Accurso FJ, Rowe SM, Durie PR, Konstan MW, Dunitz J, Hornick DB, Sagel SD, Boyle MP, Uluer AZ, Upadhyay D, Ramsey BW, Freedman SD, Dong Q, Ahmed AM, Stone AJ, Olson ER, Ordenez CL, Clancy JP, Campbell PW, Ashlock MA. Interim results of Phase IIa study of VX-770 to evaluate safety, pharmokinetics and biomarkers of CFTR activity in cystic fibrosis subjects with G551D. Pediatr Pulmonol 2008; Suppl 31: 267 page 295. (Poster) 

Fig 1. Frank Accurso

Results from an interim analysis in 20 patients with the G551D mutation who received 14 days of oral VX-770, a potentiator of CFTR, 25mg, 75mg or 150mg 12 hourly or placebo. Those on highest dose of VX-770 (150mg twice daily) had an impressive response. They had increases in FEV1 of 10.1%, their sweat chloride fell from a mean of 95.5 to 53.2 mmol/l, nasal potential difference showed significant changes towards normal.(-5.4mv in treated CF with -1.7mv in controls).

An early but very encouraging result arising from the CF Foundation’s search for chemical activators of mutant CFTR. The change in sweat electrolytes is particularly impressive and this is the first drug to affect the level of sweat electrolytes in people with CF.

A Phase II trial with 16 patients for 28 days started in 2008 and impressive progress was reported in 2009 (Boyle et al. Pediatr Pulmonol 2009; Suppl 32:287. Poster 217). A further Phase III trial was reported in Novemeber 2011 which resulted in the VX-770 (ivacaftor now called Kalydeco) being approved by the FDA (Ramsay BW et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365:1663-1672. below).[PubMed]

Dr Frank Accurso (fig. 1)  is Professor of Pediatrics and Head of Pulmonary Medicine at the University of Colorado. Following the selection of the University of Colorado as one of the Cystic Fibrosis Foundation’s Therapeutics Development Centers, Dr Accurso has been increasingly active in the development and study of new therapies and techniques for outcomes research.

Aurora P, Carby M, Sweet S. Selection of cystic fibrosis patients for lung transplantation. Curr Opin Pulm Med 2008; 14:589-594. Review. [PubMed]

Fig. 2 Paul Aurora              author’s photo

A review of the current recommendations for timing of lung transplantation in individuals with end-stage cystic fibrosis lung disease and on the rationale behind listing decisions. Guidelines for the referral and selection of patients suitable for lung transplantation were recently updated by the pulmonary council of the International Society for Heart and Lung Transplantation. However, an analysis published in 2007 has questioned whether lung transplantation extends life in children with cystic fibrosis. There are some concerns regarding this analysis, and these are discussed in detail. Most importantly, the analysis is specific to the United States and predates the introduction of the lung allocation score, which has had a marked impact on how transplant organs are allocated in this country.

It is likely that lung transplantation can extend life in both adults and children with cystic fibrosis, provided the procedure is correctly timed. Further development of the lung allocation score has the potential to increase the survival benefit from the procedure in the United States.

Paul Aurora, (Fig.2) consultant respiratory paediatrician at Great Ormond Street Hospital London, defended the benefit derived by children from lung transplantation in a number of publications and supports the view that both children and adults benefit from the procedure – it having been suggested from the USA that children failed to benefit. He has had extensive experience in supervising the UK paediatric transplant service at Great Ormond Street Hospital, London.

Baral VR, Dewar AL, Connett GJ. Colloidal silver for lung disease in cystic fibrosis. J R Soc Med 2008; 101 Suppl 1:S51-52. [PubMed] (go to PubMed and then free text link to J RSM for full details)

Fig. 3 Vijayendra Baral. SingHealth

Cystic Fibrosis families commonly consider alternative or complimentary therapies of questionable value. A report of a 12-year-old boy with severe CF lung complications who was treated by his family with colloidal silver. This severely ill boy had a remarkable sustained improvement in his condition following the start of the colloidal silver treatment. Over the next three months the patient achieved a sustained improvement in symptoms, which persisted following weaning from oral steroids, nebulized antibiotics and regular asthma medications.

— Another reference to colloidal silver in CF concerned an 11 year old boy who reported bluish skin discolouration associated with a raised serum silver level after he began taking colloidal silver to facilitate mucus clearance. The skin colour and serum silver level both normalised when the treatment was stopped (Baker et al. Curr Opin Pediatr 2007; 19:733-735.[PubMed]). These are the only two references to colloidal silver as a treatment for CF up to present (2024)

Dr Vijayendra Ranjan Baral (fig. 3)  is at the Regional Cystic Fibrosis Service, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD.

Barker HC, Haworth CS, Williams D, Roberts P, Bilton D. Clostridium difficile pan colitis in adults with cystic fibrosis. J Cyst Fibros 2008; 7:444-447. [PubMed]

Fig. 4. Helen C Barker royalpapworth.nhs.uk

Three cases of Clostridium difficile pancolitis in adults with cystic fibrosis (CF) in whom the presenting symptoms were atypical. All three required treatment with systemic steroids, in addition to oral vancomycin and metronidazole to achieve resolution of the colitis. This experience suggests that C. difficile colitis should be considered in individuals with CF presenting with non-specific abdominal symptoms.

— There have been sporadic reports of C. difficile infection in people with CF. Some have been in patients who have had lung transplants. Also, asymptomatic carriage seems to be relatively common in CF. In a minority the infection leads to serious clinical illness, as in the cases reported here.

Dr Helen C Barker (fig.4)  is a consultant in Respiratory and General Internal Medicine at the Adult Cystic Fibrosis Centre, Papworth Hospital, Cambridge, CB23 3RE, UK.

Brimicombe RW, Dijkshoorn L, van der Reijden TJ, Kardoes I, Pitt TL, van den Broek PJ, Heijerman HG. Transmission of Pseudomonas aeruginosa in children with cystic fibrosis attending summer camps in The Netherlands. J Cyst Fibros 2008; 7:30-36.[PubMed]
This study aimed to establish the degree of transmission resulting in subsequent infection of P. aeruginosa among 80 children with CF attending holiday camps in The Netherlands. The study was performed in the summer of 2001 in four camps organised simultaneously at different locations. Sputum was collected on day 1 of the holiday, and three and six months later. Different morphotypes of P. aeruginosa from sputum were genotyped by AFLP analysis. Criteria were defined for the degree of evidence of transmission.
There were 18 cases of “possible”, 2 cases of “probable” transmission and 1 case of “highly probable” transmission. Two predominant types of P. aeruginosa were found (types 18 and 23). Type 18 was already prevalent on day 1 mostly in younger children and was involved in eleven cases of transmission; type 23 was involved in six cases of transmission among older children.
There was a considerable risk of transmission of P. aeruginosa during these holiday camps for children with CF in The Netherlands. Two genotypes of P. aeruginosa appeared to be easily transmissible, one of which seemed common in the Dutch CF population.

Previous work from the Netherlands had shown little evidence of cross infection at camps and at the time the professionals involved considered the benefits of the holidays outweighed the risks of infection. For example in 1995 Hoogkamp-Korstanje et al (J Clin Microbiol 1995; 33:572-575.[PubMed]) considered the risk was comparable with that observed in the community e.g. “We conclude that the risk of cross infection is trivial compared with the obvious joy and social benefit derived from a holiday camp”. It is interesting how many years elapsed before these findings were published – holiday in 2001 and publication in 2008. A similar long interval occurred in the paper from Copenhagen (Ojeniyi et al, 2000. [PubMed] when the study in 1990 was reported in 2000.[PubMed]

R W Brimicombe is at the Department of Medical Microbiology, HagaZiekenhuis, 2545 CH The Hague, The Netherlands.

Bryon M, Shearer J, Davies, H. Eating disorders and disturbance in children and adolescents with cystic fibrosis. Children’s Health Care 2008; 37:67-78.
Also – Shearer JE. Bryon M. The nature and prevalence of eating disorders and eating disturbance in adolescents with cystic fibrosis. J R Soc Med 2004; 97 Suppl 44:36-42[PubMed]

Fig 5. Mandy Bryon

Dr Mandy Bryon (fig. 5) is Consultant Clinical Psychologist and Joint Head of Paediatric Psychology at Great Ormond Street Hospital in London. She is a leading authority on psychological issues in children with CF and a member of the CF team at the hospital.

Buckley SM, Waddington SN, Jezzard S, Bergau A, Themis M, MacVinish LJ, Cuthbert AW, Colledge WH, Coutelle C. Intra-amniotic delivery of CFTR-expressing adenovirus does not reverse cystic fibrosis phenotype in inbred CFTR-knockout mice. Mol Ther: J Am Soc Gene Ther 2008; 16:819-824. [PubMed]
Due to its early onset and severe prognosis, CF has been suggested as a candidate disease for in utero gene therapy (Cohen JC, Larson JE. Dev Dynam 2006; 235:2736-2748 [PubMed]).
In 1997, a study was published claiming that transient prenatal expression of CF transmembrane conductance regulator (CFTR) from an in utero-injected adenovirus vector could achieve permanent reversal of the CF intestinal pathology in adult CF knockout mice, despite the loss of CFTR transgene expression (Larson JE et al. Lancet 1997; 349:619-620). [PubMed] This would imply that the underlying cause of CF is a prenatal defect for which lifelong cure can be achieved by transient prenatal expression of CFTR.
Despite criticism at the time of Larson’s 1997 publication, no independent verification of this contentious finding has been achieved or published so far. This is obviously vital for the development of future therapeutic strategies as it may determine whether CF gene therapy should be performed prenatally or postnatally

Buckley et al therefore reinvestigated this finding with an identical adenoviral vector and a knockout CF mouse line (Cftr (tmlCam)) with a completely inbred genetic background to eliminate any effects due to genetic variation. After delivery of the CFTR-expressing adenovirus to the fetal mouse, both vector DNA and transgenic CFTR expression were detected in treated animals postpartum but statistically no significant difference in survival was observed between the Cftr(-/-) mice treated with the CFTR-adenovirus and those treated with the control vector

Suzanne M Buckley is in Department of Haematology, Haemophilia Centre and Thrombosis Unit, Royal Free & University College Medical School, London, UK

—  So this is an important study from a leading group of UK researchers that refutes the frequent claim of Larson and colleagues that, to be effective, gene therapy must be delivered in utero. The members of the UK Gene Therapy Consortium have always questioned Larson’s findings and in this study these authors have been unable to repeat them. Finally, it is very unlikely that most researchers, clinicians and regulatory authorities would approve the use of intrauterine gene therapy even if it were shown to be effective.

A further similar study failed to show improved survival in CFTR knockout mice after in utero adenovirus mediated expression of CFTR (Davies LA et al. Mol Ther 2008; 16)812-818. [PubMed]). Also the subject of fetal gene therapy was reviewed by David AL & Peebles D.( Best Pract Res Clin Obstet Gynaecol 2008; 22:203-218. [PubMed]) who state that “recent developments in the understanding of genetic disease, vector design, and minimally invasive delivery techniques have brought fetal gene therapy closer to clinical practice. However more research needs to be done in before it can be introduced as a therapy”.
There is obviously continuing interest in this area by the Prenatal and Gene Therapy Group, EGA Institute for Women’s Health, University College, London. (Mehta V et al. Methods Mol Biol 2012; 891:291-328.[PubMed]).

