocal diagnosis. A survey of European practice suggested inconsistencies in the evaluation and management of these infants. the authors undertook a consensus process using a modified Delphi method. This has enabled input of CF specialists from a wide geographical area to a rigorous process that has provided a clear pathway to a consensus statement. A core group produced 21 statements, which were modified over a series of three rounds (including a meeting arranged at the European CF Conference). A final document of 19 statements was produced, all of which achieved a satisfactory level of consensus. The statements cover four themes; sweat testing, further assessments and investigations, review arrangements and database. This consensus document will provide guidance to CF specialists.As neonatal screening has now been widely adopted it is unfortunate, but likely, that not all infants who are detected as possibly having CF will be seen at CF centres. Therefore this document provides good evidence based on experience of the contributors for dealing with the infant where the diagnosis is in doubt.

— There is a helpful list of most of the eventualities that one is likely to encounter. In my experience of over 20 years neonatal CF screening in Leeds these cases are the exception but often require long term follow-up if only to reassure the family.

Dr Sarah Mayell (fig.23) is a consultant paediatrician at Alder Hey Children’s Hospital Liverpool and departmental lead for Respiratory Medicine.

Millar FA, Simmonds NJ, Hodson ME. Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985-2005. J Cyst Fibros 2009; 8:386-391. [PubMed]
A retrospective analysis of sputum microbiology from adult CF patients (1985 to 2005) using the Royal Brompton Hospital CF database. Infection with Pseudomonas aeruginosa or Staphylococcus aureus between 1985 and 2005 remained stable (77 to 82%, p=0.159; 54 to 47%, p=0.108; respectively). Haemophilus influenzae (48 to 6%; p<0.001), Aspergillus species (18 to 9%; p=0.002) and Burkholderia cepacia complex (9 to 4%; p=0.041) prevalence decreased. Stenotrophomonas maltophilia and MRSA increased (1 to 4%, p=0.02; 1 to 6%, p=0.002, respectively). So P. aeruginosa infection remained stable; there has been a decline in B. cepacia complex, H. influenzae and Aspergillus sp., and only a small increase in S. maltophilia and MRSA. Intensive antibiotic strategies have been employed, which, so far, have not resulted in clinically significant emergence of new pathogens.
This provides a record of the microbiological situation at the Royal Brompton Hospital in London. Interesting that the prevalence of Aspergillus has fallen as some centres have seen a rise in this fungus over recent years.

From Adult Cystic Fibrosis Dept, NHLI/Imperial College and Royal Brompton Hospital, London, United Kingdom.

Moran A, Dunitz J, Nathan B, Saeed A, Holme B, Thomas W. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care 2009; 32:1626-1631[PubMed

Fig.24 Antoinette Moran med.umn.edu

Cystic fibrosis (CF)-related diabetes (CFRD) diagnosis and management have considerably changed since diabetes was first shown to be associated with a poor prognosis in subjects with CF. Current trends in CFRD prevalence, incidence, and mortality were determined from a comprehensive clinical database.Data were reviewed from 872 CF patients followed at the University of Minnesota during three consecutive intervals: 1992-1997, 1998-2002, and 2003-2008. CFRD is currently present in 2% of children, 19% of adolescents, and 40-50% of adults. Incidence and prevalence are higher in female subjects aged 30-39 years; otherwise, there are no sex differences. In younger individuals, CFRD without fasting hyperglycemia predominates, but fasting hyperglycemia prevalence rises with age. CFRD mortality has significantly decreased over time. From 1992-1997 to 2003-2008, mortality rate in female subjects dropped by >50% from 6.9 to 3.2 deaths per 100 patient-years and in male subjects from 6.5 to 3.8 deaths per 100 patient-years. There is no longer a sex difference in mortality. Diabetes was previously diagnosed as a perimorbid event in nearly 20% of patients, but of 61 patients diagnosed with diabetes during 2003-2008, only 2 died. Lung function but not nutritional status is still worse in CF patients with diabetes compared with those without diabetes. Nutritional status and pulmonary status are similar between patients without fasting hyperglycemia and those with fasting hyperglycemia.
The authors concluded that the previously noted sex differences in mortality have disappeared, and the gap in mortality between CF patients with and without diabetes has considerably narrowed. They believe that early diagnosis and aggressive treatment have played a major role in improving survival in these patients. A comprehensive review of changes in the features of CFRD by Antoinette Moran an expert on CFRD from Minnesota.

Prof. Antoinette Moran (fig. 24) is a paediatric endocrinologist in the University of Minnesota and a world expert on cystic fibrosis diabetes.

McDermott S, Barry SC, Judge EE, Collins S, de Jong PA, Tiddens HA, McKone EF, Gallagher CC, Dodd JD. Tracheomalacia in adults with cystic fibrosis: determination of prevalence and severity with dynamic cine CT. Radiology 2009; 252:577- 586. [PubMed]

Fig.25 Shaunagh McDermott Massachusetts General Hospital

To determine the prevalence and severity of tracheomalacia in adults with cystic fibrosis (CF) by using dynamic cine multidetector computed tomography (CT) and to correlate these findings with pulmonary function test (PFT) results and the severity of parenchymal lung disease.Tracheomalacia was demonstrated in 24 (69%) patients and no control subjects during forced expiratory maneuvers (P = .001) and in 10 (29%) patients and one (10%) control subject during coughing. There was no correlation between tracheal cross-sectional luminal reduction and either the predicted FEV(1) or CT score. Tracheomalacia depicted at dynamic cine multidetector CT is a highly prevalent finding in adults with CF.

