The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

Aitken ML, Bellon GT, De Boeck K, Flume PA, Fox HG, Geller DE, Haarman EG, Hebestreit HU, Lapey A, Schou IM, Zuckerman JB, Charlton B. CF302 Investigators. Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study.
Am J Respir Crit Care 2012; 185:645-652.
[PubMed]
A study to determine whether long-term treatment with inhaled mannitol improves lung function and morbidity. This was a double-blind, randomized, controlled trial of inhaled mannitol, 400 mg twice a day (n = 192, "treated" group) or 50 mg twice a day (n = 126, "control" group) for 26 weeks, followed by 26 weeks of open-label treatment. The primary endpoint was absolute change in FEV(1) from baseline in treated versus control groups, averaged over the study period.

The treated group had a mean improvement in FEV(1) of 105 ml (8.2% above baseline). The treated group had a relative improvement in FEV(1) of 3.75% (P = 0.029) versus the control group. Adverse events and sputum microbiology were similar in both treatment groups. Exacerbation rates were low, but there were fewer in the treated group, although this was not statistically significant. In the 26-week open-label extension study, FEV(1) was maintained in the original treated group, and improved in the original control group to the same degree.

The authors concluded inhaled mannitol, 400 mg twice a day, resulted in improved lung function over 26 weeks, which was sustained after an additional 26 weeks of treatment. The safety profile was also acceptable, demonstrating the potential role for this chronic therapy for CF.

 

Although the beneficial effects in the treated group were relatively modest this is one of the important new mucolytic treatments developed over the past decade which is now available for use by patients . See also Bilton D et al. Eur Respir J 2011; 38:1071-1080. [PubMed] and the early work by Robinson M et al. Eur Respir J 1999; 14:678-685.[PubMed].

 

 

Moira Aitken

Fig. 3: Moira Aitken.From www.depts.washington.edu/pulmcc/
Professor Moira Aitken (figure 3) is Professor in the Division of Pulmonary and Critical Care at the University of Washington Medical Center. She states that her overall objectives are to understand the mechanisms of airway inflammation and infection in cystic fibrosis. She is also involved in Phase I and II clinical trials and in epidemiological studies of CF.

 

Balaguer A, Gonzalez de Dios J. Home versus hospital intravenous antibiotic therapy for cystic fibrosis. Update of Cochrane Database Syst Rev. 2008;(3):CD001917; PMID: Cochrane Database of Systematic Reviews. 3:CD001917, 2012. [PubMed]
To determine whether home intravenous antibiotic therapy in cystic fibrosis is as effective as inpatient intravenous antibiotic therapy and if it is preferred by individuals or families or both. Although 18 studies were identified by the searches, only one study was included. So current evidence is restricted to a single randomized clinical trial. It suggests that, in the short term, home therapy does not harm individuals, entails fewer investigations, reduces social disruptions and can be cost-effective. There were both advantages and disadvantages in terms of quality of life. The authors suggested that the decision to attempt home treatment should be based on the individual situation and appropriate local resources. The authors concluded that more research was urgently required.

 

It is interesting that these reviewers (neither of whom appear to have published any other papers on cystic fibrosis) considered only one study comparing home and hospital intravenous antibiotic treatment to be acceptable when there have been numerous studies reporting experience since the mid-eighties - yet they rejected the information contained in seventeen such reports! It seems both the researchers who designed these rejected studies and the editors who accepted them for publication should examine their standards!! The present reviewers' suggestion that the decision to undertake home intravenous antibiotic treatment should be based on "the individual situation and appropriate local resources" is obviously the answer. The decision whether to use home IVs will obviously depend on the local resources available, the advice of the CF team and the patient's wishes. It would appear to this reviewer that there are now more pressing research questions to be answere

 

Belessis Y, Dixon B, Hawkins G, Pereira J, Peat J, Macdonald R, Field P, Numa A, Morton J, Lui K, Jaffe A. Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index. Am J Resp Crit Care 2012; 185:862-873. [PubMed]
A study to determine whether the lung clearance index (LCI) is a sensitive and repeatable noninvasive measure of airway infection and inflammation in newborn-screened children with CF.  Forty-seven well children with CF (mean age, 1.55 yr) and 25 healthy children (mean age, 1.26 yr) underwent multiple-breath washout testing. LCI within and between-test variability was assessed. Children with CF also had surveillance bronchoalveolar lavage performed. The LCI correlated with bronchoalveolar lavage IL-8 (R(2) = 0.20, P = 0.004) and neutrophil count (R(2) = 0.21, P = 0.001). An LCI below the upper limit of normality had a high negative predictive value (93%) in excluding Pseudomonas.

margin-top: 0;">The authors of this study from Sydney concluded that the LCI is elevated (abnormal) early in children with CF, especially in the presence of Pseudomonas and airway inflammation. The results support their suggestion that LCI is a feasible, repeatable, and sensitive noninvasive marker of lung disease in young children with CF. The lung clearance index seems to be emerging as practical and accurate measure of airway function particularly useful in very young patients.
Fig.4: Yvonne Belessis. From www.researchgate.net

Dr Yvonne Belessis (figure 4) is a Paediatric Respiratory Consultant at the Sydney Children's Hospital and Director of the Flexible Bronchosopy Service.

 

 

Bruni T, Mameli M, Boniolo G. Cystic fibrosis carrier screening in Veneto (Italy): an ethical analysis.  Med Health Care Philos. 2012 Aug;15(3):321-8. doi: 10.1007/s11019-011-9347-7.

[PubMed]

 

Cardines R, Giufre M, Pompilio A, Fiscarelli E, Ricciotti G, Bonaventura GD, Cerquetti M. Haemophilus influenzae in children with cystic fibrosis: antimicrobial susceptibility, molecular epidemiology, distribution of adhesins and biofilm formation.
Int J Med Microbiol 2012; 302:45-52.
[PubMed]
Haemophilus influenzae commonly infects the respiratory tract of patients with cystic fibrosis (CF), early in childhood. In this investigation, 79 H. influenzae isolates were recovered from the respiratory secretions of 64 CF patients (median age: 5 years) included in a 5-year follow-up study. Fifteen of the 64 patients contributed two or more H. influenzae isolates overtime. Serotyping, antibiotic susceptibility testing, genotyping, detection of both hmwA and hia adhesin genes and hypermutable strains was carried out. Biofilm formation ability was investigated.

Most strains (72/79, 91.2%) were nonencapsulated or nontypeable (NTHi). Resistance to ampicillin (13.9%) and imipenem (17.7%) was the most detected. Few isolates (2.5%) exhibited the hypermutable phenotype. The NTHi strains showed 55 different genotypes, but 19 clusters of closely related strains were identified. Nine clusters included strains that cross-colonised several patients over a long-time period (mean: 3.7 years). Most patients with sequential isolates harboured strains genetically unrelated, but persistent colonisation with the same clone was observed in 37.5% of patients. Over 45% of NTHi strains contained hmwA-related sequences, 26.3%, hia, 8.3% both hmwA and hia, while 19.4% lacked both. A significant association was found between occurrence of an adhesive gene (irrespective of which) and both persistence (P<0.0001) and long-term cross-colonisation (P<0.0001). Mean biofilm level formed by the persistent strains was found significantly increased compared to non-persistent ones (P<0.0001). Hia-positive strains produced significantly more biofilm than hmwA-carrying strains (P<0.01). Although a high turnover of NTHi strains in FC patients was observed, distinct clones with increased capacity of persistence or cross-colonisation occurred.

 

This is a timely study for H. influenzae has not received the same attention and respect as P. aeruginosa from clinicians, yet there are patients in whom the organism reappears on numerous occasions and from whom it is obviously not eradicated after only a short course of antibiotics even though the initial post treatment cultures are negative. Any evidence that the organism is recurring should be dealt with by more aggressive treatment - even including a course of intravenous antibiotics and more long term oral antibiotic treatment.

 

Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW, De Boeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR, Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Roseluth DB, Rubenstein RC, Schechter MS, Botfield M, Ordonez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K, Konstan MW. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.
Thorax 2012; 67:12-18.
[PubMed]
VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. This randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.

The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups.

There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.


The authors concluded that VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit.