Castellani C, Cuppens H, Macek M Jr, Cassiman JJ, Kerem E, Durie P, Tullis E, Assael BM, Bombieri C, Brown A, Casals T, Claustres M, Cutting GR, Dequeker E, Dodge J, Doull I, Farrell P, Ferec C, Girodon E, Johannesson M, Kerem B, Knowles M, Munck A, Pignatti PF, Radojkovic D, Rizzotti P, Schwarz M, Stuhrmann M, Tzetis M, Zielenski J, Elborn JS. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros 2008; 7:179-196. [PubMed]

Fig 6  Carlo Castellani

It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. This is a major review by an international group of experts of the best way to use mutation analysis in cystic fibrosis.

Fig 8. Harry Cuppens

   Fig 7. Milan Macek

Professor Milan Macek Jr. (fig.7) is the chairman of the largest academic medical genetics institution in the Czech Republic (http://ublg.lf2.cuni.cz/). He is also the President of the Czech Society of Medical Genetics (www.slg.cz), Board member of the European Society for Cystic Fibrosis (www.ecfs.eu) and the current President of the European Society of Human Genetics (www.eshg.org). His major specialty comprises DNA diagnostics in pediatric genetics with a particular focus on cystic fibrosis which serves as a paradigm for rare diseases. His institute is a “clearing centre” for dissemination of knowledge gathered within various international projects, such as CF Thematic Network, EuroGentest, to all interested fellows from Central and Eastern Europe and his laboratory was awarded the FP5 EU Marie Curie Training Site.

Professor Harry Cuppens (fig. 8) is a molecular geneticist at the Center for Human Genetics in Leuven, Belgium and a professor at the University of Leuven.He has been involved in DNA diagnostics and research of inherited diseases. His expertise involves the genetics of cystic fibrosis, CFTR-related diseases in general, as well as adult complex diseases such as COPD and Crohn’s disease. In the beginning of the nineties, he developed a diagnostic test for the simultaneous identification of the most common CFTR mutations causing cystic fibrosis, which was subsequently commercialized by Innogenetics NV (Belgium). In 2004, this CFTR test had a market share of 33% in Europe and annual sales of 60 million €. Since one year he is developing a CFTR sequencing assay based on WGS GS-FLX sequencing, and the obtained experience is of interest and relevance in this project.

Desax MC, Ammann RA, Hammer J, Schoeni MH, Barben J. Swiss Paediatric Respiratory Research Group. Nanoduct sweat testing for rapid diagnosis in newborns, infants and children with cystic fibrosis. Eur J Pediatr 2008; 167:299-304. [PubMed]

Fig. 9 Marie-Clairee Desax ResearchGate 

Determination of chloride concentration in sweat is the current diagnostic gold standard for CF. Nanoduct is a new analyzing system measuring conductivity which requires only 3 microliters of sweat and gives results within 30 minutes. The authors concluded that the Nanoduct test is a reliable diagnostic tool for CF diagnosis: It has a failure rate comparable to other sweat tests and can be used as a simple bedside test for fast and reliable exclusion, diagnosis or suspicion of CF. In cases with borderline conductivity (60-80 mmol/L) other additional methods (determination of chloride and genotyping) are indicated.

– In the past rapid methods of sweat testing, such as the chloride electrode have proved unreliable. However, this method does seem to be a more reliable method – always remembering the potential for disastrous diagnostic mistakes which can occur as a result of unreliable sweat tests

Marie-Claire Desax (fig. 9) is in the Department of Pediatrics, University of Berne, Berne, Switzerland.

Dechecchi MC, Nicolis E, Norez C, Bezzerri V, Borgatti M, Mancini I, Rizzotti P, Ribeiro CM, Gambari R, Becq F, Cabrini G. Anti-inflammatory effect of miglustat in bronchial epithelial cells. J Cyst Fibros 2008; 7:555-565.[PubMed]

Fig. 10 Maria Cristina Decheechi Loop (Fontiers)

The role of CFTR deficiency in promoting inflammation remains unclear. Perez et al. recently demonstrated that the inhibition of function of w/t CFTR produces an inflammatory profile that resembles that observed in CF patients (Perez A et al. CFTR inhibition mimics the cystic fibrosis inflammatory profile. Am J Physiol Lung Cell Mol Physiol 2007; 292:L383-L395.[PubMed]), whereas the authors found that correction of F508del-CFTR function with MPB-07 down-modulates the inflammatory response to P. aeruginosa in CF bronchial cells (Dechecchi MC et al. MPB-07 reduces the inflammatory response to Pseudomonas aeruginosa in cystic fibrosis bronchial cells. Am J Respir Cell Mol Biol 2007; 36, 615-624.[PubMed]).

Since both studies support a link between CFTR function and inflammation, the authors extended this investigation to other F508del-CFTR correctors, such as miglustat (Norez C. 2006.[PubMed]16546175 ), an approved drug for Gaucher disease, in comparison with the galactose analogue NB-DGJ. Here they report that miglustat but not NB-DGJ restores F508del-CFTR function in CF bronchial epithelial IB3-1 and CuFi-1 cells. Miglustat and NB-DGJ reduce the inflammatory response to P. aeruginosa in both CF and non-CF bronchial cells, indicating that the anti-inflammatory effect is independent of the correction of F508del-CFTR function. Miglustat also inhibits the inflammatory response induced by the supernatant of mucopurulent material obtained from the lower airway tract of cystic fibrosis patients with chronic bacterial colonization (Ribeiro CM et al. 2005.[PubMed]). Both compounds do not interfere with the adherence of P. aeruginosa to the cells and reduce the expression of IL-8 not only after challenge with P. aeruginosa but also after exposure to TNF alpha or IL-1 beta, suggesting an effect on transduction proteins downstream and in common with different receptors for pathogens. Finally, miglustat has no major effects on overall binding activity of transcription factors NF-kappaBNF-kB and AP-1. Since miglustat is an approved drug, it could be investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF patients.

Increasing interest in miglustat since the first report of its effect on CF cells by Norez et al, 2006 [PubMed] of particular interest as a “low hanging fruit” drug that is already licensed for the treatment of Gaucher’s disease. This is a helpful review.

Dr Maria Cristina Decheechi (fig.10)  is at the Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Haematology, University Hospital of Verona, Verona, Italy.

Douros K, Loukou I, Doudounakis S, Tzetis M, Priftis KN, Kanavakis E. Asthma and pulmonary function abnormalities in heterozygotes for cystic fibrosis transmembrane regulator gene mutations. Int j clin exp med 2008; 1:345-349. [PubMed]
The aim of this study is to evaluate the association between CFTR gene mutations with asthma and pulmonary function abnormalities. For this purpose, 214 mutation carriers were compared to 185 non-carriers. Although the relative risk of asthma did not differ between groups (OR=0.61, 95% CI: 0.23-1.61, p=0.32), the values of FEV1, and FEV1/FVC ratio were lower in carriers (p=0.001, and p<0.001, respectively). This may imply that heterozygosity may be related with a silent obstructive pulmonary profile.

Dr Konstantinos Douros is Associate Professor of Paediatrics,  National and Kapodistrian University of Athens

Edenborough FP, Borgo G, Knoop C, Lannefors L, Mackenzie WE, Madge S, Morton AM, Oxley HC, Touw DJ, Benham M, Johannesson M. Guidelines for the management of pregnancy in women with cystic fibrosis. J Cyst Fibros 2008: S2-S32. [PubMed]

Fig 11 Frank Edenborough Respiratory Medicine

Optimal treatment of all aspects of CF needs to be maintained from the pre conceptual period until after the baby is born. Clinicians must be prepared to modify their treatment to accommodate the changing physiology during pregnancy and to be aware of changing prescribing before conception, during pregnancy, after birth and during breast feeding.

This supplement offers detailed consensus guidelines based on review of the literature and experience of paediatricians, adult and transplant physicians, and nurses, physiotherapists, dietitians, pharmacists and psychologists experienced in CF and anaesthetists and obstetricians with experience of CF pregnancy.

Dr Frank Edenborough (fig 11) is consultant at the Adult CF Centre, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK.

Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008; 153:S4-S14.[PubMed]

Fig 12 Philip Farrell pediatrics.wisc.edu

The diagnosis of infants detected by neonatal CF screening is not always straightforward and this report gives advice to employ a combination of clinical presentation, laboratory testing and genetics to confirm a diagnosis of CF.
A European CF Society consensus report also dealt with problem of equivocal diagnosis after neonatal CF screening and dealt with sweat testing, further assessment and investigations, review arrangements and the database (Mayell SJ et al. J Cyst Fibros 2009; 8:71-78. [PubMed] ).

Prof. Philip Farrell (fig. 12) a neonatologist and pediatric pulmonologist in the University of Wisconsin since. In addition to patient care and student teaching responsibilities, he has been engaged in productive research on respiratory disorders in infants and children— most recently focusing on cystic fibrosis (CF).

Ghayyda SN, Roland D, Cade A. Seat belt associated central line fracture–a previously unreported complication in cystic fibrosis. J Cyst Fibros 2008; 7:448-449.[PubMed]
It is not routine practice to advise on seating position within the car in relationship to the seatbelt placement over the anterior chest wall. Line failure due to direct pressure from a seatbelt worn to prevent injury in the sudden deceleration involved during a motor vehicle accident (MVA) has not been described previously in the CF literature They report the case of an 8 year old child who fractured her Vascuport(R) line secondary to seatbelt trauma following a road traffic accident (RTA). Children and adults with CF should be advised to sit in the car on the side that places the shoulder strap of the seatbelt on the opposite side to the TIVAD line. This is a useful practical report which will help to prevent a complication not previously reported.

Salim N S Ghayyda is in the Department  of Paediatrics, Derriford Hospital, Plymouth, Devon UK.

Grassmé H. Becker KA. Zhang Y. Gulbins E. Ceramide in bacterial infections and cystic fibrosis. Biol Chem 2008; 389:1371-1379. [PubMed]. 

Fig 13. Hieke Grassmé

Ceramide is formed by the activity of sphingomyelinases, by degradation of complex sphingolipids, reverse ceramidase activity or de novo synthesized. The formation of ceramide within biological membranes results in the formation of large ceramide-enriched membrane domains. These domains serve the spatial and temporal organization of receptors and signaling molecules. The acid sphingomyelinase-ceramide system plays an important role in the infection of mammalian host cells with bacterial pathogens such as Neisseria gonorrhea, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, Salmonella typhimurium and Pseudomonas aeruginosa. Ceramide and ceramide-enriched membrane platforms are also involved in the induction of apoptosis in infected cells, such as in epithelial and endothelial cells after infection with Pseudomonas aeruginosa and Staphylococcus aureus, respectively. Finally, ceramide-enriched membrane platforms are critical regulators of the release of pro-inflammatory cytokines upon infection. The diverse functions of ceramide in bacterial infections suggest that ceramide and ceramide-enriched membrane domains are key players in host responses to many pathogens and thus are potential novel targets to treat infections.