Clinically tracheomalacia has been observed on occasion but the present study demonstrates how common is the condition. It is interesting that similar tracheal abnormalities occur commonly in CF pigs where there is in particular some degree of maldevelopment of the tracheal cartilage    The tendency to tracheomalacia in people with CF is well documented and at times clinically evident as a tendency to severe expiratory wheeze (Fischer AJ et al, 2014 [PubMed]). Similar tracheal abnormalities have been documented in animal CF models (Adam RJ et al. 2013.[PubMed])

Dr Shaunagh McDermott (fig.25) is a radiologist at the time of this study in the Department of Radiology, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland.

Moran A, Pekow P, Grover P, Zorn M, Slovis B, Pilewski J, Tullis E, Liou TG, Allen H. Cystic Fibrosis Related Diabetes Therapy Study Group. Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial. Diabetes Care 2009; 32:1783-1788. [PubMed]

Cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia (CFRD FH-) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment.The Cystic Fibrosis Related Diabetes Therapy (CFRDT) Trial sought to determine whether diabetes therapy improves BMI in these patients.A three-arm multicenter randomized trial compared 1 year of therapy with premeal insulin as part, repaglinide, or oral placebo in subjects with cystic fibrosis who had abnormal glucose tolerance. One hundred adult patients were enrolled. Eighty-one completed the study, including 61 with CFRD FH- and 20 with severely impaired glucose tolerance (IGT). During the year before therapy, BMI declined in all groups. Among the group with CFRD FH-, insulin-treated patients lost 0.30 +/- 0.21 BMI units the year before therapy. After 1 year of insulin therapy, this pattern reversed, and they gained 0.39 +/- 21 BMI units (P = 0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (P = 0.45). Repaglinide-treated patients had an initial significant BMI gain (0.53 +/- 0.19 BMI units, P = 0.01), but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared with the year before (P = 0.33). Among patients with IGT, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group.Insulin therapy safely reversed chronic weight loss in patients with CFRD fasting hyperglycaemia.

A conclusive result showing that insulin improves the nutritional state of people with CF who have impaired glucose tolerance with fasting hyperglycaemia.

Miller AR, Condin CJ, McKellin WH, Shaw N, Klassen AF, Sheps S. Continuity of care for children with complex chronic health conditions: parents’ perspectives. BMC Health Services Research. 2009; 9:242. [PubMed

Fug. 26 Anton R Miller                                BC Children’s Hospital

Continuity of care has been explored largely from academic and service provider perspectives, and in relation to adult patient/client groups. The authors interviewed parents of children with complex chronic health conditions to examine how their experiences and perceptions of continuity of care fit with these perspectives; and to identify the salient factors in the experience of, and factors contributing to, continuity in this population.A thorough knowledge of the child on the part of service providers emerged as extremely important to parents; such knowledge was underpinned by continuity of personal relationships, principally, and also by written information. For this population, notions of continuity extend to the full range of service providers these children and families need to achieve optimal health status, and are not limited to physicians and nurses. Communication among providers was seen as integral to perceived continuity. Compartmentalization of services and information led to parents assuming a necessary, though at times, uncomfortable, coordinating role. Geographic factors, institutional structures and practices, provider attitudes, and, on occasion, parent preferences and judgments, were all found to create barriers to “seamless” management and provision of care continuity across providers, settings, and sectors.

– Although the authors suggest that “These findings add new perspectives to the understanding of continuity within chronically ill children’s health care. They are relevant to contemporary initiatives to improve continuity of services to children with special health care needs, demonstrate the need for parental support of their important role in maintaining continuity, and suggest avenues for further research”, they are, of course, the basic principles upon which good care for CF is organised in the best CF centres.Undoubtedly lack of continuity of care is now one of the major deficiencies of our UK National Health Service.

Dr Anton R Miller (fig. 26) is at Department of Pediatrics, University of British Columbia, British Columbia, Canada.

Norez C, Antigny F, Noel S, Vandebrouck C, Becq F. A cystic fibrosis respiratory epithelial cell chronically treated by miglustat acquires a non-cystic fibrosis-like phenotype. Am J Respir Cell Mol Biol 2009; 41(2):217-225. [PubMed

Fig 27 Caroline Norez LinkedIn

Miglustat (N-butyldeoxynojirimycin, Zavesca), an inhibitor of the alpha-1,2 glucosidase, has been proposed for clinical use in CF because of its effect as a corrector of the defective trafficking of F508del-CFTR. In the present study daily treatment for 2 months with low concentrations of miglustat on the human CF nasal epithelial cell line, JME/CF15 (F508del/F508del-CFTR), results in progressive, stable, reversible, and sustained correction of F508del-CFTR trafficking, down-regulation of sodium hyperabsorption, and regulation of the calcium homeostasis.

– These authors provide the first evidence that a respiratory CF cell can acquire a non-CF-like phenotype when chronically treated with low concentrations of a pharmacological drug. However a subsequent clinical trial published in 2012 failed to show significant changes in total chloride secretion assessed by nasal potential difference or sweat chloride values (Leonard A et al. A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference. J Cyst Fibros 2012; 11: 231-236. [PubMed])

Professor Caroline Noreen (fig. 27)  is at IPBC, Université de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers, France.