 

Dowman JK, Watson D, Loganathan S, Gunson BK, Hodson J, Mirza DF, Clarke J, Lloyd C, Honeybourne D, Whitehouse JL, Nash EF, Kelly D, van Mourik I, Newsome PN. Long-term impact of liver transplantation on respiratory function and nutritional status in children and adults with cystic fibrosis. Am J Transplant 2012; 12:954-964. [PubMed]
Early liver transplant (LT) has been advocated for patients with cystic fibrosis liver disease (CFLD) and evidence of deterioration in nutritional state and respiratory function to prevent further decline. A retrospective analysis of the outcomes of 40 (21 adult/19 pediatric) patients with CFLD transplanted between 1987 and 2009 with median follow-up of 47.8 months (range 4-180) is reported. One and five-year actuarial survival rates were 85%/64% for adult and 90%/85% for pediatric LT cohorts, respectively. Lung function remained stable until 4 years (FEV(1) % predicted; pretransplant 48.4% vs. 45.9%, 4 years post transplant) but declined by 5 years (42.4%). Up to 4 years post transplant mean annual decline in FEV(1) % was lower (0.74%; p = 0.04) compared with the predicted 3% annual decline in CF patients with co-morbidities including diabetes. Number of courses of intravenous antibiotics was reduced following LT, from 3.9/year pre transplant to 1.1/year, 5 years post transplant. Body mass index was preserved post transplant; 18.0 kg/m(2) (range 15-24.3) pre transplant versus 19.6 kg/m(2) (range 16.4-22.7) 5 years post transplant.

Fig. 4a: David Honeybourne

From www.spirehealthcare.com/

The authors concluded liver transplantation to be an effective treatment for selected patients with cirrhosis due to CFLD, stabilizing aspects of long-term lung function and preserving nutritional status. A substantial number of these patients did well after liver transplantation with good survival rates, stable lung function and a slowing of FEV1 decline. Also there were nutritional benefits. Although clinicians have observed such benefits in individual patients since the first liver transplants in people with CF were reported (Mieles LA et al. Lancet 1989:i:1073. above) it is good to have the benefits of such a major procedure confirmed in a relatively large series.


Dr David Honeybourne (figure 4a) is a consultant respiratory physician in Birmingham and until recently Director of the Regional Adult Cystic Fibrosis Unit at the Heartlands Hospital. He has published extensively on a variety of respiratory conditions and, particularly in recent years, on cystic fibrosis.

 

Döring G, Flume P, Heijerman H, Elborn JS,: for the Consensus Study Group. Treatment of lung infection in patients with cystic fibrosis: Current and future strategies.  J Cyst Fibros  2012; 11:461-479. [PubMed]

This group discusses the present status of antibiotic therapy for the major pathogens in CF airways and outline measures to optimize maintenance treatment for infection in the light of novel antibiotic drug formulations. They also discuss new developments in culture-independent microbiological diagnostic techniques and the use of tools for monitoring the success of antibiotic treatment courses. Finally, cost-effectiveness analyses for antibiotic treatment in CF patients are discussed.

An extremely useful well referenced review. It is disappointing that S. aureus is dealt with so briefly and that the case against antibiotic prophylaxis relies on the 2002 paper of Stutman et al (above), particularly as so many people with CF are still allowed to become chronically infected with this damaging pathogen. For example from the CF Foundation Patient Registry 2011 over half the patients were infected by S. aureus even from early childhood. Also S. aureus is frequently isolated from an early age in bronchoscopy specimens in very young infants diagnosed after neonatal screening.

 

Doull I, Evans H. South and Mid Wales Paediatric Cystic Fibrosis Network. Full, shared and hybrid paediatric care for cystic fibrosis in South and Mid Wales. Arch Dis Child 2012; 97:17-20. [PubMed]
Although care for children with cystic fibrosis is increasingly shared between CF centres and local CF clinics, the optimal model is unclear. The authors compared three models of care within the well established CF network in Wales: full centre care; local clinic based care with annual review by the CF centre; and hybrid care, where the child is usually reviewed at least three times a year by the specialist CF centre.

Of 199 children and young people with CF in South and Mid-Wales, 77 were receiving full care, 102 shared care and 20 hybrid care. There were no significant differences in baseline characteristics, nutritional outcomes or use of chronic therapies. There was however a statistically significant difference between full, shared and hybrid care in mean forced expiratory volume in 1 s (FEV(1)) per cent predicted (89.2% vs 74.5% vs 88.9%; p=0.001).

These differences in pulmonary function are likely to reflect the model of care received, and may affect long term outcomes.

 

Although this important study shows an advantage for children who received all their care at the Wales CF Centre in Cardiff, the results were not accepted by all Iolo Doull's colleagues in Wales and drew a vigorous response from paediatricians working in two of the local CF clinics involved - in Newport (Bowler I, Pierrepoint M, Evans R. Arch Dis Child 2012; 97:88) and Lanarkshire (Dryden C et al. Arch Dis Child 2012; 97: 88-89). So the discussion continues in the UK as to whether CF centre care is superior to care shared between a CF Centre and a local hospital clinic.

 

Griesenbach U, Alton EW. Progress in gene and cell therapy for cystic fibrosis lung disease.  Curr Pharm Design 2012; 18:642-62, 2012. [PubMed]
Although the development of gene therapy for cystic fibrosis (CF) was high priority for many groups in academia and industry in the first 10 to 15 years after cloning the gene, more recently active research into CF gene therapy is only being performed by a small number of committed, mainly academic, groups. However, despite the waning enthusiasm, which is largely due to the realisation that gene transfer into lungs is more difficult than originally thought and the fact that meaningful clinical trials are expensive and difficult to perform, gene therapy continues to hold promise for the treatment of CF lung disease. Problems related to repeat administration of adenovirus and adeno-associated virus-based vectors led to a focus on non-viral vectors in clinical trials.

 

The UK CF Gene Therapy Consortium is currently running (2013-2014) the only active gene therapy programme, aimed at assessing if repeated administration of a non-viral gene transfer agent can improve CF lung disease. However, the recent suggestion that lentiviral vectors may be able to evade the immune system and, thereby, allow for repeat administration and long lasting expression opens new doors for the use of viral vectors in the context of CF gene therapy.

In addition, early pre-clinical studies have recently been initiated to address cell therapy-based approaches for CF. This involves systemic and topical administration of a variety of stem/progenitor cells, as well as first attempts as producing a tissue-engineered lung. Recent studies in viral and non-viral vector developments, as well as cell therapy will be discussed and an update on clinical gene therapy studies will be provided here.


An up to date review of the present situation regarding gene therapy by Uta Griesenbach and Eric Alton of the UK Gene Therapy Consortium who embarked on a multidose trial of gene therapy in 2012.

 

Prof. Alton reports in late 2013 that the full complement of 120 patients has been recruited and approximately half have received all 12 doses of gene therapy or placebo given at monthly intervals. The final dose in the final patient is due in June 2014 and it is hoped to present the findings at the NACF Conference in October 2014.

 

Develpment of a new Wave 2 viral delivery method is already well advanced in development and seems to be more effective in delivering the gene.
Personal photo
Fig. 5: Uta Griesenbach. From www.imperial.ac.uk
Janet Stocks
Fig. 6: Janet Stocks. From www.ebpom.org
Dr Uta Griesenbach (figure 5) is Reader in Molecular Medicine at the National Heart and Lung Institute. Since 1997 her research has focused on gene therapy for cystic fibrosis and she a leading member of the UK Gene Therapy Consortium. Dr Griesenbach is a member of the Consortium strategy group (total of 8 people from 3 sites) who direct research and finances for the Consortium.

 

Griffiths AL, Wurzel DF, Robinson PJ, Carzino R, Massie J. Australian epidemic strain Pseudomonas (AES-1) declines further in a cohort segregated cystic fibrosis clinic. J Cyst Fibros 2012; 11:49-52. [PubMed]
To evaluate changes in prevalence of an epidemic strain of Pseudomonas aeruginosa (AES-1, Australian epidemic strain, type 1) in a paediatric CF centre practising cohort segregation, to describe the patients' clinical characteristics at acquisition and observe mortality rates.

Cohort segregation was introduced in the paediatric CF clinic January 2000. The prevalence of AES-1 declined significantly from 21% in 1999 to 14% in 2002 and to 6% in 2007. New acquisitions after the introduction of cohort segregation were uncommon (10 by 2002 and another 7 by 2007) with a declining incidence of 3.3 cases/year (1999 to 2002) compared to 1.4 cases/year (2002 to 2007). Twenty-two of 32 (69%) deaths between 1999 and 2007 occurred in patients infected with AES-1.