There is increasing interest in ceramide in the airways in CF. More recently there has been a useful full text review which is available as a free download (Wojewodka G et al. Ceramide in Cystic Fibrosis: A potential new target for therapeutic intervention. J Lipids 2011; 2011:674968.[PubMed]).

Heike Grassmé (fig 13) is in the Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany.

Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008; 63:129-134. pubmed.ncbi.nlm.nih.gov/17675316/
The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal lung function more readily than spirometry in children and teenagers with CF, but its relationship to structural lung abnormalities is unknown. The authors concluded that LCI is a more sensitive indicator than FEV1 or FEF75 for detecting structural lung disease in CF, and a normal LCI almost excludes HRCT abnormalities. The finding of an abnormal LCI in some patients with normal HRCT scans suggests that LCI may be even more sensitive than HRCT scanning for detecting lung involvement in CF. The lung clearance index is gaining increasing support as a measure of early non-invasive lung function also useful in young children.

P M Gustasson is at the Queens Silvia Children’s Hospital and Department of Pediatrics, The Sahlgrenska Academy at Göteborg, Sweden.

Hayes D Jr, Kanga JF, Anstead MI, Kuhn RJ. Novel approach to the eradication of Pseudomonas aeruginosa in an infant with CF after outpatient treatment failure. Pediatr Pulmonol 2008; 43:511-513[PubMed]

Fig 14 Don Hayes Jr
Cincinnati Children’s

Intravenous continuous infusion of betalactam (CIBL) antibiotic and high dose extended interval (HDEI) aminoglycoside therapy theoretically maximize bacterial killing in treatment of Pseudomonas aeruginosain pulmonary exacerbations of cystic fibrosis (CF). A 3-month-old female infant with CF failed outpatient eradication of Pseudomonas with subsequent eradication using intravenous CIBL antibiotic and HDEI aminoglycoside therapy.

This antibiotic combination should be considered in order to optimize pharmacodynamics for Pseudomonas eradication in CF patients before development of chronic colonization An important case report from Kentucky of an aggressive and successful eradication of P. aeruginosa not accepting failure. The use of continuous IV beta lactam (eventually aztreonam here) and intermittent high dose IV tobramycin would be worth further investigation.

The fact that failed eradication is receiving attention from a centre in the USA is encouraging and indicates a new approach.    It is important to leave no stone unturned when attempting to eradicate P. aeruginosa; this often involves giving intravenous antibiotics to small children with CF who do not appear unwell. In these circumstances it would seem sensible to use the antibiotics in the optimal way as in this report.

Don Hayes Jr (fig 14) is in the Departments of Pediatrics and Internal Medicine, University of Kentucky College of Medicine, J410 Kentucky Clinic, 740 South Limestone Street, Lexington, Kentucky 40536, USA.

Hansen CR, Pressler T, Høiby N. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience. J Cyst Fibros 2008; 7:523-530. [PubMed]

 Fig 15. Christine Hansen Author’s photo

Since 1989, CF-patients intermittently colonized with Pseudomonas aeruginosa have been treated with inhaled colistin and oral ciprofloxacin in the Copenhagen CF-centre. The study evaluates 15 years results of this treatment. All isolates of P. aeruginosa from CF-patients intermittently colonized with P. aeruginosa from 1989 to 2003 were identified. All anti-P. aeruginosa treatments were evaluated for antibiotics used, treatment duration, pseudomonas-free interval and development of chronic infection. All P. aeruginosa isolates were assessed for resistance and for non-mucoid or mucoid phenotype.

146 CF-patients were included in the study (1106 patient-years). 99 patients had first ever isolate during the study period. Median observation time 7 years (0.1-14.9). 12 patients developed chronic infection. A Kaplan Meyer plot showed protection from chronic infection in up to 80% of patients for up to 15 years. 613 colistin/ciprofloxacin treatments were given. There was no difference in pseudomonas-free interval comparing 3 weeks (5 months) and 3 months (10.4 months) of colistin and ciprofloxacin, but a significant difference compared to no treatment (1.9 months). Patients developing chronic infection had significantly shorter pseudomonas-free interval after treatment of first ever isolate compared to patients remaining intermittently colonized (p<0.003). Treatment failure (P. aeruginosa-positive culture immediately after ended treatment of first ever isolate) was a strong risk factor for development of chronic infection after 3-4 years, OR 5.8. 1093 pseudomonas-isolates were evaluated (86.6% non-mucoid). No colistin-resistance was found. Ciprofloxacin-resistance was found in 4% of isolates.

The authors concluded that treatment of intermittent P. aeruginosa colonization in CF-patients using colistin and ciprofloxacin can protect up to 80% of patients from development of chronic infection for up to 15 years. A positive culture immediately after treatment of first ever isolate is a strong risk factor for development of chronic infection. They found no colistin-resistance and minimal ciprofloxacin-resistance.

This valuable experience from the team in Copenhagen is reported in full as it represents experience from one of the first European CF centres to introduce early eradication therapy for P. aeruginosa in the late Eighties. The effect of this treatment has protected many patients from chronic P. aeruginosa infection for many years. There was some resistance (as reported in Johansen et al 2008 [PubMed]), but this was not a major problem.

Dr Christine Hansen (fig. 15) is one of the senior clinicians at the Danish CF Centre in Copenhagen.

Hirsh AJ, Zhang J, Zamurs A, Fleegle J, Thelin WR, Caldwell RA, Sabater JR, Abraham WM, Donowitz M, Cha B, Johnson KB, St George JA, Johnson MR, Boucher RC. Pharmacological properties of N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N’-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate (552-02), a novel epithelial sodium channel blocker with potential clinical efficacy for cystic fibrosis lung disease. J Pharmacol Exp Ther 2008; 325:77-88. [PubMed]

Fig.16 Andrew Hirsch

A more potent and durable ENaC blocker than amiloride, tailored for aerosol delivery, was synthesized (Parion compound N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N’-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate (552-02)). Compared with amiloride, compound 552-02 was 60 to 100-fold more potent, 2 to 5-fold less reversible, slower at crossing the epithelium, and exhibited a 170-fold slower k(off) value. 552-02 exhibited greater airway surface liquid expansion over 8 hrs in vitro and it was more effective than amiloride at increasing mucociliary clearance immediately and 4 to 6 hrs after dosing. When combining hypertonic saline and 552-02, there was synergy. So the preclinical data support the clinical use of 552-02 +/- hypertonic saline for CF lung disease.

The development this compound continued as Gilead GS9411, Parion 522 having provided proof of principle with this study. Further development of Gilead GS9411 progress is funded by the CF Foundation where it is stated that a Phase I trial has been completed.

Andrew J Hirsch (fig. 16) at this time was with Parion Sciences Inc., 2525 Meridian Pkwy., Suite 260, Durham, NC 27713, USA.

In 2014 the following paper resulted in the withdrawal of GS-9411.

Thomas G O’RiordanKarl H DonnPeter HodsmanJohn H AnsedeTerry NewcombSandra A LewisWilliam D FlitterVicki Shigekane WhiteM Ross JohnsonA Bruce MontgomeryDavid G Warnock.Richard C Boucher.   Acute hyperkalemia associated with inhalation of a potent ENaC antagonist: Phase 1 trial of GS-9411. Aerosol med Pulm Drug Deliv 2014 Jun;27(3):200-8.doi: 10.1089/jamp.2013.1037. Epub 2013 Aug 1.

“Inhaled GS-9411 was well tolerated except for the emergence of transient clinically significant hyperkalemia; this finding resulted in termination of further clinical development of this drug..”    Support for the development was withdrawn by the CF Foundation in 2014.

Infante Pina D, Redecillas Ferreiro S, Torrent Vernetta A, Segarra Cantón O, Maldonado Smith M, Gartner Tizziano L, Hidalgo Albert E. Improvement of intestinal function in cystic fibrosis patients using probiotics. [Spanish] Anales de Pediatria 2008; 69:501-505.  PMID 19128761

Fig. 17 Damaso Infante Pina Hospital Universitari tenerla de Catalunya

In some cases, cystic fibrosis may include intestinal inflammation and bacterial overgrowth. Probiotics are considered as immunomodulatory, anti-inflammatory and microbiotic regulator substances. The aim of this study is to determine the prevalence of bacterial overgrowth in cystic fibrosis patients and try to improve the intestinal function with the administration of probiotics. They examined 20 patients with cystic fibrosis (mean age 10.33, range 5 to 17 years). The expired hydrogen test with a 2 g/kg of 20% dextrose overload was performed on 10 patients. After the test, Lactobacillus rhamnosus LGG 10(11) CFU was administered twice daily for four weeks. Faecal near infrared spectroscopy (FENIR) of water, fat, nitrogen and sugar content in faeces was performed before and after probiotics administration. Five patients (50%) showed bacterial overgrowth. We obtained a positive correlation between the hydrogen test and steatorrhoea (R = 0.57) and sugar in faeces (R = 0.52). The FENIR results pre-treatment vs post-treatment were: fat 6.2 g +/- 3.3 g vs. 4.9 g +/- 2.1 g (p < 0.05), sugar 6.7 +/- g 3.6 g vs. 5 g +/- 2.6 g (p < 0.05) and nitrogen 0.87 g +/- 0.27 g vs. 0.91 g +/- 0.14 g (NS) respectively. Thirteen patients (81.25%) had improved stool appearance and intestinal comfort and nine (56.25%) decreased the number of daily stools. Probiotics improved not only clinical but also biochemical intestinal function in cystic fibrosis patients. These could be given as a regular treatment in this type of patients and in those with bacterial overgrowth.

One of the few papers on the use of probiotics in people with CF. With the increasing evidence of bacterial overgrowth and tissue inflammation it is likely that probiotics may have a role in treatment of gastrointestinal problems. Later priobiotics were shown to reduce pulmonary exacerbations (Weiss B et al. Pediatr Pulmonol 2010; 45:536-540. [PubMed]).
The latest Cochrane Database Syst Rev. 2020 Jan 22;1(1): CD012949     (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984633/)   was not really helpful and concluded -“Probiotics significantly reduce faecal calprotectin (a marker of intestinal inflammation) in children and adults with CF, however the clinical implications of this require further investigation. Probiotics may make little or no difference to pulmonary exacerbation rates, however, further evidence is required before firm conclusions can be made. Probiotics are associated with a small number of adverse events including vomiting, diarrhoea and allergic reactions. In children and adults with CF, probiotics may be considered by patients and their healthcare providers. Given the variability of probiotic composition and dosage, further adequately‐powered multicentre RCTs of at least 12 months duration are required to best assess the efficacy and safety of probiotics for children and adults with CF”.

Dámaso Infante Pina (fig 17) is at the Unidad de Gastroenterología, Hepatología y Soporte Nutricional, Hospital Materno-Infantil Vall d’Hebron, Universidad Autónoma de Barcelona, Barcelona, España.