Okusanya OO, Bhavnani SM, Hammel J, Minic P, Dupont LJ, Forrest A, Mulder GJ, Mackinson C, Ambrose PG, Gupta R. Pharmacokinetic and pharmacodynamic evaluation of liposomal amikacin for inhalation in cystic fibrosis patients with chronic Pseudomonal infection. Antimicrob Agent Ch 2009; 53:3847-3854. [PubMed]
The pharmacokinetics and pharmacodynamics of a novel liposomal amikacin for inhalation were evaluated in cystic fibrosis patients with chronic Pseudomonas infection. Twenty-four patients from two studies received 500 mg of liposomal amikacin by inhalation once daily for 14 days. While significant relationships between absolute change in PFT endpoints and the ratio of serum or sputum area under the concentration-time curve to the MIC (AUC/MIC) were not observed, relationships between change in log10 CFU and serum AUC/MIC ratio and change in log10 CFU and absolute changes in all PFT endpoints were significant.
Together, these findings likely represent drug effect and warrant the further development of liposomal amikacin for inhalation.One of the few new antibiotic preparations which are going forward for further evaluation.

From the Institute for Clinical Pharmacodynamics, Ordway Research Institute, Inc., Albany, New York, USA.

Ouyang L, Grosse SD, Amendah DD, Schechter MS. Healthcare expenditures for privately insured people with cystic fibrosis. Pediatr Pulmonol 2009; 44:989-996. [PubMed]

Fig. 28 Liking Ouyang ResearchGate

The authors identified people with CF in the USA who were currently receiving medical care for the disorder and characterized their medical expenditures during the period 2004-2006.The annual medical care expenditure for a person with actively managed CF averaged $48,098 in 2006 dollars, which was 22 times higher than for a person without CF.This ratio is high relative to other chronic disorders. Outpatient prescription medications made up the largest component of total expenditures for people with CF (39%). Those who were recorded in claims data as having a liver or lung transplant, malnutrition, diabetes, or a chronic Pseudomonas aeruginosa pulmonary infection incurred much higher expenditures than people without these conditions. People with CF will incur high medical expenditures throughout their life span. These findings will assist in the development of economic evaluations of future CF screening and management initiatives.

This study confirms the very high cost of CF care which is likely to be similar in the UK. Both the absolute cost and the unfavorable comparison with other chronic disorders presents a major problem which is likely to increase as a greater proportion of the CF population are adults requiring multiple expensive treatments.

Dr Lijing Ouyang (Fig. 28) is an economist at the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Perera E, Massie J. Phillips RJ. Treatment of acne with oral isotretinoin in patients with cystic fibrosis. Arch Dis Child 2009; 94:583-586. [PubMed]

Fig. 29 Eshini Perera ResearchGate

Theoretical concerns about liver disease and vitamin A deficiency have limited the use of oral isotretinoin for troublesome acne in adolescents with cystic fibrosis. Oral isotretinoin was administered to nine patients with cystic fibrosis who had troublesome acne unresponsive to antibiotics. All patients were followed for 1-4 years after cessation of treatment. Isotretinoin treatment cleared active acne lesions in all patients. It was well tolerated, and no patient had significant side effects. All nine patients were pleased or delighted with the improvement in their skin. Adolescents with cystic fibrosis and acne can be treated with oral isotretinoin. Oral isotretinoin should be considered for adolescents with cystic fibrosis who have acne associated with scarring, acne not clearing with topical and antibiotic treatment, acne associated with depression or severe cystic acne.

– This is a reassuring paper for those considering the use of isotretinoin but who may have reservations regarding liver toxicity as clearing acne lesions in adolescents has a major effect on their quality of life.

Dr Eshini Perera (Fig. 29)  is in the Faculty of Medicine, University of Melbourne, Melbourne, Australia.

Post PN, Wittenberg J, Burgers JS. Do specialized centers and specialists produce better outcomes for patients with chronic diseases than primary care generalists? A systematic review. Int J Qual Health Care 2009; 21:387-396. [PubMed]
The authors searched Embase from 1987 through March 2008 for studies reporting the effect of treatment in a specialised or high-volume center or by subspecialists on clinically relevant outcomes. The authors concluded the available literature suggests that among patients with rheumatoid arthritis, diabetes mellitus or cystic fibrosis, outcomes are not superior in specialised centers or with subspecialists compared with other forms of chronic illness care.

   It is of some concern where a conclusion is based merely on the published work that reviewers, who may be of relatively limited clinical experience, come to a conclusion which is different to that of generations of experienced CF physicians and families.  It would be more helpful if reviewers were to assess all the evidence, not merely only the trials which come up to their rigorous at time unrealistic academic standards. Although it is unlikely that studies of this type will affect many clinicians’ firm conviction that centre care is preferable to local hospital care for people with CF, it is of some concern that such a study may be used by health care providers to deny patients extra funding to attend a specialist CF centre as has occurred in the past in the UK. It should be mentioned that only three trials concerning CF were included in this review.

Piet N Post is at the Dutch Institute for Healthcare Improvement CBO, 3502 LB Utrecht, The Netherlands.