The authors concluded that cohort segregation has been associated with reductions in the prevalence of AES-1 in their CF clinic. Mortality was higher in patients infected with AES-1 than other organisms.

 

The effects of this Australian epidemic strain of P. aeruginosa have been reported previously and although segregation has significantly reduced the numbers who were infected, the effects have been serious during the decade (Griffiths AL et al. Am J Resp Crit Care 2005; 171:1020-1025.[PubMed]).

 

2012 Gustafsson JK, Ermund A, Ambort D, Johansson ME, Nilsson HE, Thorell K, Hebert H, Sjövall H, Hansson GC. Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J Exp Med 2012;209(7):1263-72. [PubMed])

Cystic fibrosis (CF) is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator [CFTR]), but the link to the phenomenon of stagnant mucus is not well understood. Mice lacking functional CFTR (CftrΔ508) have no lung phenotype but show similar ileal problems to humans. We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM). In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties. This knowledge may provide novel therapeutic options for CF.

 

Fig 6a: Gunnar C Hansson

Professor Gunnar Hansson (figure 6a) is joint leader of the very active University of Gothenburg Mucin Biology Group. Amongst the numerous basic scientific publications from the group there are some relating to CF such as the one abstracted above.

 

Haidopoulou K, Lum S, Turcu S, Guinard C, Aurora P, Stocks J, Sonnappa S. Alveolar LCI vs. standard LCI in detecting early CF lung disease. Respir Physiol Neurobiol 2012; 180:247-251. [PubMed]
Multiple breath washout (MBW) is a sensitive technique that detects early airways disease. However in very young children, large equipment and physiological dead space relative to lung volumes may result in a higher Lung Clearance Index (LCI).

The authors investigated whether alveolar LCI (aLCI) is a more sensitive index than standard LCI in children.

The authors concluded that LCI is minimally affected by airway deadspace, or relative equipment deadspace, and is an appropriate measure of lung function in infancy.

Further evidence supporting the use of lung clearance index in young children.

 

Professor Janet Stocks (figure 6) is Professor of Respiratory Physiology and Head of the Portex Unit at the Institute of Child Health, London.  Professor Stocks has published widely on the development and validation of tests for assessing lung function in infants and young children and many other areas relating to respiratory function in infants and children with cystic fibrosis.

 

Hoo AF, Thai LP, Nguyen TT, Bush A, Chudleigh J, Lum S, et al. London Cystic Fibrosis Collaboration. Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening. Thorax 2012; 67:874-881. [PubMed](http://dx.doi.org/10.1136/thoraxjnl-2012-201747 for full text)
Long-term benefits of newborn screening (NBS) for cystic fibrosis (CF) have been established with respect to nutritional status, but effects on pulmonary health remain unclear. Lung clearance index (LCI) and functional residual capacity (FRC) using multiple breath washout (MBW), plethysmographic (pleth) FRC and forced expirations from raised lung volumes were measured in 71 infants with CF (participants in the London CF Collaboration) and 54 contemporaneous healthy controls age ∼3 months.

Compared with controls, and after adjustment for body size and age, LCI, FRC(MBW) and FRC(pleth) were significantly higher in infants with CF (mean difference (95% CI): 0.5 (0.1 to 0.9), p=0.02; 0.4 (0.1 to 0.7), p=0.02 and 0.9 (0.4 to 1.3), p<0.001, z-scores, respectively), while forced expiratory volume (FEV(0.5)) and flows (FEF(25-75)) were significantly lower (-0.9 (-1.3 to -0.6), p<0.001 and -0.7 (-1.1 to -0.2), p=0.004, z-scores, respectively). 21% (15/70) of infants with CF had an elevated LCI (>1.96 z-scores) and 25% (17/68) an abnormally low FEV(0.5) (below -1.96 z-scores). While only eight infants with CF had abnormalities of LCI and FEV(0.5), using both techniques identified abnormalities in 35% (24/68). Hyperinflation (FRC(pleth) >1.96 z-scores) was identified in 18% (10/56) of infants with CF and was significantly correlated with diminished FEF(25-75) (r=-0.43, p<0.001) but not with LCI or FEV(0.5).

The authors concluded that despite early diagnosis of CF by NBS and protocol-driven treatment in specialist centres, abnormal lung function, with increased ventilation inhomogeneity and hyperinflation and diminished airway function, is evident in many infants with CF diagnosed through NBS by 3 months of age.

 

This is an important study from the UK’s leading paediatric respiratory group confirming that many screened CF infants already have abnormal lung function - 61% of the screened infants had had some respiratory symptoms (52% mild, 9% severe), 23% a positive cough swab and 73% had received antibiotics in addition to their routine prophylactic medication. With the exception of a significantly lower FEV 0.5 in those who had received additional antibiotics for symptoms or positive cough swab, there was no significant association between LF outcomes and the infant’s genotype, clinical status, growth trajectory or treatment prior to the LFTs at 3 months of age.

 

It is perhaps encouraging that many infants who had been treated aggressively for respiratory exacerbations in the first few months had entirely normal LF by 3 months, whereas others with no prior symptoms or cause for concern had evidence of early lung disease. So damage from very early infection is not inevitable but does support the view that early specialised management is absolutely essential to achieve the maximum benefit from newborn CF screening; also lends some support for the case for prophylactic anti staphylococcal antibiotics from diagnosis.

 

Konstan MW, Ratjen F. Effect of dornase alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis. J Cyst Fibros 2012; 11:78-83.[PubMed]
Observational studies indicate that dornase alfa is often reserved for "sicker" patients. A 2-year, early intervention study of dornase alfa in CF patients with early lung disease demonstrated significant improvements in lung function and risk of exacerbation compared to placebo. A more recent analysis, using the database of the large observational Epidemiologic Study of Cystic Fibrosis (ESCF), found that initiation of dornase alfa has the potential to alter the course of CF by decreasing the rate of lung function decline in children and adults.

These encouraging results, possibly linked to indirect effects on inflammation, suggest a greater role for dornase alfa therapy in the early treatment of CF, where it may help preserve lung function and potentially extend survival. Felix Ratjen and Michael Konstan review the compelling reasons for starting early Pulmozyme rather than waiting until the infection is more advanced. In fact many UK paediatricians are now starting Pulmozyme in very small children with CF as all studies of young infants either by respiratory function or bronchoscopy indicate of the very early onset of bronchial abnormalities. Presumably, as most clinicians do not have access to infant respiratory function tests, the response is judged by clinical signs - often by a reduction in wheezing or cough.

 

Lang G, Taghavi S, Aigner C, Renyi-Vamos F, Jaksch P, Augustin V, Nagayama K, Ghanim B, Klepetko W. Primary lung transplantation after bridge with extracorporeal membrane oxygenation: a plea for a shift in our paradigms for indications.
Transplantation. 2012; 93:729-736.
[PubMed]
The authors reviewed their institutional experience with extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (LTX). Between 1998 and 2011, 38 patients (median age 30.1 years, range 13-66 years) underwent ECMO support with intention to bridge to primary LTX. The authors concluded that transplantation of patients bridged on ECMO to LTX is feasible and results in acceptable outcome.


Lindberg MF1, Carmoy N, Le Gall T, Fraix A, Berchel M, Lorilleux C, Couthon-Gourvès H, Bellaud P, Fautrel A, Jaffrès PA, Lehn P, Montier T. The gene transfection properties of a lipophosphoramidate derivative with two phytanyl chains.Biomaterials. 2012; 33(26):6240-53.[PubMed]

Cationic lipophosphoramidates constitute a class of cationic lipids we have already shown to be efficient for in vivo gene transfer. Herein, we report the synthesis of a cationic lipophosphoramidate bearing two phytanyl chains (BSV18) as hydrophobic domain, and studied its gene transfection properties. In vitro, BSV18 exhibited a high transfection efficacy associated with a low cytotoxicity. (31)P NMR studies of various cationic lipophosphoramidates in water solution suggested that the phytanyl chains may favor the formation of an inverted hexagonal phase, a supramolecular arrangement which is presumed to enhance the endosomal escape and consequently increase the transfection efficiency. In vivo, systemic delivery of BSV18-based lipoplexes allowed a high efficiency of gene transfection into the mouse lung. With a view to clinical application, we evaluated not only the efficiency of lung transfection but also the eventual in vivo side-effects. Thus, in addition to monitoring the in vivo transfection efficiency by bioluminescent imaging and identifying by immunohistochemistry the cell types transfected, we also assessed in living animals the potential liver reaction as well as the inflammatory and immune responses induced by BSV18-mediated transfection. All those adverse effects were actually highly transient. Thus, taken together, these results indicate that lipophosphoramidates equipped with two phytanyl chains may have great potential for lung gene therapy, in particular for Cystic Fibrosis.