Johansen HK, Moskowitz SM, Ciofu O, Pressler T, Høiby N. Spread of colistin resistant non-mucoid Pseudomonas aeruginosa among chronically infected Danish cystic fibrosis patients. J Cyst Fibros 2008; 7:391-397[PubMed]

Fig. 18 Helle Krogh Johansen
DTU Orbit

Colistin resistant Pseudomonas aeruginosa have rarely been reported in cystic fibrosis (CF) patients. The authros performed a 17-year prospective study on colistin susceptibility and compared our findings with clinical variables. The first outbreak started in 1995 and lasted 5 years. It involved 27 CF patients who had inhaled colistin twice daily for a median of 10 years. Colistin resistant isolates persisted in individual patients for a median of 75 days after colistin was withdrawn. A second outbreak started in 2004. It involved 40 patients, 17 of whom were the same as in the first outbreak. Most resistant isolates belonged to two major clones that had similar genotypes in the two outbreaks. The P. aeruginosa isolates were all non-mucoid and they appeared in a group of chronically infected patients that had been admitted to the same ward for antibiotic treatment and had been followed at the same week-days in the outpatient clinic. Patients were individually isolated to avoid cross-infection and colistin inhalation was avoided in the CF outpatient clinic and in the ward after both outbreaks.Since 2004, no further spread has been observed. it is important that the colistin resistant clones do not spread to non-infected patients since colistin is an important antibiotic for eradication of initial and intermittent P. aeruginosa colonisation. Infrequent resistance even with widespread use of colistin in the Danish CF centre.

Helle Krogh Johansen (fig 18)  is in the Department of Clinical Microbiology, Dept. 9301 and Danish Cystic fibrosis Centre, Dept. 5003, Rigshospitalet, Copenhagen, Denmark

Jaques A, DFaviskas E, Turton nJA, McKay K, Cooper P, Stirling RG, Robertson CF, Bye PT, Lesouef PN, Shadbolt B, Anderson SD, Charlton B. Inhaled mannitol improves lung function in cystic fibrosis. Chest 2008; 133:1388-1396. [PubMed].

Fig. 19 Anna Jaques

This study examined the efficacy and safety of therapy with inhaled mannitol over a 2-week period in a randomized, double-blind, placebo-controlled, crossover study. Thirty-nine subjects with mild-to-moderate CF lung disease inhaled 420 mg of mannitol or placebo twice daily for 2 weeks. Following a 2-week washout period, subjects were entered in the reciprocal treatment arm. Lung function, respiratory symptoms, quality of life, and safety were assessed. Mannitol treatment increased FEV(1) from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, – 3.4 to 4.0; p < 0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL; 95% CI, – 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, – 6.5 to 24.6) compared to that with placebo (increase, 0.7%; 95% CI, – 8.3 to 9.7; p < 0.02).
The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed. Inhaled mannitol treatment over a period of 2 weeks significantly improved lung function in patients with CF.

— Mannitol therapy was safe and well tolerated and subsequently was developed as a mucolytic treatment for people with CF (Bilton D et al, Eur Respir J 2011; 38:1071-1080. [PubMed]; Aitken ML et al. Am J Respir Crit Care Med 2012; 185:645-652.[PubMed]). However, although a number of supportive studies appeared, the treatment never became popular and is not mentioned as a recognised inhaled therapy on the CFF patient Registry. Only 3% of patients in the UK were receiving mannitol in 2021.

Anna Jaques (fig 19) at the time  in  the Department of Clinical Research, Pharmaxis Ltd, Frenchs Forest, NSW, Australia.

Jacobs JL, Fasi AC, Ramette A, Smith JJ, Hammerschmidt R, Sundin GW. Identification and onion pathogenicity of Burkholderia cepacia complex isolates from the onion rhizosphere and onion field soil. Appl & Environ Microbiol 2008; 74:3121-3129. [PubMed]

Fig 20 Janette Jacobs

Genotypic identification and pathogenicity characterization were performed on B. cepacia complex isolates from the rhizosphere of onion and organic soils in Michigan.
A total of 1,290 isolates, 980 rhizosphere and 310 soil isolates, were assigned to the species B. cepacia (160), B. cenocepacia (480), B. ambifaria (623), and B. pyrrocinia (27). The majority of isolates identified as B. cepacia (85%), B. cenocepacia (90%), and B. ambifaria (76%) were pathogenic in a detached onion bulb scale assay and caused symptoms of water soaking, maceration, and/or necrosis.
This study confirmed that multiple B. cepacia complex species colonize the onion rhizosphere and have the potential to cause sour skin rot disease of the onion. In addition, the onion rhizosphere is a natural habitat and a potential environmental source of B. cenocepacia. Following the introduction of segregation of patients growing B. cepacia, most new infections were with such environmentally acquired organisms.

Janette L Jacobs (fig. 20) is the Department of Plant Pathology, Michigan State University, 62 PBL, East Lansing, MI 48824, USA.

Kellerman D, Rossi Mospan A, Engels J, Schaberg A, Gorden J, Smiley L. Denufosol: a review of studies with inhaled P2Y(2) agonists that led to Phase 3. [Review] Pulmon Pharmacol Therap 2008; 21:600-607.[PubMed]

Fig. 21 Donald Kellerman  theorg.com

The pharmacology of P2Y(2) agonists has been confirmed in several preclinical and clinical studies. Denufosol tetrasodium is a novel second-generation, metabolically stable, selective P2Y(2) receptor agonist currently in Phase 3 clinical development. In radio labelled deposition studies of P2Y(2) agonists in healthy non-smokers and smokers, approximately 7mg of a 40-mg nebulizer (PARI LC Star) load was deposited in the lungs. In a pharmacokinetic study in healthy volunteers, very limited systemic exposure was observed when doses of 200mg of denufosol were nebulized. Thus, it appears that high concentrations of denufosol can be achieved in the airways with very low systemic absorption. Denufosol has been generally well-tolerated in healthy volunteers and patients with CF. The most common adverse events were in the respiratory system, with cough having the highest frequency. Doses of 20-60mg have been evaluated in Phase 2 trials of up to 28 days duration, and superiority relative to placebo on FEV1 has been observed in patients with relatively normal lung function (FEV1 greater than or equal to 75% of predicted). The first Phase 3 trial is a comparison of denufosol 60mg and placebo in 350 patients with CF with FEV1 at study entry greater than or equal to 75% of predicted.Denufosol was one of the more hopeful new therapies with the particular aim of increasing hydration of the respiratory mucosa.

— However, the drug failed at the final Phase III trial for 48 weeks when the drug “did not improve pulmonary function or reduce the incidence of pulmonary exacerbations” so development was stopped (Ratjen F et al. J Cyst Fibros 2012. [PubMed]).

Donald Kellerman (fig 21) at the time was with Development, Inspire Pharmaceuticals, Inc., 4222 Emperor Blvd, Suite 200, Durham, NC, USA.

Koch AK, Brömme S, Wollschläger B, Horneff G, Keyszer G. Musculoskeletal manifestations and rheumatic symptoms in patients with cystic fibrosis (CF) no observations of CF-specific arthropathy. J Rheumatol 2008; 35:1882-1891. [PubMed]
In CF patients, the prevalence of rheumatic symptoms increases with age and CF severity. Our data suggest an association of infections with P. aeruginosa and A. fumigatus with the occurrence of rheumatic symptoms. However, no association of CF with definite inflammatory joint or connective tissue diseases was observed, and no CF-specific pattern of musculoskeletal symptoms was seen.
We did report a definite association between the severity of the joint pains and severity of the chest infection in a Leeds child with CF as the pains quite definitely improved during a course of intravenous antibiotics (Bowler IM, Littlewood JM. Episodic arthritis in cystic fibrosis. lancet 1992; 340:244.[PubMed])

Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, Elfring GL, Northcutt VJ, Miller LL, Kerem B, Wilschanski M. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008; 372:719-727. [PubMed]

Fig. 22 Eitan Kerem       cipp-meeting.org 2023

PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR: This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment.The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle.Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p<0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycle’s treatment phase (p<0.0001) and in eight of the 21 patients in the second cycle (p<0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle’s treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded.

The authors concluded that in patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction.

A subsequent study – International randomised, Double Blind, placebo controlled Ataluren Confirmatory trial in Cystic Fibrosis”  showed “Neither ppFEV1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive”  [https://pubmed.ncbi.nlm.nih.gov/31983658/]

Finally, there is a recent Cochrane Review –

Aisha A AslamIan P SinhaKevin W Southern  Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis. Cochrane Database Syst Rev.2023 Mar 3;3(3):CD012040. doi: 10.1002/14651858.CD012040.pub3.                         Authors’ Conclusions: “There is currently insufficient evidence to determine the effect of ataluren as a therapy for people with CF with class I mutations. One trial reported favourable results for ataluren in a post hoc subgroup analysis of participants not receiving chronic inhaled aminoglycosides, but these were not reproduced in the later trial, suggesting that the earlier results may have occurred by chance. Future trials should carefully assess for adverse events, notably renal impairment, and consider the possibility of drug interactions. Cross-over trials should be avoided, given the potential for the treatment to change the natural history of CF”.

Linnane BM, Hall GL, Nolan G, Brennan S, Stick SM, Sly PD, Robertson CF, Robinson PJ, Franklin PJ, Turner SW, Ranganathan SC. AREST-CF. Lung function in infants with cystic fibrosis diagnosed by newborn screening. Am J Resp Critical Care 2008; 178:1238-1244[PubMed].

Fig. 23 Barry Linnane www.ul.ie

A study to measure lung function in infants with CF diagnosed by newborn screening and describe its association with pulmonary infection and inflammation. Lung function, measured by forced expiration, is normal in infants with CF at the time of diagnosis by newborn screening but is diminished in older infants. These findings suggest that in CF the optimal timing of therapeutic interventions aimed at preserving lung function may be within the first 6 months of life.Many, including this writer, would consider that treatment should begin within the first weeks of life.

Prof. Barry M Linnane (fig. 23) at the time was at Department of Respiratory Medicine, Royal Children’s Hospital Melbourne, Parkville, Australia.    Subsequently Director of Paediatric Cystic Fibrosis Programme, Paediatric Respiratory Consultant, University Hospital, Limerick.

Lubamba B, Lecourt H, Lebacq J, Lebecque P, De Jonge H, Wallemacq P, Leal T. Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Resp Crit Care 2008; 177:506-515. [PubMed]

Fig. 24 Bob A Lubamba          LinkedIn

The effect of sildenafil was observed in vitro but in the presence of doses roughly equivalent to 300 times larger than those commonly used for treating erectile dysfunction. The effect of a single intraperitoneal injection of sildenafil (0.7 mg/kg) or vardenafil (0.14 mg/kg) was investigated in F508del, cftr knockout and normal homozygous mice. In F508del mice, the chloride conductance was corrected 1 hour after sildenafil administration. A more prolonged effect, persisting for at least 24 hours, was observed with vardenafil.These results provide further preclinical evidence that both drugs stimulate chloride transport activity of F508del-CFTR protein (also Dormer et al, 2001 and 2005 above; Pochet et al, 2007 above). The investigation of these two drugs continues and they show promise as a pharmacological therapy for DF508 mutations (also similar comment by Antoniu SA. Exp Opin Invest Drugs 2008; 17:965-968. [PubMed]).

Dr Bob Lubamba (fig.24)  is at the Department of Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium.