Razvi S, Quittell L, Sewall A, Quinton H, Marshall B, Saiman L. Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005. Chest 2009; 136:1554-1560.[PubMed]

Fig 30. Samiya Razvi apollo247.com

Data from the Cystic Fibrosis Foundation Patient Registry were used to examine trends in the incidence and prevalence of bacterial pathogens isolated from patients with CF in the United States from 1995 to 2005. The number of patients with CF in the patient registry increased from 19,735 in 1995 to 23,347 in 2005. During the study period, the reported annual prevalence of Pseudomonas aeruginosa significantly declined from 60.4% in 1995 to 56.1% in 2005 (p < 0.001). The decline was most marked in children 6 to 10 years old (48.2 to 36.1%) and adolescents 11 to 17 years old (68.9 to 55.5%). Both the incidence (21.7% in 1995 and 33.2% in 2005) and prevalence (37.0% in 1995 and 52.4% in 2005) of methicillin-susceptible Staphylococcus aureus significantly increased and the age-specific prevalence was highest in patients 6 to 17 years old. The prevalence of methicillin-resistant S aureus increased from 0.1% in 1995 to 17.2% in 2005 and from 2002 to 2005 was highest in adolescents 11 to 17 years old. Both the prevalence and incidence of Burkholderia cepacia complex declined, while the prevalence of Haemophilus influenzae, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans increased.

– Data from the patient registry suggest that the epidemiology of bacterial pathogens in patients with CF changed during the study period.The prevalence of both S. aureus and P. aeruginosa are higher in the USA than in UK and particularly in UK centres where both anti-staphylococcal prophylaxis and early eradication of Pseudomonas are routine.

Dr Samiya Razvi (Fig. 30) at the time was at the Department of Pediatrics, Columbia university, New York, ; Morgan Stanley  Children’s Hospital of New York-Presbyterian, New York. Subsequently at Apollo Hospitals Jubilee Hills, Hyderabad.

Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM, McCoy KS, Montgomery AB, Cooper PJ. Efficacy and safety of inhaled aztreonam lysine for airway Pseudomonas in cystic fibrosis. Chest 2009; 135:1223-1232.[PubMed]

Fig 31. George Retsch-Bogart

A randomized, double-blind, placebo-controlled, international study (AIR-CF1 trial; June 2005 to April 2007), patients (n = 164; >or= 6 years of age) with FEV(1) >or= 25% and <or= 75% predicted values, and no recent use of anti-Pseudomonal antibiotics or azithromycin were treated with 75 mg of AZLI (three times daily for 28 days) or placebo (1:1 randomization), then were monitored for 14 days after study drug completion. The primary efficacy end point was change in patient-reported respiratory symptoms. Secondary end points included changes in pulmonary function (FEV1), sputum PA density, and non-respiratory CFQ-R scales. After 28 days of treatment, AZLI improved the mean CFQ-R respiratory score (9.7 points; p < 0.001), FEV1 (10.3% predicted; p < 0.001), and sputum PA density (- 1.453 log(10) cfu/g; p < 0.001), compared with placebo. The incidence of “productive cough” was reduced by half in AZLI-treated patients. PA aztreonam susceptibility at baseline and end of therapy were similar.So in patients with CF, PA airway infection, moderate-to-severe lung disease, and no recent use of anti-Pseudomonal antibiotics or azithromycin, 28-day treatment with AZLI significantly improved respiratory symptoms and pulmonary function, and was well tolerated.(Also McCoy KS et al. Am J Respir Crit Care Med 2008; 178:921-928. [PubMed]).

Inhaled aztreonam lysine is one of the major new additions to choices for inhaled antibiotic therapy during the decade.

Dr. George Retsch-Bogart (fig. 31) is a senior Pediatric Pulmonologist at the University of North Carolina Hospitals at Chapel Hill and University of North Carolina Hospitals. He has special interest and expertise in cystic fibrosis.

Ratjen F, Munck A, Kho P, Angyalosi G. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax 2009: 65:286-291. [PubMed]

Fig. 32 Felix Ratjen

The EarLy Inhaled Tobramycin for Eradication (ELITE) study was designed to assess the efficacy and safety of two regimens (28 and 56 days) of tobramycin inhalation solution (TIS) 300 mg/5 mL (TOBI(R)) twice daily for the treatment of early onset P. aeruginosa infection in CF patients. Children aged 6 months and over with early P. aeruginosa infection were treated for 28 days with TIS twice daily after which they were randomised to either stop or to receive a further 28 days treatment. The primary endpoint was the median time to recurrence of P. aeruginosa (any strain). Secondary endpoints included the proportion of patients free of P. aeruginosa infection one month after cessation of therapy and safety assessments.
The median time to recurrence of P. aeruginosa (any strain) was similar between the two groups. In total, 93% and 92% of the patients were free of P. aeruginosa infection one month after the end of treatment and 66% and 69% remained free after 27 months in the 28-day and 56-day groups, respectively.

So eventually it was shown treatment with inhaled tobramycin for 28 days was an effective and well tolerated therapy for early P. aeruginosa infection in CF patients. This was an important study as it confirmed for paediatricians in N. America that 28 days of inhaled tobramycin was highly effective in eradicating early infection with P. aeruginosa.