Fig. 6a: Pierre Lehn

Professor Pierre Lehn (figure 6a) is a leading French scientist and researcher into various aspects of gene therapy. He has held various senior advisory positions in the charities relating to cystic fibrosis and muscular dystrophy. He is a member of the scientific advisory committe of the UK Gene Therapy Consortium and from 2009 President du Conseil Strategique de la Recherche de Vaincre La Mucoviscidose.

 

Lindig j, Steger C, Beierdorf N, Michl R, Beck JF, Hummel T, Mainz JG. Smell in cystic fibrosis. Eur Arch Otorhinolaryngol 2012; Aug 14.[PubMed]
An interesting study of smell in people with CF. Normosmia (a normal sense of smell) was found in 62.8% of healthy controls but only in 28.6% of people with cystic fibrosis. The importance of these findings to appetite and nutrition was stressed by the authors.

 

Martin B, Schechter MS, Jaffe A, Cooper P, Bell SC, Ranganathan S. Comparison of the US and Australian cystic fibrosis registries: the impact of newborn screening.
Pediatrics 2012; 129:e348-55.
[PubMed]
The authors compared the 2003 US and Australian registries. Data on 12994 US and 1220 Australian patients aged <=18 years were analyzed. A significant difference was noted in the proportion who had been diagnosed after newborn screening (Australian 65.8% vs United States 7.2%; P < .001). Australian children had significantly greater mean height percentile (41.0 vs 32.6; P < .001) and weight percentile (43.5 vs 36.1; P = .028) than US children. Mean forced expiratory volume in 1 second (FEV(1)) percent predicted adjusted for age, gender, and genotype was similar in the 2 countries (P = .80). Patients diagnosed after newborn screening had higher mean FEV(1) percent predicted (5.3 [95% confidence interval (CI): 3.6-7.0]) and BMI (0.26 [95% CI: 0.09-0.43]). Mean FEV(1) of Australian patients diagnosed after newborn screening was lower by 5.2 (95% CI: 2.8-7.6) percent predicted compared with US children.

 

The authors concluded that children diagnosed with CF after newborn screening benefited from better lung function and BMI than those diagnosed clinically. The benefit of newborn screening on lung function was significantly less in Australian children compared with US children. Statistical comparisons between CF registries are feasible and can contribute to benchmarking and improvements in care.

 

McEwan FA, Hodson ME, Simmonds NJ. The prevalence of "risky behaviour" in adults with cystic fibrosis. J Cyst Fibros 2012; 11:56-58. [PubMed]
The prevalence of "risky-behaviour" including alcohol and illicit drug use, smoking and unprotected sexual intercourse, of adults with cystic fibrosis (CF) is unknown. This is a prospective questionnaire-based study to further explore this issue.

The authors conclude that participation in risky behaviour was modest. With improved life expectancy this may increase. Awareness of this is important so that health promotion measures can be introduced early.

An interesting study from the world's largest Adult CF clinic at the Royal Brompton in London. Adults with CF seem to have the same degree of "risky habits" as the non-CF populations except, understandably, very few of them smoke.

 

Miroballi Y, Garber E, Jia H, Zhou JJ, Alba L, Quittell LM, Angst D, Cabana M, Saiman L. CF Infection control knowledge, attitudes, and practices among cystic fibrosis patients and their families. Infection Control Study Consortium. Pediatr Pulmonol 2012; 47:144-152. [PubMed].
In 2003, the Cystic Fibrosis (CF) Foundation in the United States published evidence-based infection control guidelines and distributed these to CF care centers. However, it is unclear how well the guidelines have been disseminated to patients and families, how well patients and families understand the principles of infection control, and what barriers they experience implementing the guidelines.

Overall, 65% of respondents were aware of the CF infection control guidelines, but only 30% had discussed them more than once with their CF care team. More than one discussion was associated with increased knowledge of infection control, including routes of pathogen transmission; the importance of avoiding close contact with other CF patients; increased confidence in practicing infection control; and increased belief in the health benefits of infection control.

The study revealed that 65% of CF patients and families are aware of the infection control guidelines, but that only 30% had discussed them more than once with their CF teams. The authors stress that their findings underscore the importance of engaging patients and their families in regular discussions about infection control that address questions and concerns including the potential impact of infection control on health and well-being. Further strategies are needed to overcome barriers to implementing these guidelines.

 

Munck A, Pesle A, Cunin-Roy C, Gerardin M, Ignace I, Delaisi B, Wood C. Recurrent abdominal pain in children with cystic fibrosis: a pilot prospective longitudinal evaluation of characteristics and management. J Cyst Fibros 2012; 11:46-48. [PubMed].
Children with cystic fibrosis commonly experience abdominal pain; however this remains poorly characterised. This prospective cross-sectional study with a longitudinal design, examined the prevalence, causes and effect of pain management via daily diaries, validated questionnaires for pain characteristics, anxiety status and quality of life.

One hundred and thirty CF patients aged 8 to 18 years, regularly followed at the centre, were questioned on recurrent abdominal pain. Eight patients fulfilled the criteria; all wished to enter the study. Pain management included behavioural intervention with effective pain relief, and had a positive impact on anxiety and quality of life.

 

This study is the first one to prospectively assess recurrent abdominal pain in CF. The authors documented a very low prevalence of 6% and suggest that, ruling out abdominal discomfort, only a minority of CF children presented recurrent abdominal pain with a true negative impact on daily life. They emphasise the need for further studies including larger cohorts.

The low prevalence of recurrent abdominal pain in this series from Paris is probably related to the first author's interest in gastrointestinal problems in CF and the management the patients receive in the clinic by a pediatrician with an interest in gastroenterology (Littlewood JM. Abdominal pain in cystic fibrosis. J R Soc Med 1995; 88 Suppl 25:9-17. [PubMed])

 

Mayer-Hamblett N, Kronmal RA, Gibson RL, Rosenfeld M, Retsch-Bogart G, Treggiari MM, Burns JL, Khan U, Ramsey BW. EPIC Investigators. Initial Pseudomonas aeruginosa treatment failure is associated with exacerbations in cystic fibrosis. Pediatr Pulmonol 2012; 47:125-134. [PubMed]
Study to determine if failure of antibiotic therapy to eradicate Pseudomonas aeruginosa (Pa) and frequency of Pa recurrence are associated with increased exacerbation risk. The cohort included 282 children with CF who participated in the EPIC trial ages 1-12 yrs with newly acquired Pa, defined as either a first lifetime Pa positive respiratory culture or positive after two years of negative cultures (past isolation of Pa but >2 years prior to the trial). All received antibiotics to promote initial eradication followed by 15 months of intermittent maintenance antibiotics. Quarterly cultures were used to define initial eradication success and subsequent number of Pa recurrences. A standardized symptom-based definition of exacerbation was utilized. Cox proportional hazards models were used to estimate exacerbation risk.

Failure to initially eradicate Pa was associated with exacerbation risk (hazard ratio [HR]: 2.49, 95% confidence interval [CI] 1.26, 4.93). In 245/282 with successful initial eradication during the trial, past isolation of Pa >2 years before the trial was the most significant predictor of exacerbation (HR 1.62, 95% CI 1.12, 2.35). In 37/282 who failed initial eradication, persistent Pa during the maintenance phase (1 or more Pa recurrences after failure to initially eradicate) added even greater exacerbation risk (HR 4.13, 95% CI 1.28, 13.32).

The authors concluded that children with CF who fail to eradicate after initial antibiotic treatment are at higher risk of subsequent exacerbation, suggesting clinical benefit to successful early eradication of Pa infection.

 

This is interesting, valuable data but of course quite predictable. It will be no surprise to many European clinicians who have been advising early eradication for the past 25 years! There has been increasing evidence that initial asymptomatic colonisation of the airways is followed by infection and a deterioration in a number of clinical parameters (Valerius et al, 1991). However, this is an important study to provide further hard data on such an important matter to encourage those clinicians responsible for care of children and adults with CF to eradicate P. aeruginosa even if this entails considerable and invasive treatment in patients who, at the time, have no complaints.