Mohan K, Fothergill JL, Storrar J, Ledson MJ, Winstanley C, Walshaw MJ. Transmission of Pseudomonas aeruginosa epidemic strain from a patient with cystic fibrosis to a pet cat. Thorax 2008; 63:839-840. https://pubmed.ncbi.nlm.nih.gov/18728207/

Fig. 25 Kamlesh Mohan. liverpool chest specialist.co.uk

Chronic infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) and certain strains are more transmissible and virulent than others. Of these, the Liverpool Epidemic Strain (LES) is highly transmissible and cross infection has been reported between patients with CF and healthy non-CF relatives. However, the risk of transmission from humans to animals is unknown
The first report of interspecies transmission of the LES strain of P. aeruginosa from an adult patient with CF to a pet cat is described. This development further complicates the issue of infection control policies required to prevent the spread of this organism.

Dr Kamlesh Mohan (fig.25)  is at the Adult Cystic Fibrosis unit, The Cardiothoracic Centre NHS Trust, Thomas Drive, Liverpool L14 3PE, UK.

McLaughlin AM, McGrath E, Barry R, Egan JJ, Gallagher CG. Treatment of lobar atelectasis with bronchoscopically administered recombinant human deoxyribonuclease in cystic fibrosis? Clin Respir J 2008; 2:123-126. [PubMed]

Fig. 26 Charles Gallager svcpc.ie

The objective of this study was to describe our experience in which rhDNase (Pulmozyme) was administered by bronchoscopic instillation into atelectatic lobes in five adults with CF. This method was successful in treating lobar atelectasis, which was resistant to conventional therapy with antibiotics and physiotherapy. In all but one of the cases described, administration of DNase in this manner resulted in a radiographic and clinical improvement of the atelectasis. The authors recommend that respiratory physicians consider this as a second line treatment in the management of atelectasis.
Although not the first to use this treatment for atelectasis, confirmation of the success of this treatment is useful for clinicians faced with resistant atelectasis.

Prof. Charles Gallagher (fig. 26) is Director, National Referral Centre for Adult Cystic Fibrosis and has been closely associated with impressive developments in the care of people with CF in Ireland. He has wide clinical and research interests in various aspects of CF and other respiratory disorders.

Mrugacz M, Kasacka I, Bakunowicz-Lazarczyk A, Kaczmarski M, Kulak W. Impression cytology of the conjunctival epithelial cells in patients with cystic fibrosis. Eye 2008; 22:1137-1140. [PubMed] Cystic fibrosis affects all secretory epithelia, including the eye, and belongs to the group of ocular surface epithelial diseases, termed keratoconjunctivitis sicca or dry eye syndrome. The aim of this study was to evaluate goblet cell population and conjunctival epithelial morphology in patients with CF. A total of 20 CF patients and 20 controls underwent conjunctival impression cytology. Impression cytology showed conjunctival squamous metaplasia and goblet cell loss in patients with CF. The reduced goblet cell numbers and squamous metaplasia may be indicative of a higher degree of epithelial damage of conjunctival epithelial cells in CF patients, and the presence of neutrophils is a strong sign for an inflammatory background of this disease.

— In view of the simple, noninvasive nature of impression cytology, this technique may prove to be an important tool for the diagnosis and monitoring of dry eye changes in CF patients.These changes are mentioned in a number of reports dealing with vitamin A status and still appear to be present even when the vitamin levels are normal. (Ansari EA et al. 1999. [PubMed]) to the extent that it has been suggested that dry eye could be a primary manifestation of CF.

Professor M Mrugacz  is in the Department of Pediatric Ophthalmology, Medical University of Bialystok, Bialystok, Poland.

Maiuri L, Luciani A, Giardino I, Raia V, Villella VR, D’Apolito M, Pettoello-Mantovani M, Guido S, Ciacci C, Cimmino M, Cexus ON, Londei M, Quaratino S. Tissue Transglutaminase Activation Modulates Inflammation in Cystic Fibrosis via PPAR{gamma} Down-Regulation. J Immunol 2008; 180:7697-7705. [PubMed]

Fig. 27  Luigi Maiuri react-congress.org

Several studies have shown an increased proinflammatory activity in the CF tissues. Defective CFTR induces a remarkable up-regulation of tissue transglutaminase (TG2) in both tissues and cell lines. The increased TG2 activity leads to functional sequestration of the anti-inflammatory peroxisome proliferator-activated receptor gamma and increase of the classic parameters of inflammation, such as TNF-alpha, tyrosine phosphorylation, and MAPKs. Specific inhibition of TG2 was able to reinstate normal levels of peroxisome proliferator-activated receptor-gamma and dampen down inflammation both in CF tissues and CFTR-defective cells.
The authors suggest that the results highlight an unpredicted central role of TG2 in the mechanistic pathway of CF inflammation, also opening a possible new wave of therapies for sufferers of chronic inflammatory diseases.

Prof. Luigi Maiuri (fig.27) is Research Director at the European Institute for Cystic Fibrosis Research, San Raffaele Scientific Institute, Milan, Italy

Mahenthiralingam E, Baldwin A, Dowson CG. Burkholderia cepacia complex bacteria: opportunistic pathogens with important natural biology. J App Microbiol 2008; 104:1539-1551. [PubMed]

Fig 28. Eshwar Mahenthiralingam

Interaction with plants around their roots and foliage forms the natural habitat for a wide range of gram-negative bacteria such as Burkholderia, Pseudomonas and Ralstonia. During these interactions many of these bacteria facilitate highly beneficial processes such as the breakdown of pollutants or enhancement of crop growth. All these bacterial species are also capable of causing opportunistic infections in vulnerable individuals, especially people with cystic fibrosis (CF). The authors review the current understanding of the Burkholderia cepacia complex (Bcc) as a group of model opportunistic pathogens, contrasting their clinical epidemiology with their ecological importance. Currently, the B. cepacia complex is composed of nine formally named species groups which are all difficult to identify using phenotypic methods. Genetic methods such as 16S rRNA and recA gene sequence analysis have proven useful for Bcc species identification. Multilocus sequence typing (MLST) is also emerging as a very useful tool for both Bcc strain and species identification.Historically, Burkholderia cenocepacia was the most dominant Bcc pathogen in CF, however, probably as a result of strict infection control practices introduced to control the spread of this species, its prevalence has been reduced. Burkholderia multivorans is the now the most dominant Bcc infection encountered in the UK CF population, a changing epidemiology that also appears to be occurring in the US CF population. The distribution of Bcc species residing in the natural environment may vary considerably with the type of environment examined. Clonally identical Bcc strains have been found to occur in the natural environment and cause infection. The contamination of medical devices, disinfectants and pharmaceutical formulations has also been directly linked to several outbreaks of infection.In the last 10 years considerable progress has been made in understanding the natural biology and clinical infections caused by this fascinating group of bacteria.

An up to date review of the B. cepacia complex by Esch. Malhenthiralingam (fig 28) , an expert on the subject of BC complex. The summary is reproduced in full.

Meachery G, De Soyza A, Nicholson A, Parry G, Hasan A, Tocewicz K, Pillay T, Clark S, Lordan JL, Schueler S, Fisher AJ, Dark JH, Gould FK, Corris PA. Outcomes of lung transplantation for cystic fibrosis in a large UK cohort. Thorax 2008; 63:725-731.[PubMed]

Fig. 30 Gerard Meachery Newcastle upon Tyne Hospitals.

Fig 29 John Dark

176 patients with CF underwent lung transplantation at the Freeman Hospital Newcastle UK. The majority (168) had bilateral sequential lung transplantation. Median age at transplantation was 26 years. Diabetes was common pretransplantation (40%). Polymicrobial infection was common in individual recipients. A diverse range of pathogens were encountered, including the Burkholderia cepacia complex (BCC). The bronchial anastomotic complication rate was 2%. Pulmonary function (FEV1 % predicted) improved from a pretransplantation median of 0.8 l (21% predicted) to 2.95 l (78% predicted) at 1 year following transplantation. There was an acute rejection rate of 41% within the first month. The survival values were 82% survival at 1 year, 70% at 3 years, 62% at 5 years and 51% at 10 years.Patients with BCC infection had poorer outcomes and represented the majority of those who had a septic death. Data are presented on those free from these infections. Bronchiolitis obliterans syndrome (BOS) and sepsis were common causes of death. Freedom from BOS was 74% at 5 years and 38% at 10 years. Biochemical evidence of renal dysfunction was common although renal replacement was infrequently required (<5%).The authors concluded that lung transplantation is an important therapeutic option in patients with CF even in those with more complex microbiology. Good functional outcomes are noted although transplantation associated morbidities accrue with time.

— These excellent results, from the Freeman Hospital in Newcastle are from the UK’s largest transplant centre and the summary is reproduced in full..

Mr John Dark (fig. 29) is Professor of Cardiothoracic Surgery and the senior transplant surgeon.

Dr Gerard Meachery (fig.30) is Consultant in Respiratory & Transplant Medicine and
Director of Transplantation

Mueller-Abt PR, Frawley KJ, Greer RM, Lewindon PJ. Comparison of ultrasound and biopsy findings in children with cystic fibrosis related liver disease. J Cyst Fibros 2008; 7:215-221. [PubMed]
The objective of this study from Brisbane was to determine if hepatic ultrasound findings in paediatric patients with cystic fibrosis and suspected liver disease are related to histopathological results derived from liver biopsies.

The authors concluded that the diagnosis of early liver disease in cystic fibrosis cannot reliably be made on the basis of ultrasound alone. A normal ultrasound does not preclude significant liver fibrosis in cystic fibrosis. An abnormal ultrasound that suggests cirrhosis predicts the presence of moderate to severe liver disease.

Peter R Mueller-Abt is in the Department of Medical Imaging, Royal Children’s Hospital Brisbane, Herston, QLD 4029, Australia

Nash KL, Allison ME, McKeon D, Lomas DJ, Haworth CS, Bilton D, Alexander GJ. A single centre experience of liver disease in adults with cystic fibrosis 1995-2006. J Cyst Fibros 2008; 7:252-257. [PubMed]

         Fig 31. Di Bilton

Liver disease is an important cause of death in adults with cystic fibrosis. Ursodeoxycholic acid (UDCA) may slow progression. Managing varices and timely evaluation for liver transplantation are important.

154 patients attending the CF Centre at Papworth, Cambridge in the UK were followed for a median 5 years. 43 had significant liver disease. Only one patient developed chronic liver failure and none required liver transplantation. 27 underwent endoscopy; 1 required variceal banding, the others had insignificant varices. Ultrasound was normal in 97 patients while five had steatosis; nine further patients had splenomegaly but no other evidence of portal hypertension. Neither spleen size nor platelet count correlated with portal hypertension.
So liver disease was common in adults with CF but disease progression was rare.Thus liver disease detected and closely monitored in adults appeared to have a milder course than in childhood CF. Splenomegaly, unrelated to portal hypertension may be a consequence of the cystic fibrosis.

Professor Di Bilton (fig. 31) was previously centre director of this adult CF centre at Papworth, Cambridge and in 2007 she moved to Royal Brompton Hospital London. Di is a leading figure in UK CF care and research but sadly retired early in 2015 due to ill health.