Felix Ratjen (fig 32) from the Division of Respiratory Medicine, Department of Pediatrics, University of Toronto, Hospital for Sick Children, 555 University Avenue, Toronto

Riethmuller J, Anthonyamay J, Serra E, Schwab M, Doring G, Gulbins E. Therapeutic efficacy and safety of amitriptyline in patients with cystic fibrosis. Cell Physiol Biochem 2009; 24:65-72. [PubMed]

Fig 33. Joachim Riethmuller

Amitriptyline is a blocker of acid sphingomylinase and acid ceramidse and reduces lung inflammation in CF mice.  In a randomised, double-blinded, placebo-controlled, cross-over pilot study, 4 adult CF patients received 37.5 mg of amitriptyline or placebo twice daily for 14 days. Subsequently in a phase II study 19 adult CF patients were randomly allocated to three treatment groups receiving amitriptyline once daily for 28 days at doses of 25 mg (n=7), 50 mg (n=8), or 75 mg (n=8) or placebo (n=13). The primary outcome was the difference of forced expiratory volume in 1 sec (FEV(1)) at day 14 between amitriptyline and placebo. Primary endpoint measures improved significantly in three of four patients in the pilot study after amitriptyline treatment vs placebo (relative FEV(1): 14.7+/-5%; p = 0.006) and in the 25 mg treatment group of the phase II study (relative FEV(1): 4.0+/-7%; p = 0.048).

The authors concluded the drug was well tolerated in both studies and 96% of the patients completed the studies. Amitriptyline as a novel therapeutic option in patients with CF is safe and seems to be efficacious.

Dr Joachim Riethmuller (fig.33) is Head of Pediatric Clinical Research and co-worker in the CF center in Tubingen.

Roux AL, Catherinot E, Ripoll F, Soismier N, Macheras E, Ravilly S, Bellis G, Vibet MA, Le Roux E, Lemonnier L, Gutierrez C, Vincent V, Fauroux B, Rottman M, Guillemot D, Gaillard JL, Jean-Louis Herrmann for the OMA Group. Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in France. J Clin Microbiol 2009; 47:4124-4128. [PubMed]

Fig. 34 Anne-Laure Roux 21.uvsq.fr

A multicenter prevalence study of nontuberculous mycobacteria (NTM) involving 1,582 patients (mean age, 18.9 years; male/female ratio, 1.06) with cystic fibrosis in France. The overall NTM prevalence (percentage of patients with at least one positive culture) was 6.6% (104/1,582 patients), with prevalences ranging from 3.7% (in the east of France) to 9.6% (in the greater Paris area). Mycobacterium abscessus complex (MABSC; 50 patients) and Mycobacterium avium complex (MAC; 23 patients) species were the most common NTM, and the only ones associated with fulfillment of the American Thoracic Society bacteriological criteria for NTM lung disease. The “new” species, Mycobacterium bolletii and Mycobacterium massiliense, accounted for 40% of MABSC isolates. MABSC species were isolated at all ages, with a prevalence peak between 11 and 15 years of age (5.8%), while MAC species reached their highest prevalence value among patients over 25 years of age (2.2%).

A large survey of NTM in France showing an overall prevalence of 6.6%.

Dr Anne-Laure Roux (fig. 34) is at   EA3647, UFR de Médecine Paris Ile-de-France Ouest, Université de Versailles Saint Quentin en Yvelines, Guyancourt, France.

Rosenecker J, Naundorf S, Rudolph C. Airway surface liquid contains endogenous DNase activity which can be activated by exogenous magnesium. Eur J Med Res 2009; 14:304-308.[PubMed]

Fig.35 Joseph Rosenecker ResearchGate

Increasing the magnesium concentration in the airway surface liquid by aerosolisation of magnesium solutions or oral magnesium supplements could improve the removal of highly viscous mucus in chronic lung disease by activating endogenous DNase activity.

An interesting observation as shortage of magnesium had already been involved in failure of DNase therapy in some people with CF (Sanders NN et al. 2006.[PubMed]).

Prof. dr. Joseph Rosenecker (Fig. 35)  is at the Department of Pediatrics, University of Munich, Lindwurmstr. 2a, 80337 Munich, Germany.

Sagel SD. Gibson RL. Emerson J. McNamara S. Burns JL. Wagener JS. Ramsey BW. Impact of Pseudomonas and Staphyloccus on inflammation and clinical status in young children with cystic fibrosis. J Pediatr 2009; 154:183-188. [PubMed]

Fig. 36 Scott Sagel som.cuanschutz.edu

To assess the effects of Pseudomonas aeruginosa and Staphylococcus aureus infection on lower airway inflammation and clinical status in young children with cystic fibrosis (CF). The authors studied 111 children age < 6 years who had 2 P. aeruginosa-positive oropharyngeal cultures within 12 months. They examined bronchoalveolar lavage fluid (BALF) inflammatory markers (ie, cell count, differential, interleukin [IL]-8, IL-6, neutrophil elastase), CF-related bacterial pathogens, exotoxin A serology, and clinical indicators of disease severity.
Young children with CF with both upper and lower airway P aeruginosa infection had higher neutrophil counts, higher IL-8 and free neutrophil elastase levels, increased likelihood of positive exotoxin A titers, and lower Shwachman scores compared with those with positive upper airway cultures only.S aureus was associated with increased lower airway inflammation, and the presence of both P aeruginosa and S aureus had an additive effect on concentrations of lower airway inflammatory markers. BALF markers of inflammation were increased with the number of different bacterial pathogens detected.The authors concluded that young children with CF who have upper and lower airway P. aeruginosa infection have increased endobronchial inflammation and poorer clinical status compared with those with only upper airway P. aeruginosa infection. The independent and additive effects of S. aureus on inflammation support the significance of polymicrobial infection in early CF lung disease.