 

Dr Nicole Mayer-Hamblett (figure 7) is a biostatistician and research associate professor in Seattle Children's Hospital. She is Co-Director of Biostatistics at the Cystic Fibrosis Therapeutics Development network Coordinating Center. She is involved design and analysis of clinical trials and in the development of new outcome measures for CF in particular the validation of biomarkers to enable early evaluation of new therapies.

Fig. 7: Nicole Mayer-Hamblett. From www.seattlechildrens.org

 

Fig.8: Stephen Stick

www.health.wa.gov.au/

Fig. 9: Colin Robertson

 

Mott LS, Park J, Murray CP, Gangell CL, de Klerk NH, Robinson PJ, Robertson CF, Ranganathan SC, Sly PD, Stick SM. AREST CF. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 2012; 67:509-516. [PubMed]

To determine whether early CF structural lung disease, detected by limited slice CT scans, persists and progresses over 1 year the authors studied 143 children aged 0.2-6.5 years with CF from a newborn screened population. They found that once detected, bronchiectasis persisted in 98/133 paired scans (74%) and air trapping in 178/220 (81%). The extent of bronchiectasis increased in 139/227 (63%) of paired scans and air trapping in 121/264 (47%); progression was associated with severe CFTR genotype, worsening neutrophilic inflammation and pulmonary infection.

The authors concluded that early intervention is required to prevent or arrest the progression of structural lung disease in young children with CF.

Further evidence to show that there is early onset and progression of lung disease even in screened infants indicating this is an area which requires attention and treatment, more likely to be available at a specialist CF centre. There is no indication as to the treatment these infnts were receiving - for example prophylactic antistaphyloccal antibiotics?

 

Professor Stephen Stick (figure 8) graduated from Cambridge University and completed his paediatric training in the UK before moving to the Department of Respiratory Medicine at the Princess Margaret Hospital Perth in 1987, becoming head of the department in 1998. He is Clinical Professor in the School of Paediatrics and Child Health in the University of Western Australia.

 

Professor Colin Robertson (figure 9) is Chief of Medicine , Respiratory and Sleep Physician at the Royal Children's Hospital Melbourne. Afvter graduating in 1974 he trained in paedaitric sand respiratory medicine in Adelaide, Kings College Hospital LOndon and the Hospital for Sick Children Toronto.  He has published on a wide variety of paediatric respiratory topics involving epidemiology, physiology, cystic fibrosis and trials of clinical management

 

Mohd Hafiz AA, Staatz CE, Kirkpatrick CM, Lipman J, Roberts JA. Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics. [Review] Minerva Anestesiol 2012; 78:94-104. [PubMed]
The authors elected to systematically investigate the published literature describing the comparative pharmacokinetic/pharmacodynamic (PK/PD) and clinical outcomes of beta-lactam antibiotics administered by continuous or intermittent infusion. They found that the studies have been performed in various patient populations including critically ill, cancer and cystic fibrosis patients. Available in vitro PK/PD data conclusively support the administration of beta-lactams via continuous infusion for maximizing bacterial killing from consistent attainment of pharmacodynamic end-points. In addition, clinical outcome data supports equivalence, even with the use of a lower dose by continuous infusion. However, the present clinical data is limited with small sample sizes common with insufficient power to detect advantages in favour of either dosing strategy.The authors suggest that with abundant positive pre-clinical data as well as documented in vivo PK/PD advantages, large multi-centre trials are needed to describe whether continuous administration of beta-lactams is truly more effective than intermittent dosing.

 

There is increasing evidence that beta-lactam antibiotics are more effective when given as a constant infusion rather than the intermittent dosing widely practised in most clinics. This is particularly important when using the drug as part of optimal intravenous antibiotic therapy when inhaled and oral treatment has failed to eradicate early P. aeruginosa.

 

O'Clock GD, Lee YW, Lee J, Warwick WJ. High-frequency and low-frequency chest compression: effects on lung water secretion, mucus transport, heart rate, and blood pressure using a trapezoidal source pressure waveform. IEEE Transactions on Biomedical Engineering 2012; 59:106-114. [PubMed]
High-frequency chest compression (HFCC), using an appropriate source (pump) waveform for frequencies at or above 3 Hz, can enhance pulmonary clearance for patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Using a trapezoidal HFCC source pressure waveform, secretion of water from epithelial tissue and transport of mucus through lung airways can be enhanced for patients with CF and COPD. At frequencies below 3 Hz, low-frequency chest compression (LFCC) appears to have a significant impact on the cardiovascular system. For a trapezoidal source pressure waveform at frequencies close to 1 Hz, LFCC produces amplitude or intensity variations in various components of the electrocardiogram time-domain waveform, produces changes at very low frequencies associated with the electrocardiogram frequency spectra (indicating enhanced parasympathetic nervous system activity), and promotes a form of heart rate synchronization. It appears that LFCC can also provide additional cardiovascular benefits by reducing peak and average systolic and diastolic blood pressure for patients with hypertension.

 

The latest publication from Warren Warwick and colleagues. High frequency chest compression which Warren described in the earl Nineties has been validated in a number of studies and is now widely used particularly in the USA. Now here is evidence of additional cardiovascular effects.

 

Pezzulo AA, Tang XX, Hoegger MJ, Alaiwa MH, Ramachandran S, Moninger TO, Karp PH, Wohlford-Lenane CL, Haagsman HP, van Eijk M, Bánfi B, Horswill AR, Stoltz DA, McCray PB Jr, Welsh MJ, Zabner J. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature. 2012; 487(7405):109-13. [PubMed]

The authors found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO(3)(-) transport. Without CFTR, airway epithelial HCO(3)(-) secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. They suggest that these findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions.

Fig. 9a: Alejandro Pezzulo

Dr Alejandro Pezzulo is on the staff of University of Iowa Carver College of Medicine and has published extensively on various aspects of cystic fibrosis both clinical and laboratory research and on CF animal models - particulalry many studies relating to CF pigs.

 

 

Pezzulo AA, Stoltz DA, Hornick DB, Durairaj L. Inhaled hypertonic saline in adults hospitalised for exacerbation of cystic fibrosis lung disease: a retrospective study.
BMJ Open. 2012; 2(2):e000407.
[PubMed]
The authors examined the tolerability and efficacy of hypertonic saline (HTS) use among adult subjects hospitalised with a CF pulmonary exacerbation in a pilot retrospective non-randomised study. They found that that HTS is well tolerated during treatment of a CF pulmonary exacerbation but offers no clear outcome benefits.

 

Although the design of this study would be unacceptable to Cochrane reviewers it is quite useful information showing that, in the experience of these authors, the addition of HTS to their usual treatment regimen for treating pulmonary exacerbations was not helpful - although clinicians may wish try the addition of HTS for individual patients where progress was less than expected.

 

Pittman JE, Johnson RC, Davis SD. Improvement in pulmonary function following antibiotics in infants with cystic fibrosis. Pediatr Pulmonol 2012; 47:441-446. [PubMed]
Pre- and post-antibiotics pulmonary function test (PFT) data was available on 11 infants with CF, with a mean age of 102 weeks at the time of the first PFT. The majority of infants were symptomatic prior to antibiotics, and showed statistically significant improvement in clinical parameters following treatment. Prior to antibiotics, PFTs showed evidence of substantial obstructive disease. Following antibiotics, all of the parameters showed statistically significant improvement.

 

The authors have shown a statistically significant improvement in infant PFT measures following antibiotic therapy in a cohort of 11 infants with CF, which paralleled improvement in clinical parameters. However, alhough infant PFTs showed improvement, it is not unexpected that they remained abnormal in the majority of subjects, with persistent air-trapping and hyperinflation after antibiotic therapy.

So these findings suggest that infant PFTs are sensitive to acute clinical changes in children with CF, and may be a useful tool in managing infants with CF.  Although these findings are to be expected the increasing use of more accurate objective measurement in young CF infants is an important advance, particularly as the emphasis is increasingly on very early intervention with treatment such as antibiotics, rhDNase, hypertonic saline and even the more specific drugs. Once again it is evident that a significant proportion of these CF infants already had changes in their respiratory function, which persisted after antibiotic therapy.