Nikolaizik WH, Vietzke D, Ratjen F. A pilot study to compare tobramycin 80 mg injectable preparation with 300 mg solution for inhalation in cystic fibrosis patients. Can Respir J 2008; 15:259-262. [PubMed]
In an open crossover study of CF patients, subjects were randomly allocated to receive either 80 mg tobramycin twice-daily continuous treatment or 300 mg tobramycin twice daily in cycles of 28 days on and 28 days off treatment. After three months, patients were switched to the alternative treatment regimen.
A total of 32 patients with a mean (+/- SD) age of 18.5+/-8.6 years were included in the study. Compared with the treatment period using colistin, forced expiratory volume in 1 s decreased by -2.1+/-13.8% in the 80 mg tobramycin group and increased by +2.3+/-13.0% in the 300 mg group. Similar changes were observed in forced vital capacity (-2.5+/-12.9% in the 80 mg tobramycin group versus +2.5+/-9.6% in the 300 mg tobramycin group).Variability in responses was large but the differences were not statistically significant. Personal preference indicated that the majority of patients preferred the high-dose cycle compared with the lower dose continuous inhalation, but this was not linked to objective data on efficacy.

– The present trial fails to provide convincing evidence for superiority in efficacy of either of the two treatment regimens of inhaled tobramycin in CF patients.     In the UK Canada and Europe since the Eighties injectable tobramycin off-label was nebulised by people with CF to suppress their chronic P. aeruginosa chest infection. It is disappointing that the results in this trial were inconclusive although the dose difference appeared to tip the balance in favour of the TOBI. Tobramycin injectable is no longer licensed for inhalation in the UK.

Wilfred H Nikolaizik is in the Department of Pediatrics, University Hospital Essen, Essen, Germany.

Nilsson E, Larsson A, Olesen HV, Wejaker PE. Kollberg H. Good effect of IgY against Pseudomonas aeruginosa infections in cystic fibrosis patients. Pediatr Pulmonol 2008; 43:892-899.[PubMed]

Fig. 32 Hans Kollberg
author’s photo

This is the next recent installment of an extended open study of oral prophylactic treatment with egg yolk antibodies against Pseudomonas aeruginosa (anti-Pseudomonas IgY) of 17 Swedish patients with CF. They have been on prophylactic IgY treatment for up to 12 years and altogether for the equivalent of 114 patient years. A group of 23 Danish CF patients served as controls. There has been a total absence of adverse events. Only 29 cultures have been positive for P. aeruginosa (cultures after chronic colonization not included), that is, 2.3/100 treatment months compared to 7.0/100 months in the control group (P = 0.028). In the IgY treated group only one pair of siblings (2/17) has been chronically colonized with P. aeruginosa compared to seven patients (7/23) in the control group. Atypical mycobacteria, S. maltophilia, A. xylosoxidans, and A. fumigatus have appeared only sporadically. There have been no cultures positive for B. cepacia. There was no decrease in pulmonary functions within the IgY group. Body mass index values were normal or close to normal for all IgY treated patients. In conclusion, Anti-Pseudomonas IgY has great potential to prevent P. aeruginosa infections.

Hans Kollberg (fig. 32) has relentlessly pursued the value of gargling with Anti-Pseudomonas IgY as a preventive treatment against Pseudomonas and the progress is recorded in a number of publications (Carlander D et al. Immunol Res 2000; 21:1-6. [PubMed] Carlander D et al, Biodrugs 2002; 16:433-437[PubMed];Kollberg H et al, 2003 above; Nilsson et al, 2007 above).

— However, it must be observed that the numbers are small and the cruel lesson of the anti-Pseudomonas Aerugen vaccine trial comes to mind where an initial small study showed definite benefit but a large multicentre trail was quite negative. However, a large European funded multicentre study of IgY commenced in 2011  .A multicentre European clinical trial was in progress in 2012 (http://www.clinical trials.gov/ct2/show/NCT01455675) but not completed by 2018.

Last publication by Hans Kollberg in 2019 “More than 22 years of clinical studies on anti-pseudomonas IgY to cystic fibrosis patients. Journal of HIVV& Retro Virus. Extended abstract 2019 Vol. 5 Iss. 1.  Hopefully the now running double-blind, randomized phase III study will give results as expected and Anti-PA IgY might be registered and physicians will be able to give anti-PA IgY to all eligible CF patients”.

Not aware these final results are yet published in 2023.  However, I contacted Dr Audrey Niemann-Jönsson (IMPACT project coordinator) who informed me “there was no significant difference between placebo and the IgY, in the trial, I believe because the placebo (based on egg yellow extract) showed same effect as the IgY did”.
A very sad ending to the 20-year Anti-PA IgY story.

Padman R, Werk LN, Ramirez-Garnica G, Ye G, Nathanson I. Association between practice patterns and body mass index percentile in infants and young children with cystic fibrosis. J Cyst Fibros 2008; 7:385-390[PubMed]

Data from the CF Registry on 165 infant who were using Pulmozyme before the age of 2 years suggested that this early use of dornase alpha may improve nutritional outcome through age six.

— Many CF clinics have found that the early “off-label” treatment of infants with Pulmozyme as soon as they can manage the inhalations, is clinically beneficial.

Dr Raj Padman is a paediatric pulmonologist at the Department of Pediatrics, Alfred I. duPont Hospital for Children, Nemours Children’s Clinic, 1600 Rockland Rd, Wilmington, DE 19803, United States.

Prasad SA, Main E, Dodd ME; Association of Chartered Physiotherapists. Finding consensus on the physiotherapy management of asymptomatic infants with cystic fibrosis. Pediatr Pulmonol 2008; 43:236-244. [PubMed]

Fig. 33 Ammani Prasad    gosh.nhs.uk/

This study aimed to provide expert consensus regarding the physiotherapy management of asymptomatic infants with CF using a Delphi consensus method. Twenty-five senior paediatric physiotherapists from Specialist CF Centres throughout the UK participated in the study. Consensus was high but consensus could not be achieved on whether routine daily chest physiotherapy is necessary in ‘asymptomatic’ babies. An agreed amendment to the original statement allows professionals to modify or change traditional practice with the sanction of their senior colleagues. There had been a considerable amount of discussion as to the practice of tipping infants in the head down position which Brenda Button and her colleagues from Melbourne found caused oesophageal reflux in a significant proportion.

Ammani Prasad (fig 33) is senior physiotherapist at Great Ormond Street Hospital. She specialised in paediatric respiratory care, working extensively in the fields of paediatric intensive care and paediatric respiratory medicine, particularly cystic fibrosis. Subsequently also she has been involved in coordinating the work within the Cystic Fibrosis Unit at GOSH.

Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet 2008; 372:415-417. [PubMed]

Fig 34. Paul Quinton

For more than 20 years, the abnormally thick mucus (mucoviscidosis) in cystic fibrosis has been widely shown to be linked to a genetic defect in the cystic fibrosis transmembrane conductance regulator Cl(-) channel. The defect is widely thought to cause mucus to become dehydrated as a result of basic defects in Cl(-) dependent fluid transport. However, this widely held explanation is inconsistent with the known physiological properties and functions of organs affected by cystic fibrosis. During the process of releasing highly condensed mucins from intracellular granules, Ca(2+) and H(+) cations must be removed to enable the mucins to expand by as much as 1000 times, forming extracellular mucus-gel networks. Over the past few years it has become apparent that HCO(3)(-) transport is also defective in patients with cystic fibrosis.Paul Quinton proposes that HCO(3)(-) is crucial to normal mucin expansion because it forms complexes with these cations. Thus, because HCO(3)(-) secretion is defective in cystic fibrosis, mucins in organs affected by cystic fibrosis tend to remain aggregated, poorly solubilised, and less transportable. If the hypothesis is valid, pathogenesis in cystic fibrosis could be due as much to defective transport of HCO(3)(-) as to defective Cl(-) transport.

Paul Quinton (fig 34) has discussed the role of bicarbonate previously. Here is a clear explanation of his theory describing a central role for bicarbonate in normal mucin expansion. Paul Quinton is a leading CF scientist having discovered that the basic defect in the Cystic Fibrosis (CF) sweat gland was due to anion impermeability. This discovery is regarded as one of the major advances in understanding the basic defect in this genetic disease.

Alton EW, Griesenbach U, Ovari G, Vag J, Da Paula AC, Crawford RM, Varga G, Amaral MD, Mehta A, Lonovics J, Argent BE, Gray MA. CFTR gene transfer to human cystic fibrosis pancreatic duct cells using a Sendai virus vector. J Cell Physiol 2008; 214:442-455. [PubMed]

Fig. 35 Eric Alton

The aim was to investigate the potential of a recombinant Sendai virus (SeV) vector to introduce normal CFTR into human CF pancreatic duct (CFPAC-1) cells, and to assess the effect of CFTR gene transfer on the key transporters involved in HCO3- transport. Using polarized cultures of homozygous F508del CFPAC-1 cells as a model for the human CF pancreatic ductal epithelium the authors showed that Sendai virus was an efficient gene transfer agent when applied to the apical membrane. The presence of functional CFTR was confirmed using iodide efflux assay. CFTR expression had no effect on cell growth, monolayer integrity, and mRNA levels for key transporters in the duct cell, but did upregulate the activity of apical Cl-/HCO3- and Na+/H+ exchangers. In CFTR-corrected cells, apical Cl-/HCO3- exchange activity was further enhanced by cAMP, a key feature exhibited by normal pancreatic duct cells.
This paper is abstracted in some detail as most studies of gene therapy refer to the chest whereas this involves the pancreas. The authors’ data shows that SeV vector is a potential CFTR gene transfer agent for human pancreatic duct cells and that expression of CFTR in CF cells is associated with a restoration of both Cl- and HCO3- transport at the apical membrane. It is encouraging that work of this type is in progress by a group expert in this area.

– It is to be hoped that that this may lead to a “Pancreatic Consortium” as it would be of enormous benefit to patients if their decline of pancreatic function could be arrested, in particular, if there were preservation of the islets of Langerhans so as to avoid diabetes mellitus, which at present is almost inevitable in older adults.

Raso T, Bianco O, Grosso B, Zucca M, Savoia D. Achromobacter xylosoxidans respiratory tract infections in cystic fibrosis patients. APMIS. 2008; 116:837-841. [PubMed]
This study investigated the PFGE genetic pattern and antimicrobial resistance profile of 42 A. xylosoxidans isolates obtained over 4 years from the respiratory tract of 22 CF patients. The majority of the isolates showed multi drug resistance; imipenem and piperacillin were the most active drugs. During the course of A. xylosoxidans chronic infection forced expiratory volume and body mass index values were not significantly lowered.
The data suggest that in some cases the infection may have been acquired from other patients or from a common contaminated source.
Further epidemiological studies may be important for the design and implementation of prophylactic measures in CF centers. Another emerging pathogen for people with CF.

Tiziana Raso is in the Department of Clinical and Biological Sciences, University of Torino, Orbassano (TO), Italy.