– These results were to be expected and this study once more emphasises the importance of S. aureus which seems to receive less attention than P. aeruginosa although it is a serious pathogen for people with CF. The study lends some support to the UK recommendation for long term anti-Staphylococcal treatment for the first 3 years and more vigorous early eradication measures when the organism is first cultured when it is possible to clear it from the airways.

Dr Scott D Sagal (fig.36) is Professor in the Department of Pediatrics, The Children’s Hospital and University of Colorado Health Sciences Center, Aurora, CO 80045, US

Simmonds NJ, Cullinan P, Hodson ME. Growing old with cystic fibrosis – the characteristics of long-term survivors of cystic fibrosis. Respir Med 2009; 103:629-635. [PubMed]

Fig 37. Nicholas Simmonds

The proportion of patients with cystic fibrosis (CF) who are middle-aged is increasing – and is likely to continue to do so. The authors surveyed a population of long-term CF survivors to assess their burden of illness and profile their disease characteristics. The full spectrum of disease is represented in this population and, importantly, 30% are DeltaF508 homozygous. Provision needs to be made for the healthcare needs of this increasing population of older patients.

This is invaluable experience from the largest adult CF centre in the world.

Dr Nicholas Simmonds (fig.37) is a consultant respiratory physician at the Royal Brompton Hospital, London. He specialises in care of adults with cystic fibrosis.

Switzer M, Rice J, Rice M, Hardin DS. Insulin-like growth factor-I levels predict weight, height and protein catabolism in children and adolescents with cystic fibrosis. J Pediatr Endocrinol 2009; 22:417-424. [PubMed]

Fig 38 Dana Hardin

There was also a strong relationship between leucine rate of appearance (a measure of protein catabolism) and IGF-I. These results suggest a strong correlation between IGF-I and height, weight and protein catabolism and emphasize the need to normalize IGF-I levels in children with cystic fibrosis.

Dana Hardin (Fig. 38) of Columbus Ohio has written a number of papers on the use of growth hormone in CF over the past decade; also other endocrine aspects of CF such as diabetes, nutritional disorders including bone problems. Here the authors analyze the IGF-1 levels in the patients with CF previously studied.
It is interesting that in recent animal studies involving CF pigs there seems to be a relationship between IGF-1 and the growth potential of the affected animals (Rogan MP et al. 2010. [PubMed]).

Sly PD, Brennan S, Gangell C, de Klerk N, Murray C, Mott L, Stick SM, Robinson PJ, Robertson CF, Ranganathan SC. Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST-CF). Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Resp Crit Care 2009; 180:146-152. [PubMed]

Fig 39. Peter Sly

Fifty-seven infants (median age, 3.6 mo) with CF underwent bronchoalveolar lavage and chest computed tomography (CT) using a three-slice inspiratory and expiratory protocol.Despite the absence of respiratory symptoms in 48 (84.2%) of infants, a substantial proportion had lung disease with bacterial infection detected in 12 (21.1%), including Staphylococcus aureus (n = 4) and Pseudomonas aeruginosa (n = 3); neutrophilic inflammation (41. 4 x 10(3) cells/ml representing 18.7% of total cell count); proinflammatory cytokines, with 44 (77.2%) having detectable IL-8; and 17 (29.8%) having detectable free neutrophil elastase activity. Inflammation was increased in those with infection and respiratory symptoms; however, the majority of those infected were asymptomatic. Radiologic evidence of structural lung disease was common, with 46 (80.7%) having an abnormal CT; 11 (18.6%) had bronchial dilatation, 27 (45.0%) had bronchial wall thickening, and 40 (66.7%) had gas trapping. On multivariate analysis, free neutrophil elastase activity was associated with structural lung disease.Most children with structural lung disease had no clinically apparent lung disease.

The authors suggested that these data support the need for full evaluation in infancy and argue for new treatment strategies, especially those targeting neutrophilic inflammation, if the promise of new born screening for CF is to be realised.

— There is now increasing evidence that lung infection and damage occurs very early in CF infants. The frequency and severity will, of course, depend on the treatment the infant receives from diagnosis. For example the use of long term prophylactic anti-staphylococcal treatment (as recommended in the UK) and aggressive early eradication treatment of Pseudomonas would certainly improve the situation revealed in these Australian studies. Certainly the findings support the advice that all screened CF infants should be treated at a CF Centre.

Professor Peter Sly (fig. 39) is Deputy Director of Queensland Children’s Medical Research Institute  He is involved in a number of areas relating to environmental health including the WHO.  He is a paediatric respiratory physician with extensive research experience in respiratory physiology.  Peter Sly’s research aims to understand the mechanisms underlying chronic childhood lung diseases in order to improve clin9ical management and to delay or prevent their onset, with consequent reductions in adult lung diseases.