 

Register KB, Sukumar N, Palavecino EL, Rubin BK, Deora R. Bordetella bronchiseptica in a Paediatric Cystic Fibrosis Patient: Possible Transmission from a Household Cat. Zoonoses & Public Health 2012: 59:246-250. [PubMed]
Bordetella bronchiseptica is a zoonotic respiratory pathogen commonly found in domesticated farm and companion animals, including dogs and cats. This report concerns the isolation of B.bronchiseptica from a sputum sample of a cystic fibrosis patient recently exposed to a kitten with an acute respiratory illness. Genetic characterization of the isolate and comparison with other isolates of human or feline origin strongly suggest that the kitten was the source of infection.

Domestic pets seem to be increasingly identified as a source of respiratory infection for people with CF. This is a new one!

 

Rosenfeld M, Ratjen F, Brumback L, Daniel S, Rowbotham R, McNamara S, Johnson R, Kronmal R Davies SD; ISIS Study Group Collaborators (80). Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA 2012; 307:2269-77. [PubMed]

A trial to determine if hypertonic saline reduces the rate of protocol-defined pulmonary exacerbations in patients younger than 6 years with CF.  The Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS), a multicenter, randomized, double-blind, placebo-controlled trial conducted from April 2009 to October 2011 at 30 CF care centers in the United States and Canada. Participants were aged 4 to 60 months and had an established diagnosis of CF. A total of 344 patients were assessed for eligibility; 321 participants were randomized; 29 (9%) withdrew prematurely. The active treatment group (n = 158) received 7% hypertonic saline and the control group (n = 163) received 0.9% isotonic saline, nebulized twice daily for 48 weeks. Both groups received albuterol or levalbuterol prior to each study drug dose.   Comparison of the rate, during the 48-week treatment period, of protocol-defined pulmonary exacerbations treated with oral, inhaled, or intravenous antibiotics.

 

The mean pulmonary exacerbation rate (events per person-year) was 2.3 (95% CI, 2.0-2.5) in the active treatment group and 2.3 (95% CI, 2.1-2.6) in the control group; the adjusted rate ratio was 0.98 (95% CI, 0.84-1.15). Among participants with pulmonary exacerbations, the mean number of total antibiotic treatment days for a pulmonary exacerbation was 60 (95% CI, 49-70) in the active treatment group and 52 (95% CI, 43-61) in the control group. There was no significant difference in secondary end points including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores.

Infant pulmonary function testing performed as an exploratory outcome in a subgroup (n = 73, with acceptable measurements at 2 visits in 45 participants) did not demonstrate significant differences between groups except for the mean change in forced expiratory volume in 0.5 seconds, which was 38 mL (95% CI, 1-76) greater in the active treatment group. Adherence determined by returned study drug ampoules was at least 75% in each group. Adverse event profiles were also similar, with the most common adverse event of moderate or severe severity in each group being cough (39% of active treatment group, 38% of control group).

 

The authors concluded that among infants and children younger than 6 years with cystic fibrosis, the use of inhaled hypertonic saline compared with isotonic saline did not reduce the rate of pulmonary exacerbations over the course of 48 weeks of treatment.

 

Although this study failed to show a signifcant treatment effect, a subsequent study showed lung clearance index in young children was significantly improved by hypertonic saline.  (Subbarao P et al. Am J Respir Crit Care Med. 2013;188:456-60. [PubMed] see abstract below).

 

Rowe SM, Borowitz DS, Burns JL, Clancy JP, Donaldson SH, Retsch-Bogart G, Sagel SD, Ramsey BW. Progress in cystic fibrosis and the CF Therapeutics Development Network. Thorax 2012; 67:882-890.[PubMed] Full text available

Cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians, affects approximately 70 000 individuals worldwide. In 1998, the Cystic Fibrosis Foundation (CFF) launched the CF Therapeutics Development Network (CF-TDN) as a central element of its Therapeutics Development Programme. Designed to accelerate the clinical evaluation of new therapies needed to fulfil the CFF mission to control and cure CF, the CF-TDN has conducted 75 clinical trials since its inception, and has contributed to studies as varied as initial safety and proof of concept trials to pivotal programmes required for regulatory approval.

This review highlights recent and significant research efforts of the CF-TDN, including a summary of contributions to studies involving CF transmembrane conductance regulator (CFTR) modulators, airway surface liquid hydrators and mucus modifiers, anti-infectives, anti-inflammatories, and nutritional therapies. Efforts to advance CF biomarkers, necessary to accelerate the therapeutic goals of the network, are also summarised.

 

This is an excellent update of the growing points in CF clinical research; full text is available online.

 

Salvatore D, Buzetti R, Baldo E, Furnari ML, Lucidi V, Manunza D, Marinelli, Messore B, Neri AS, Raia V, Mastella G. An overview of international literature from cystic fibrosis registries. Part 4: Update 2011.J Cyst Fibros 2012; 11:480-493. [PubMed]

A total of 53 national cystic fibrosis (CF) patient registry studies published between July 2008 and November 2011 have been reviewed, focusing on the following topics: CF epidemiology, nutrition, microbiology, clinical complications, factors influencing diagnosis and lung disease, effects of socioeconomic status, therapeutic strategy evaluation, clinical trial methodology. The studies describe the clinical characteristics of CF patients, the incidence and prevalence of disease and role of gender gap, as well as the influence of socioeconomic status and environmental factors on clinical outcomes, covering a variety of countries and ethnic groups. Original observations describe patients as they get older, with special reference to the adult presentation of CF and long-term survival. Methodological aspects are discussed, covering the design of clinical trials, survival analysis, auxometry, measures of quality of life, follow up of lung disease, predictability of disease progression and life expectancy. Microbiology studies have investigated the role of selected pathogens, such as Burkholderia species and MRSA. Pulmonary exacerbations are discussed both as a factor influencing morbidity and an endpoint in clinical trials. Finally, some studies give insights on complications, such as CF-related diabetes and hemoptysis, and emerging problems, such as chronic nephropathy.

 

A comprehensive review supporting the value of patient registries which yield so much important information.

 

Scurnik D, Davis MR Jr, Benedetti D, Moravec KL, Cywes-Bentley C, Roux D, Traficante DC, Walsh RL, Marylander T, Cassidy SK, Harems CR, Martin TR, Assaultable EL, Vargas SO, Macadam AJ, Lie berm an TD, Cushion R, Li puma JJ, Pier GB, Goldberg JB, Probe GP. Targeting pan-resistant bacteria with antibodies to a broadly conserved surface polysaccharide expressed during infection. J Infect Dis 2012; 205:1709-1718. [PubMed]
The bacterial surface polysaccharide poly-beta-(1-6)-N-acetyl-glucosamine (PNAG) mediates biofilm formation by some bacterial species, and antibodies to PNAG can confer protective immunity. By analyzing sequenced genomes, the authors found that potentially multidrug-resistant bacterial species such as Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, and the Burkholderia cepacia complex (BCC) may be able to produce PNAG. The presence of PNAG on BCC was assessed and antibodies to PNAG were tested using opsonophagocytic assays and for protective efficacy against lethal peritonitis in mice.  PNAG is expressed in vitro and in vivo by the BCC, and cystic fibrosis patients infected by the BCC species B. dolosa mounted a PNAG-specific opsonophagocytic antibody response. Antisera to PNAG mediated opsonophagocytic killing of BCC and were protective against lethal BCC peritonitis even during coinfection with methicillin-resistant Staphylococcus aureus. The authors concluded this was a potential new therapeutic options against PNAG-producing bacteria, including even pan-resistant pathogen.


This is an interesting approach as pan-resistant bacteria are becoming an ever increasing problem as the age of people with CF increases and they receive repeated courses of antibiotics. BCC remains a serious and often intractable problem. So this different approach is to be welcomed.

 

Scotet V, Dugueperoux I, Saliou P, Rault G, Roussey M, Audrezet MP, Ferec C. Evidence for decline in the incidence of cystic fibrosis: a 35-year observational study in Brittany, France. Orphanet J Rare Dis 2012; 7:14. [PubMed]
This study reported time trends in the birth incidence of CF over a long period (35 years: 1975-2009) in an area where CF is frequent (Brittany, France) and where newborn screening (NBS) has been implemented for more than 20 years. The average number of patients born each year declined from 18.6 in the late 1970's (period 1975-79) to 11.6 recently (period 2005-09). The corresponding incidence rates dropped significantly from 1/1983 to 1/3268, which represented a decline close to 40% between these two periods A clear breakpoint in incidence rate was observed at the end of the 1980's (p < 0.0001). However, the incidence rate has remained quite stable since that time. The authors observed a 40% drop in incidence which seems related to the availability of prenatal diagnosis.