Ren CL, Pasta DJ, Rasouliyan L, Wagener JS, Konstan MW, Morgan WJ. Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Relationship between inhaled corticosteroid therapy and rate of lung function decline in children with cystic fibrosis. J Pediatrics 2008; 153:746-751. [PubMed]

Fig 36 Clement L Ren CHOP Research Institute

To assess the relationship between inhaled corticosteroids (ICS) use and lung function decline in children with cystic fibrosis (CF) using the Epidemiologic Study of Cystic Fibrosis, an observational study of patients with CF in North America.
In this retrospective analysis of prospectively collected data, ICS therapy in patients with CF was associated with a significant reduction in the rate of FEV(1) decline (-1.52% vs. 0.44% pa) , decreased linear growth, and increased insulin/oral hypoglycemic use. This study looks at the use of inhaled steroids from another angle to that of Ian Balfour- Lynn. [PubMed].These results could have been predicted and support previous knowledge of inhaled steroids gained from experience and the few small studies already published. The growth effect is of course dependant on the dose used – sometimes the heroic doses used for various drugs for children with CF have serious side effects – one has seen growth totally arrested by very large doses of inhaled steroids in a small child with CF.The study leaves the paediatrician to decide in the case of individual patients if inhaled steroids are indicated. It is clear that there are some children who certainly do benefit from and should receive inhaled corticosteroid treatment.

Dr Clement Ren (Fig 36) is in the Department of Pediatrics, University of Rochester, Rochester, NY, USA.

Retsch-Bogart GZ, Burns JL, Otto KL, Liou TG, McCoy K, Oermann C, Gibson RL. AZLI Phase II Study Group. A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol 2008; 43:47-58. [PubMed]

Fig. 37  G Z Retsch-Bogart

This double-blind, randomized, placebo-controlled Phase 2 study evaluated the safety, tolerability and efficacy of 75 mg and 225 mg aztreonam lysine (AZLI) administered twice daily for 14 days There was a statistically significant reduction, compared to placebo, in P. aeruginosa CFU density in each AZLI group at Days 7 and 14 (P<0.001). The planned primary analysis, percent change in FEV1 at Day 14, demonstrated no statistically significant difference. Further analysis demonstrated significant increase in FEV1 at Day 7 for the subset of patients with baseline FEV1<75% predicted in the 225 mg AZLI group. Bronchodilator use was associated with greater improvement in FEV1, as well as greater reduction in P.aeruginosa bacterial density and higher plasma aztreonam concentrations in the 225 mg AZLI group. The authors concluded that these data support the further development of AZLI and provide information for the design of subsequent studies (Retsch-Bogart et al, 2008 below).

Retsch-Bogart GZ, McCoy KS, Gibson RL, Oermann C, Montgomery AB. Source of improvement in lung function in patients with cystic fibrosis following treatment with aztreonam lysine for inhalation (AZLI). Pediatr Pulmonol 2008; Suppl 31: Abstract 336:320.
Phase III study of treatment with 28 days of AZLI 75mg three times daily led to significant improvements in FEV1 and FVC compared to controls. At 28 days treated group had 10.2 better FEV1% and 5 better FVC% than did controls.So inhaled aztreonam lysine is a valuable addition to the inhaled antibiotics available for treating people with CF and was licensed by 2010.

Prof. George Retsch-Bogart (fig.37) is a pediatric pulmonologist in  Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7220, USA.

Rogers CS, Abraham WM, Brogden KA, Engelhardt JF, Fisher JT, McCray PB, McLennan G, Meyerholz DK, Namati E. The porcine lung as a potential model for cystic fibrosis. Am J Physiol-Lung Cell Mol Biol 2008; 295:L240-L263. [PubMed]
In many respects, the anatomy, biochemistry, physiology, size, and genetics of pigs resemble those of humans. Thus pigs with a targeted CFTR gene might provide a good model for CF. This is a review of aspects of porcine airways and lung that are relevant to CF. (Also comments by Verkman AS. From the farm to the lab: the pig as a new model of cystic fibrosis lung disease. Am J Physiol – Lung Cell Mol Physiol 2008; 292:L238-9. [PubMed]).Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA, Kabel AC, Wohlford-Lenane CL, Davis GJ, Hanfland RA, Smith TL, Samuel M, Wax D, Murphy CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 2008; 26; 321(5897):1837-1841. [PubMed]

Christopher S Rogers is at the Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.

Pigs share many anatomical and physiological features with humans. The authors generated pigs with a targeted disruption of both CFTR alleles that developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF.Progress was reviewed by Michael Welsh and colleagues in 2009 (Welsh et al, 2009. [PubMed]);  also some features of the pathology of the CF pig were reviewed. Lesions resembling those in humans with CF were detected in intestine, pancreas, liver, gallbladder, and cystic duct. These organs had four common features. First, disease was accelerated compared with that in humans, which could provide a strategy to discover modifying factors. Second, affected organs showed variable hyperplastic, metaplastic, and connective tissue changes, indicating that remodeling was a dynamic component of fetal life. Third, cellular inflammation was often mild to moderate and not always present, which raises new questions as to the role of cellular inflammation in early disease pathogenesis. Fourth, epithelial mucus-producing cells were often increased, producing a striking accumulation of mucus with a layered appearance and resilient structure. Thus, mucus cell hyperplasia and mucus accumulation appear to play prominent roles in early disease. It was shown that luboprostone stimulates secretion from the tracheal submucosal glands of sheep, pigs and humans (Joo N S et al. 2009.[PubMed]). Subsequently hyposecretion of fluid from submucosal glands of CFTR-deficient pigs was demonstrated (Joo N S et al. 2010. [PubMed]).[There is a free detailed and fully illustrated PMC article entered via Pubmed.

Smyth A, Lewis S, Bertenshaw C, Choonara I, McGaw J, Watson A. Case-control study of acute renal failure in patients with cystic fibrosis in the UK. Thorax 2008; 63:532-535.[PubMed].

Fig. 38 Alan Smyth University of Nottingham

As there had been a recent increase in the number of reported cases of acute renal failure (ARF) in cystic fibrosis (CF), a case-control study was conducted to determine the factors which are associated with an increased risk of ARF. 24 cases of confirmed ARF were identified in patients with CF from 20 UK CF centres presenting between 1997 and 2004. Using the UK CF database, sex- and age-matched controls were identified. Risk factors were analysed by conditional logistic regression and Mantel-Haenszel analysis.
Twenty one of the 24 patients with ARF had received an aminoglycoside at the time of their episode of ARF or in the preceding week compared with only 3 of 42 controls during the same time period (p<0.001). In the year before the episode of ARF, significantly more cases than controls had received gentamicin (19/24 cases vs 1/42 controls, p<0.001). The numbers receiving tobramycin were similar (9/24 cases vs 16/42 controls, p = 0.9). A known risk factor for renal impairment (prior renal disease, acute dehydration or long-term treatment with a nephrotoxic drug) was present in 18/24 cases and 7/42 controls (OR 24.0, 95% CI 3.1 to 186.6, p = 0.002). The authors concluded in patients with CF the use of an intravenous aminoglycoside is a risk factor for acute renal failure; gentamicin is more nephrotoxic than tobramycin. Most patients who develop ARF have a risk factor which necessitates withholding aminoglycosides or more closely monitoring their use.

– This is an important and worrying paper from Alan Smyth confirming the increase in severe renal problems in people with CF. The immediate lesson being that gentamicin should not be used in people with CF who require repeated courses of intravenous aminoglycosides.

Prof. Alan Smyth (fig.38)  is in the Division of Respiratory Medicine, Clinical Sciences Building, Nottingham City Hospital, Nottingham NG5 1PB, UK.

Sueblinvong V, Loi R, Eisenhauer PL, Bernstein IM, Suratt BT, Spees JL, Weiss DJ. Derivation of lung epithelium from human cord blood-derived mesenchymal stem cells. Am J Resp Crit Care 2008; 177:701-711. [PubMed]

Fig. 39 Viranuj Sueblinvong
Emory Health

Both embryonic stem cells and adult bone marrow stem cells can participate in the regeneration and repair of diseased adult organs, including the lungs. However, there are no available in vivo data with embryonic stem cells. Human umbilical cord blood contains both hematopoietic and non-hematopoietic stem cells, which have been used clinically as an alternative to bone marrow transplantation for hematologic malignancies and other diseases.
Human cord blood was obtained from normal deliveries at the University of Vermont. Cord blood-derived mesenchymal stem cells (MSCs) were cultured in specialized airway growth media or with specific growth factors. mRNA and protein expression were analyzed with PCR and immunofluorescent staining.The MSCs were systematically administered to immunotolerant, non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice and their lungs were analyzed for the presence of human cells. When cultured in specialized airway growth media or with specific growth factors, CB-MSCs differentially expressed a variety of protein including CFTR. Furthermore, CB-MSCs were easily transduced with recombinant lentiviral vectors to express human CFTR. After systemic administration to immunotolerant, NOD-SCID, mice, rare cells were found in the airway epithelium that had acquired cytokeratin and human CFTR expression.
The authors concluded that cord blood stem cells appear to be comparable to marrow-derived stem cells in their ability to express phenotypic markers of airway epithelium and to participate in airway remodelling in vivo
There is no way to describe this study briefly and it appears to be potentially important providing as it does further evidence that stem cell therapy may be a possibility for cystic fibrosis. Cord blood-derived mesenchymal stem cells appear to be comparable to mesenchymal stem cells obtained from adult bone marrow in their ability to express phenotypic markers of airway epithelium and to participate in airway remodeling in vivo. This is relevant particularly for those CF families that have already arranged to store umbilical cord blood from any subsequent pregnancies in the hope that it may prove to be a source of stem cells which could be used to treat their previous child with CF.

Dr Viranuj Sueblinvong (fig. 39) is Associate Professor of Medicine in the Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05405, USA

Teichgraber V, Ulrich M, Endlich N, Reithmuller J, Wilker B, De Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kurthy G, Schmid KW, Weller M, Tummler B, Lang F Grassme H, Döring G, Gulbins E. Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med 2008; 14:382-391. [PubMed]
Here, the authors show that there is an age-dependent accumulation of ceramide in the respiratory tract of uninfected CF mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide. The accumulation of ceramide causes Cftr-deficient mice to suffer from constitutive age-dependent pulmonary inflammation, death of respiratory epithelial cells, deposits of DNA in bronchi and high susceptibility to severe Pseudomonas aeruginosa infections. Partial genetic deficiency of Asm in Cftr (-/-) Smpd1 (+/-) mice or pharmacological treatment of Cftr-deficient mice with the Asm blocker amitriptyline normalizes pulmonary ceramide and prevents all the pathological findings, including susceptibility to infection.
These data suggest inhibition of Asm as a new treatment strategy for cystic fibrosis.An interesting and potentially important paper which does provide one explanation for the repeatedly reported excessive inflammatory response in CF. The findings also suggests yet another possible treatment with amitriptyline, a well established drug already licensed and used as an anti-depressant – certainly a drug in the “low-hanging fruit” category. (also Reithmuller J et al, 2009. below)

Volker Teichgraber is in the Department of Molecular Biology, Hufelandstrasse 55, University of Duisburg-Essen, 45122 Essen, Germany.