Song Y, Namkung W, Nielson DW, Lee JW, Finkbeiner WE,VerkmanASAirway surface liquid depth measured in ex vivo fragments of pig and human trachea: dependence on Na+ and Cl- channel function. Am J Physiol – Lung C 2009; 297:L1131-40.[PubMed]

Fig. 40 Yuanlin Song           Research Gate

The authors established methodology to measure airway surface liquid (ASL) depth to approximately 1-microm accuracy in ex vivo fragments of freshly obtained human and pig tracheas. ASL depth in well-differentiated primary cultures of human nasal respiratory epithelium was 8.0 +/- 0.5 microm (SE 10 cultures) under basal conditions, 8.4 +/- 0.4 microm following ENaC inhibition by amiloride, and 14.5 +/- 1.2 microm following CFTR stimulation by cAMP agonists. ASL depth in human trachea was 7.0 +/- 0.7 microm under basal conditions, 11.0 +/- 1.7 microm following amiloride, 17.0 +/- 3.4 microm following cAMP agonists, and 7.1 +/- 0.5 microm after CFTR inhibition. Similar results were found in pig trachea.
This study provides the first direct measurements of ASL depth in intact human airways and indicates the involvement of ENaC sodium channels and CFTR chloride channels in determining airway surface liquid depth

Dr Yuanlin Song (Fig. 40) is Professor  in the Department of Anaesthesia and Perioperative Care, Univ. of California, San Francisco,

Thauvin-Robinet C, Munck A, Huet F, Génin E, Bellis G, Gautier E et al. Collaborating Working Group on R117H. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. J Med Genet 2009; 46:752-758.  pubmed.ncbi.nlm.nih.gov/19880712/

Fig. 41 Christel Thauvin-Robinet Translad

Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas.The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice.The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%.The authors consider that these results suggest R117H should be withdrawn from CF mutation panels used for screening programmes. They suggest that the real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

Christel Thauvin-Robinet (fig. 41) is Professor at the Centre de Génétique, Hôpital d’Enfants, 10, bd Maréchal de Lattre de Tassigny, BP 77 908, 21079 Dijon cedex, France.

Treggiari MM, Rosenfeld M, Mayer-Hamblett N, Retsch-Bogart G, Gibson RL, Williams J, Emerson J, Kronmal RA, Ramsey BW. EPIC Study Group. Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study. Contemp Clin Trials 2009; 30:256-268. [PubMed]

Fig. 42 Miriam M Traggeri scholars.duke edu

The Early Pseudomonas Infection Control (EPIC) program consists of two studies, a randomized multicenter trial in CF patients ages 1-12 years at first isolation of Pa from a respiratory culture, and a longitudinal cohort study enrolling Pa-negative patients.Using a factorial design, trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduled quarterly basis (cycled therapy) or based on recovery of Pa from quarterly respiratory cultures (culture-based therapy). The study drugs include inhaled tobramycin (300 mg BID) for 28 days, combined with either oral ciprofloxacin (15-20 mg/kg BID) or oral placebo for 14 days. The primary endpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics or hospitalization for respiratory symptoms, and the proportion of patients with new Pa-positive respiratory cultures during the study.

— This major N. American study into the early eradication of Pseudomonas is welcome. The dose of tobramycin would seem to be unnecessarily large for small children as judged by experience from successful European trials some years ago where 80mg doses of tobramycin were used.

Dr. Miriam M Treggiari (fig 42) is Vice Chair for Research and Professor of Aneasthesia  in the Department of Anaesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA.

Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Nat Acad Sci 2009; 1006:18825-18830. [PubMed]

Fig. 43 Frederick Van Goor

A description of the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (P(o)) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl(-) secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by approximately 10-fold, to approximately 50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na(+) and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures

These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway and subsequently were shown to improve CFTR function in people with G551D mutation

Frederick Van Goor (fig.43)  [From LinkedIn 2023]    Fredrick Van Goor, Ph.D., is the Vice President and Head of Cystic Fibrosis (CF) Research for Vertex Pharmaceuticals CF drug discovery program and he provides scientific leadership for the company’s research, clinical, regulatory and commercial teams. Dr. Van Goor led the biology effort for the team that discovered and developed Kalydeco, Orkambi, Symdeko, and Trikafta – Vertex’s four approved medicines that treat the underlying cause of disease in up to 90% of people with CF. In addition, Dr. Van Goor is leading Vertex’s research efforts to discover nucleic acid therapies that could potentially cure CF. Prior to joining Vertex in 2001, Dr. Van Goor was a Postdoctoral Fellow at the National Institutes of Health. Dr. Van Goor has over 20 US patents in the areas of CF and technology development and has published six book chapters in the areas of CF, ion channel drug discovery and endocrinology and authored more than 50 research articles in peer-reviewed journals including the New England Journal of Medicine, Nature Medicine, Proceedings of the National Academy of Science, Journal of Neuroscience, Journal of Biological Chemistry and Molecular Pharmacology. Dr. Van Goor received his Ph.D. in Biological Sciences from the University of Alberta, Canada.

van Ingen J, de Zwaan R, Dekhuijzen RP, Boeree MJ, van Soolingen D. Clinical relevance of Mycobacterium chelonae-abscessus group isolation in 95 patients. J Infect 2009; 59:324-331. [PubMed]

Fig. 44  Jakko van Ingen Radboudumc.nl

To determine the clinical relevance of Mycobacterium chelonae-abscessus group isolation from clinical samples the authors retrospectively reviewed medical files of all patients from whom these mycobacteria were isolated between January 1999 and January 2005. They applied the American Thoracic Society (ATS) diagnostic criteria to establish clinical relevance.Ninety-five patients were traced (56 M. chelonae, 25 Mycobacterium abscessus, 8 Mycobacterium massiliense, 6 Mycobacterium bolletii). Most isolates were cultured from pulmonary samples in patients with pre-existing pulmonary disease. Among patients with pulmonary isolates, 27% (20/74) meets ATS criteria; M. abscessus is most relevant (50%; 9/18), followed by M. massiliense (29%; 2/7), M. bolletii (20%; 1/5) and M. chelonae (18%; 8/44). Extrapulmonary disease presented as disseminated skin disease, eye disease specific for M. chelonae and otomastoiditis for M. abscessus. Treatment, especially for pulmonary M. abscessus disease, yielded limited results. One-fourth of the patients with pulmonary M. chelonae-abscessus group isolates met the ATS criteria; this percentage differs by species. Species distribution and clinical relevance differ from other regions. M. abscessus isolation in cystic fibrosis patients warrants special attention. Current ATS criteria might be too lenient to diagnose M. chelonae-abscessus group disease.