 

In other areas where neonatal screening (UK, Australia, Italy) and indeed antenatal screening (Edinburgh) have been introduced there has been a significant reduction in the incidence of infants born with CF. Theoretically the means are now available to prevent all CF births (carrier detection, antenatal diagnosis, preimplantation genetic diagnosis) however neither the finances nor the will to do this appear to be in place at present.

 

Smith C, Winn A, Seddon P, Ranganathan S. A fat lot of good: balance and trends in fat intake in children with cystic fibrosis. J Cyst Fibros 2012; 11:154-157.
The fundamental nutritional treatment of a high fat diet for cystic fibrosis (CF) is established and essentially unchanged in the last 25 years. However, recent concerns have emerged regarding the potential risks of such a diet. The authors investigated the diets of children with CF to determine the source of energy, energy imbalance, and changing trends of fat intake. Macronutrient intakes did not change significantly in their population of CF children, but there was a consistent imbalance of fat-sources with over-dependence on saturated fats which, in the context of increased survival in CF may potentially increase risk of cardiovascular disease. The authors suggested that further studies are needed to confirm their findings, investigate consequences of fat imbalance and guide clearer advice regarding appropriate proportions of sources of fat for CF patients.

 

There is increasing interest in the long term effects of various treatments in people with CF and this is becoming more relevant as the length of survival increases. It was many years ago that autopsy studies showed the arteries of people with CF were relatively free of atheroma and this was attributed to the impaired fat absorption - in the days before acid-resistant microsphere enzyme preparations. Controls had 4 times the amount of atheroma than people with CF (Holman RL, Blanc WA, Andersen D. Decreased aortic atherosclerosis in cystic fibrosis of the pancreas. Pediatrics 1959; 24:34-39). [PubMed]

 

Stalvey MS, Anbar RD, Konstan MW, Jacobs JR, Bakker B, Lippe B, Geller DE. A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis. Pediatr Pulmonol 2012; 47:252-263. [PubMed]
A multicenter, open-label, controlled clinical trial comparing outcomes in prepubertal children <14 years with CF, randomized in a 1:1 ratio to receive daily rhGH (Nutropin AQ) or no treatment (control) for 12 months, followed by a 6-month observation (month 18).

Sixty-eight subjects were randomized (control 32 and rhGH 36). Changes in glucose tolerance for the two groups were similar over the 12-month study period, with three subjects developing impaired glucose tolerance (IGT) and one CF related diabetes (CRD) in each group. One rhGH-treated patient developed increased intracranial pressure.

The authors concluded the treatment with rhGH in prepubertal children with CF was effective in promoting growth, weight, LBM, lung volume, and lung flows, and had an acceptable safety profile.

 

Another study on the use of human growth hormone for which there is now ample evidence for a positive effect - but whether clinicians will use it or even need to use it and whether children will object to the daily injections over a long period of treatment is not clear. Previous studies have come to similar conclusions (see Topics)

 

Sawicki GS, Signorovitch JE, Zhang J, Latremouille-Viau D, von Wartburg M, Wu EQ, Shi L. Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. Pediatr Pulmonol 2012; 47:44-52. [PubMed]
Though tobramycin inhalation solution has been used for over a decade to improve lung function and reduce exacerbations in patients with cystic fibrosis, its longer term effects on mortality have not been well-described. This study aimed to assess the association between use of tobramycin inhaled solution and mortality in patients with CF and chronic Pseudomonas aeruginosa (PA) infection. Adjusted mortality rates for patients reporting tobramycin inhalation solution use in all versus none of the follow-up years were 1.3% versus 2.1% at 2 years, 5.2% versus 8.0% at 5 years, and 9.9% versus 15.0% at 10 years.

The authors conclude that, after adjustment for multiple patient characteristics and known risk factors, use of tobramycin inhalation solution was associated with significantly reduced mortality among patients with CF.

 

Inhaled aminoglycosides (gentamicin and later tobramycin) have been used in Europe for some 30 years since Margaret Hodson's landmark paper on the use of inhaled gentamicin and carbenicillin in 1981. The "over a decade" mentioned in this abstract refers to the 1999 paper of Ramsey and colleagues (Ramsey B W et al. N Engl J Med 1999; 340:23-30) that preceded the approval and availability of tobramycin for inhalation (TOBI) in N. America.

Fig. 9b: Clifford Takemoto

www.hopkinschildrens.org

 

Takemoto CM. Venous thromboembolism in cystic fibrosis. Pediatr Pulmonol 2012; 47:105-112. [PubMed].
The incidence of venous thromboembolism (VTE) is increasing in the pediatric population. Individuals with CF have an increased risk of thrombosis due to central venous catheters (CVCs), as well as acquired thrombophilia secondary to inflammation, or deficiencies of anticoagulant proteins due to vitamin K deficiency and/or liver dysfunction. CVC-associated thrombosis commonly results in line occlusion, but may develop into serious life-threatening conditions such as deep venous thrombosis (DVT), superior vena cava syndrome or pulmonary embolism (PE). Post-thrombotic syndrome (PTS) may be a long complication. Local occlusion of the catheter tip may be managed with instillation of thrombolytics (such as tPA) within the lumen of the catheter; however, CVC-associated thrombosis involving the proximal veins is most often is treated with systemic anticoagulation. Initial treatment with heparin is a standard approach, but thrombolytic therapy, which may carry higher bleeding risks, should be considered for life and limb threatening episodes of VTE. Recommended duration of anticoagulation with low molecular weight heparin (LMWH) or warfarin ranges from 3 to 6 months for major removable thrombotic risks; longer anticoagulation is considered for recurrent thrombosis, major persistent thrombophilia, or the continued presence of a major risk factor such as a CVC. While CVCs are the most common risk for development of VTE in children, studies have not demonstrated a clear benefit with routine use of systemic thromboprophylaxis. The incidence and risk factors of VTE in CF patients are reviewed and principles of diagnosis and management will be summarized.

 

A useful detailed review of an uncommon but potentially serious complication in people with CF.

Dr Clifford Takemoto(figure 9b) is Associate Professor of Pediatrics at The Johns Hopkins Hospital. Currently an associate professor of pediatric hematology at Hopkins Children’s, he is also an adjunct investigator in pediatric oncology at the National Cancer Institute. Thrombosis is amongst his special interests.

 

Trapnell BC, McColley SA, Kissner DG, Rolfe MW, Rosen JM, McKevitt M, Moorehead L, Montgomery AB, Geller DE. Phase 2 FTI Study Group. Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with Pseudomonas airway infection.
Am J Respir Crit Care 2012; 185:171-178.
[PubMed]

To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV(1) greater than or equal to 25% and less than or equal to 75% predicted.

This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV(1) % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI).

A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV(1) was 49% predicted at screening. Relative improvements in FEV(1) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (-1.04 log(10) PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values.

The authors concluded that FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. They consider that FTI is a promising antipseudomonal therapy for patients with CF.

 

Apparently Gilead Sciences is developing the combination fosfomycin/tobramycin antibiotic in which the tobramycin dose is lower in the FTI product than the usual dose of inhaled tobramycin given alone; this would potentially allow continuous dosing with a lower risk of toxicity.

Fig. 10: Bruce Trapnell. From www.cincinnatichildrens.org
Dr Bruce Trapnell (figure 10) is Director of Cincinnati's Cystic Fibrosis Therapeutics Development Network Center, Assistant Director of the Adult Cystic Fibrosis Care Center, Director of the Rare Lung Diseases Clinical Research Consortium and Scientific Director of the Pulmonary Alveolar Proteinosis Foundation.

 

Tiddens HA. Editorial for effect of dornase alpha on inflammation and lung function: potential role in the early treatment of cystic fibrosis. J Cyst Fibros 2012; 11:77.