Thomas CL, O’Rourke PK, Wainwright CE. Clinical outcomes of Queensland children with cystic fibrosis: a comparison between tertiary centre and outreach services. M J Australia 2008; 188:135-139. [PubMed]
To evaluate and compare the clinical outcomes of children with cystic fibrosis (CF) managed primarily at a tertiary cystic fibrosis centre (CFC) with those treated at regional centres by local health care professionals and the cystic fibrosis outreach service (CFOS). A retrospective study of 273 children with CF born between 19 October 1982 and 19 February 2002 and with clinical data available between 1 January 2000 and 31 December 2002. Patients were grouped into CFC (n = 131) or CFOS (n = 142), with CFOS then further categorized into three groups depending on the level of care they received. There were no significant differences in pulmonary function, P. aeruginosa status, or height and weight z scores between children managed by CFC or by CFOS. Children receiving more care at the CFC (level of care [LOC] 1 and 2) were more likely to have multiple hospital admissions than children receiving more care in regional areas (LOC 3 and 4) (P < 0.001). The authors concluded the CFOS model provides effective delivery of specialised multidisciplinary care to children and adolescents living in rural and regional Queensland.

This is a reassuring study for the Australian families and professionals involved in this particular study. However, it is often difficult to translate the results of one study to another area or country i.e. the the question of “shared care ” in the UK.

Clare L Thomas is a Registered Nurse  at the Paediatric Department, Nambour General Hospital, Nambour, QLD, Australia.

Tunney MM, Field TR, Moriarty TF, Patrick S, Döring G, Muhlebach MS, Wolfgang MC, Boucher R, Gilpin DF, McDowell A, Elborn JS. Detection of anaerobic bacteria in high numbers in sputum from patients with cystic fibrosis. Am J Resp Crit Care 2008; 177:995-1001. [[PubMed]

Fig. 40 Michael Tunney pure.qub.ac.uk

Anaerobic species were isolated 64% of sputum samples from adult patients with CF. Similar anaerobic species were identified in bronchiolar lavage fluid from pediatric patients with CF. Although anaerobes were detected in induced sputum samples from 16 of 20 volunteers, they were present in much lower numbers and were generally different species compared with those detected in CF sputum. All isolates were susceptible to meropenem.So a range of anaerobic species are present in large numbers in the lungs of patients with CF. If these anaerobic bacteria are contributing significantly to infection and inflammation in the CF lung, informed alterations to antibiotic treatment to target anaerobes, in addition to the primary infecting pathogens, may improve management.Over the years there have been sporadic reports of anaerobes in the sputum of people with CF (Jeeves & Spencer. J Med Microbiol 1990; 31:271-274. [PubMed]).
As yet there is no definite information as to their importance. Their presence in induced sputum specimens of 16 of 20 volunteers is rather confusing even though their numbers were less than in the CF patients.

Michael M Tunney (fig.40) is Professor in the School of Pharmacy, material and Advanced technologies for Healthcare, Medical Biology Centre, Queen’s University Belfast, Belfast, United Kingdom

Ullrich G, Wiedau S, Schulz W, Steinkamp G. Parental knowledge and behaviour to prevent environmental P. aeruginosa acquisition in their children with CF. J Cyst Fibros 2008; 7:231-237. [PubMed]

Fig. 41 Gerald Ullrich Hellios Gesundheit

Most parents displayed erroneous beliefs regarding P. aeruginosa (PA) infection. Families performed a mean of 11 different hygienic measures, e.g. they prevented their child from being the first person to use the bathroom in the morning (72%) or from bathing in gravel pits and standing water (52%). The majority of parents felt markedly (44%) or somewhat (44%) stressed that their child might acquire PA, and many parents felt markedly (16%) or somewhat (43%) restricted and stressed by the hygienic measures. Less stressed parents tended to have more knowledge and undertook fewer measures.
The authors suggest that when informing and teaching parents on the nature of PA infection, caregivers should provide clear recommendations on reasonable actions to be taken. Also, physicians should anticipate and adequately respond to parental fears and misconceptions.It is understandable that parents seek to prevent their children being exposed unnecessarily to P. aeruginosa which is unfortunately ubiquitous in the environment. Striking a balance between a normal life style and over caution is very difficult for the parents as most of the avoidance recommendation have not been put to any form of trial. However, it seems sensible to reduce exposure to environments which are known to harbour P. aeruginosa. They can be reassured that, provided regular cultures are performed, an early infection with P. aeruginosa can be eradicated by appropriate antibiotic treatment so, although better avoided, the early infection is not the potentially disastrous occurrence it was in years gone by.

An article on the CF Trust website (www.cftrust.org.uk) reviews the likely sources of P. aeruginosa in the environment – “The environment as a source of Pseudomonas aeruginosa and some other potential pathogens”. Sept. 2007 by Jim Littlewood with expert advice from Dr Miles Denton.

Dr Gerald Ullrich (fig.41) is a clinical psychologist in the Paediatric Department, Division of Paediatric Pulmonology and Neonatology, Hannover Medical School, Germany

Van Biervliet S, Devos M, Delhaye T, Van Biervliet JP, Robberecht E, Christophe A. Oral DHA supplementation in DeltaF508 homozygous cystic fibrosis patients. Prostaglandins Leukotr Essent Fatty Acids 2008; 78:109-115. [PubMed]

Fig. 42 Stephanie Van Biervliet

The treatment group was supplemented with algal DHA-rich oil and the control group with sunflower seed oil. There was no difference between the control and treatment groups for W/H%, caloric intake, FEV1% and FVC% at the start of the study and after 1 year of supplements.So although DHA-rich oil shifted the serum phospholipid fatty acids to a less pro-inflammatory profile, no conclusive clinical improvement could be observed.

Stephanie Van Bioervliet (fig 42) is Professor at the CF Centre, Paediatric Gastroenterology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.

Visca A, Bishop CT, Hilton SC, Hudson VM. Improvement in clinical markers in CF patients using a reduced glutathione regimen: an uncontrolled, observational study. J Cyst Fibros 2008; 7:433-436). [PubMed]

Fig. 43 Alfredo Visca YouTube

The CFTR mutation, which causes cystic fibrosis (CF), has also recently been identified as causing glutathione system dysfunction and systemic deficiency of reduced glutathione (GSH). Such dysfunction and deficiency regarding GSH may contribute to the pathophysiology of CF.
Thirteen patients (age range 1-27 years) with CF who were using a regimen of reduced glutathione (GSH), including oral glutathione and inhaled buffered glutathione in an uncontrolled study, were followed in an observational study. Dosage ranged from 66-148 mg/kg/day in divided doses, and the term examined was the initial 5.5 months of GSH use (45 days of incrementally adjusted dose, plus 4 months of use at full dosage). Significant improvement in the following clinical parameters was observed: average improvement in FEV1 percent predicted (N=10) was 5.8 percentage points (p<0.0001), average weight percentile (N=13) increased 8.6 points (p<0.001), BMI percentile (N=11) improved on average 1.22 points (p<0.001. Positive sputum cultures of bacteria in 11 patients declined from 13 to 5 (p<0.03) with sputum cultures of Pseudomonas aeruginosa becoming negative in 4 of 5 patients previously culturing PA, including two of three patients chronically infected with PA as determined by antibody status.Use of a daily GSH regimen appears to be associated in CF patients with significant improvement in lung function and weight, and a significant decline in bacteria cultured in this uncontrolled study.

The authors of this study are convinced as to the value of glutathione and considered these findings warrant further clinical investigation in larger, randomized, controlled studies as has been suggested by protagonists of the use of glutathione Clark Bishop and Valerie Hudson. (see  Bishop et al, 2005 above for more detail).

Dr Alfredo Visca (fig. 43) s a Pediatric Pulmonologist, ASL Cuneo 1, Piedmont, Italy – CF Section.

Wainwright CE, Grimwood K, Carlin JB, Vidmar S, Cooper PJ, Francis PW, Byrnes CA, Whitehead BF, Martin AJ, Robertson IF, Cooper DM, Dakin CJ, Masters IB, Massie RJ, Robinson PJ, Ranganathan S, Armstrong DS, Patterson LK, Robertson CF. Safety of bronchoalveolar lavage in young children with cystic fibrosis. Pediatr Pulmonol 2008; 43:965-972. [PubMed]

Fig. 44. Claire Wainwright author’s photo

As part of Dr Claire Wainwright’s study of bronchoalveolar lavage (BAL) directed therapy, 333 BALs were carried out on 107 children median age 23.5 months (1.6 – 67.5 months); 170 (51%) were for exacerbations. 8.7% were followed by fever and 3% clinically significant episodes. 52% had minor adverse events.
The authors concluded that although adverse events were common they were usually transient and well tolerated. Parents should be warned that infants with respiratory infections had an increased risk of post-BAL fever. This is an important ongoing study further progress of which was reported by Claire Wainwright at the 2009 NACFC in Minneapolis. The study concluded in 2009 and although was a source of vast and important information, did not establish a case of managing the respiratory infections using regular bronchoscopies – undoubtedly one of the major studies of the decade. (Wainwright CE et al. JAMA 2011; 306:163-171. [PubMed] below).

Professor Claire Wainwright (fig. 44) is a paediatric respiratory physician and head of CF services at the Royal Children’s Hospital, Brisbane, Australia. She started her medical and paediatric training in London and completed her training in paediatric respiratory medicine and doctoral studies at the Royal Children’s Hospitals in Brisbane and Melbourne. Her research interests include early lung disease, airway microbiology, metabolic problems and patient-reported outcomes in CF, and management of bronchiolitis and asthma.

Wallace HL. Connell MG. Losty PD. Jesudason EC. Southern KW. Embryonic lung growth is normal in a cftr-knockout mouse model. Exp Lung Res 2008; 34:717-727. [PubMed]

Fig. 45 Helen Wallace. ed.ac.uk

The role of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel in embryonic lung growth remains uncertain. The authors used an established embryonic lung culture model to investigate the impact of cftr knockout on lung growth, airway peristalsis, and airway smooth muscle (ASM) distribution. Lung area, perimeter, lung bud count, and frequency of contraction were similar in wild-type (cftr +/+) and cftr knockout mice (cftr -/-). The percentage of mitotic cells was also consistent between genotypes in mesenchyme and epithelium. Smooth muscle distribution surrounding

Zhou J, Garber E, Saiman L. Survey of infection control policies for patients with cystic fibrosis in the United States. Am J Infect Contr 2008; 36:220-222. [PubMed]
Written infection control policies used at CF care sites in the United States were compared with recently published guidelines (Saiman et al, 2003). Most policies recommended contact precautions for hospitalized patients infected with Burkholderia cepacia complex (73%), multidrug-resistant organisms (63%), and methicillin-resistant Staphylococcus aureus (64%). Socializing among CF patients was discouraged in 80% of inpatient policies and 55% of outpatient policies. Although routine mask use by patients remains an unresolved issue, many policies advocated this practice. Future studies should address barriers to implementation of these evidence-based guidelines and continue to monitor implementation. That contact precautions were only recommended in 73% of centres even with B. cepacia is rather surprising one would have expected 100%. Permitting contact between people with B. cepacia in a CF centre would raise serious issues in the UK.

Dr Juan Zhou is in the Department of Pediatrics, Columbia University, New York, NY 10032, USA.