— There is an increasing interest in NTM in CF. This survey gives an idea of the general prevalence of the various NTMs.

Dr Jakko van Ingen (fig. 44) Mycobacteriology research Group is at is at the  Department of Pulmonary Diseases, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Varness T, Seffrood EE, Connor EL, Rock MJ, Allen DB. Oxandrolone Improves Height Velocity and BMI in Patients with Cystic Fibrosis. Internat J Pediatr Endocrin 2009:826895. [PubMed]

Fig. 45 Todd S Varness

A retrospective study to evaluate the effectiveness of oxandrolone in improving the nutritional status and linear growth of pediatric patients with cystic fibrosis (CF). Both height z score (pre-Ox = -1.64 +/- 0.63, Ox = -1.30 +/- 0.49, P = .057) and weight velocity (pre-Ox = 4.2 +/- 3.7 kg/yr, Ox = 6.8 +/- 1.0 kg/yr, P = .072) showed beneficial trends that did not reach statistical significance. No adverse events were reported.
The authors concluded oxandrolone improved the HV and BMI z score in patients with CF but larger studies were needed to determine if oxandrolone is an effective, safe, and affordable option to stimulate appetite, improve weight gain, and promote linear growth in patients with CF.

— There were a number of papers on the use of anabolic steroids before more effective pancreatic enzymes became available in the early Eighties (see Topic section – Anabolic Steroids). Although the treatment was effective, the side effects were a problem. Apparently there are fewer androgenic side effects with the newer preparation described in this paper.

Dr Todd Varness  (fig. 45) (1974-2010) was at the  Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, H4/4 Clinical Science Center, 600 Highland Avenue, Madison.   Todd died of cancer  in 2010; there is a very moving tribute on the internet.

Wainwright CE, France MW, O’Rourke P, Anuj S, Kidd TJ, Nissen MD, Sloots TP, Coulter C, Ristovski Z, Hargreaves M, Rose BR, Harbour C, Bell SC, Fennelly KP. Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis. Thorax 2009; 64:926-931. [PubMed]

Fig. 46 Claire Wainwright    Childen’s Health Queensland

Pseudomonas aeruginosa was isolated in cough aerosols of 25 subjects (89%), 22 of whom produced sputum samples. P aeruginosa from sputum and paired cough aerosols were indistinguishable by molecular typing. In four cases the same genotype was isolated from ambient room air. Approximately 70% of viable aerosols collected during voluntary coughing were of particles <or=3.3 micron aerodynamic diameter. P aeruginosa, Burkholderia cenocepacia, Stenotrophomonas maltophilia and Achromobacter xylosoxidans were cultivated from respiratory particles in this size range. Positive room air samples were associated with high total counts in cough aerosols (p = 0.003). The magnitude of cough aerosols was associated with higher forced expiratory volume in 1 s (r = 0.45, p = 0.02) and higher quantitative sputum culture results (r = 0.58, p = 0.008).

The authors concluded that during coughing, patients with CF produce viable aerosols of P aeruginosa and other Gram-negative bacteria of respirable size range, suggesting the potential for airborne transmission. This study provides further evidence of the potential for airbourne transmission of pathogens between people with CF indications that segregation rather than mere hygienic measures are required to prevent spread of infection.

Claire Wainwright (fig. 46) is Professor in the Department of Respiratory Medicine, Royal Children’s Hospital and Health Service District, Brisbane, Australia.

Zhang L, Button B, Gabriel SE, Burkett S, Yan Y, Skiadopoulos MH, Dang YL, Vogel LN, McKay T, Mengos A, Boucher RC, Collins PL, Pickles RJ. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. Plos Biology 2009; 7(7):e1000155. pubmed.ncbi.nlm.nih.gov/19621064/

Fig. 47 Liqun Zhang LinkedIn

Critical questions for the development of gene transfer strategies for CF airway disease are what airway regions require CFTR function and how many epithelial cells require CFTR expression to restore normal ASL volume regulation and mucus transport to CF airway epithelium?The data reported here (reported more fully in the abstract) demonstrate that restoration of normal mucus transport rates in CF was achieved after CFTR delivery to 25% of surface epithelial cells. In vivo experimentation in appropriate models will be required to determine what level of mucus transport will afford clinical benefit to CF patients, but they predict that a future goal for corrective gene transfer to the CF human airways in vivo would attempt to target at least 25% of surface epithelial cells to achieve mucus transport rates comparable to those in non-CF airways.

There has been considerable discussion as to the amount of CFTR activity necessary to signifcantly improve the airways of people with CF. Certainly 50% of normal apears to be adequate as is present in CF carriers. An estimate of 10% has been suggested as providing a significant effect if this could be achieved by gene therapy or other means.

Dr Liqun Zhang (fig. 47) is at the CF/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.