In this editorial, Harm Tiddens comments on the paper by Konstan and Ratjen (abstract below) discussing the importance of early treatment of CF lung disease using dornase alpha and emphasising the need to preserve healthy lungs.  Harm Tiddens reminds us that normal spirometry does not exclude chronic lower airway inflammation, infection and structural damage. He points out that large controlled trials tell us only about the group and not whether the patient in front of us will respond to a particular treatment. Until there are more reliable prediction models that allow us to predict outcome from an intervention for an individual based on key characteristics we are stuck with "one size fits all". He supports the view of Konstan and Ratjen that there is " a greater role for dornase alpha therapy in early treatment of CF where it may help preserve lung function and potentially extend survival".

Fig. 11: Harm Tiddens. From www.fcconventions .com.au/

Dr Harm Tiddens (figure 11) of the Erasmus Medical Center in Rotterdam, is one of Europe's most active paediatricians who has researched and published on a very wide variety of CF subjects particularly relating to accurate early diagnosis, various imaging techniques and treatments.

 

Vandenbranden SL, McMullen A, Schechter MS, Pasta DJ, Michaelis RL, Konstan MW, Wagener JS, Morgan WJ, McColley SA. Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Lung function decline from adolescence to young adulthood in cystic fibrosis. Pediatr Pulmonol 2012; 47:135-143. [PubMed].
The authors identified 4,680 patients in the Epidemiologic Study of Cystic Fibrosis 1994-2005 with data in both adolescence (age 14.0-17.4 years) and young adulthood (age 18.5-22.0 years) and analyzed 2,267 who had >=5 encounters and >=5 measurements of forced expiratory volume in 1 second (FEV(1) ) spanning >=1 year during both adolescence and young adulthood, and >=1 encounter with weight and height and >=1 FEV(1) measurement age 17.5-18.5 years. They compared the annualized rates of decline in FEV(1) during adolescence and young adulthood stratified by best FEV(1) around age 18. Logistic regression was used to identify risk factors associated with substantial decline (>20 points) in FEV(1) % predicted in young adulthood.

The annual rate of decline was greater in young adulthood (18-22yrs) than in adolescence (14-17.4yrs) . Risk factors for substantial decline included slower rate of FEV(1) decline, greater FEV(1) variability, faster body mass index (BMI) decline, male sex, chronic inhaled antibiotics, Hemophilus influenzae detection, and absence of multidrug-resistant Pseudomonas aeruginosa in adolescence, and lower than expected FEV(1) and BMI around age 18.

The authors concluded that decline in lung function accelerates in young adults with CF, especially in those with early stage lung disease. Adolescents at risk for substantial decline in lung function in young adulthood have higher FEV(1) and worse nutritional status, among other identifiable risk factors.

 

Waters V, Atenafu EG, Salazar JG, Lu A, Yau Y, Matukas L, Tullis E, Ratjen F. Chronic Stenotrophomonas maltophilia infection and exacerbation outcomes in cystic fibrosis.
J Cyst Fibros 2012; 11:8-13.
[PubMed].
Chronic Stenotrophomonas maltophilia infection is a risk factor for pulmonary exacerbation in cystic fibrosis (CF) but its impact on subsequent clinical outcomes is unknown. The aim of this study was to determine the effect of chronic S. maltophilia infection and associated antimicrobial therapy on the recovery of forced exiratory lung volume in 1s (FEV(1)) following pulmonary exacerbation. Patients with chronic S. maltophilia infection did not recover their baseline FEV(1) following 31% of exacerbations and had an overall mean FEV(1) decline of 1.84% predicted after exacerbation. Older (p=0.02), female (p=0.02) patients with lower BMI z score (p=0.002) and Burkholderia cepacia complex infection (p=0.005), but not chronic S. maltophilia infection (p=0.86), had a greater decrease in follow up FEV(1)% compared to baseline. The number of days of antibiotic therapy against S. maltophilia during a pulmonary exacerbation was not associated with a significant difference in the FEV(1) recovery (p=0.69) or with a longer time to subsequent pulmonary exacerbation (p=0.56).

The authors concluded that although CF patients experience a significant decline in lung function following exacerbations, chronic S. maltophilia infection and associated antimicrobial therapy do not affect subsequent lung function recovery.

 

S. maltophilia has gradually appeared as a more frequent pathogen as the prevalence of P. aeruginosa has been reduced by intensive antibiotic therapy. As happened in the early days when isolations of P. aeruginosa occurred more frequently as S. aureus was treated, initially there were doubts as to the degree of pathogenicity. It is somewhat reassuring that the course of patients infected by S. maltophilia was not significantly different from those with more usual organisms and certainly not comparable with the severe effects of B. cepacia. Again the damaging effects of pulmonary exacerbations was apparent.

 

Wiehlmann L, Cramer N, Ulrich J, Hedtfeld S, Weissbrodt H, Tummler B. Effective prevention of Pseudomonas aeruginosa cross-infection at a cystic fibrosis centre - results of a 10-year prospective study. Int J Med Microbiol 2012; 302:69-77.[PubMed]
The authors tested the efficacy of measures to prevent nosocomial acquisition of P. aeruginosa at their Paediatric CF centre in a prospective 10-year study. P. aeruginosa-positive and P. aeruginosa-negative patients were seen in alternating weeks at the outpatient clinic. Faucets were equipped with filters to prevent bacterial contamination of tap water. Serial isolates were collected since the first documentation of a P. aeruginosa-positive culture and genotyped with a multimarker micro array.

During the 10-year study, the annual prevalence of patients with at least one P. aeruginosa-positive culture was 39+/-6% in a population of 149+/-12 patients. P. aeruginosa was detected for the first time in 54 patients of whom 11 patients became chronically colonised with P. aeruginosa. Transient colonisations were recorded 97 times. A nosocomial acquisition of P. aeruginosa at the CF centre probably happened in one case. The worldwide dominant clones in the global P. aeruginosa population were also the most abundant clones in the panel of 324 early CF isolates. No rare clone had expanded by nosocomial transmission.


The authors concluded that cross-infection with P. aeruginosa was prevented with simple hygienic measures at a CF centre that had experienced local outbreaks of nosocomial spread among unrelated patients in the past. It was disappointing that 11 of the 54 (20%) paediatric patients who had P. aeruginosa for the first time became chronically infected.  However, the study is reassuring in showing that all the various precautions which are now customary are fully justifed and effective in preventing cross infection in the CF clinic.

 

Whitaker P, Naisbitt D, Peckham D. Non-immediate b-lactam reactions in patients with cystic fibrosis. Curr Opin Allergy Clin Immunol 2012; 12:369-375.[PubMed]

This review discusses new developments regarding b-lactam sensitivity in people with cystic fibrosis. It is a common complication and some 30% of patients have multiple b-lactam reactions.

 

Wong AP, Bear CE, Chin S, Pasceri P, Thompson TO, Huan LJ, Ratjen F, Ellis J, Rossant J.Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat Biotechnol. 2012; 30(9):876-82. [PubMed]

The authors describe an in vitro directed differentiation protocol for generating functional CFTR-expressing airway epithelia from human embryonic stem cells. Carefully timed treatment by exogenous growth factors that mimic endoderm developmental pathways in vivo followed by air-liquid interface culture results in maturation of patches of tight junction–coupled differentiated airway epithelial cells that demonstrate active CFTR transport function. As a proof of concept, treatment of CF patient induced pluripotent stem cell–derived epithelial cells with a small-molecule compound to correct for the common CF processing mutation resulted in enhanced plasma membrane localization of mature CFTR protein.

The study provides a much needed method for generating patient-specific airway epithelial cells for disease modeling and in vitro drug testing.

Fig. 11a: Amy Wong

holar.google.ca

Fig. 11b: James Ellis Fig. 11c: Janet Rossant

Dr Amy P Wong is a Post Doctoral fellow working in the James Ellis laboratory co-supervised by Dr Janet Rossant

 

Dr. James Ellis (figure 11b) is Senior Scientist Developmental and Stem Cell Biology at the Hospital for Sick Children and Professor in Molecular Genetics in the University of Toronto

 

Dr Janet Rossant PhD, FRS, FRSC (figure 11c)is Senior Scientist in the Developmental & Stem Cell Biology Program and Chief of Research at the

Hospital for Sick Children Toronto and Professor in the Departments of Molecular Genetics, Obstetrics/Gynaecology and Paediaitrics, University of Toronto. Her research interests centre on understanding the genetic control of normal and abnormal development in the early mouse embryo using both cellular and genetic manipulation techniques. Her interests in the early embryo have led to the discovery of a novel placental stem cell type, the trophoblast stem cell. She is Deputy Scientific Director of the Canadian Stem Cell Network.