Abstract
This review is based upon a Medline search of the literature on cystic fibrosis for the latter half of 2010 onwards. The Medline search was carried out in September 2011 and also includes some references published after September 2011. This search revealed articles relating to approximately 482 paediatric studies and 419 adult studies with much overlap between the two groups. Taking into account the multidisciplinary nature of the audience for this symposium and also taking into account the topics in the rest of the programme for the day, a shortlist of 65 papers was then derived. A diversity of topics was clearly necessary and also a mixture of paediatric and adult publications, hence the following papers were chosen.
DECLARATIONS
Within the last 3 years the author has been a member of advisory boards for Novartis, Bayer and Vertex. He holds a small number of shares in Glaxo SmithKline. The author has acquired travel grants for himself and/or CF team members from Chiesi, Novartis, Gilead, Bayer, Forest and Solvay
None
Not applicable
DH
DH is the sole contributor
Genes and the environment
The important previous publication looking at the effects of environment on the phenotype of cystic fibrosis had shown significant influences of social class, gender and region of residence on age at death from cystic fibrosis in England and Wales. 1 A very recent publication 2 reported an association between socioeconomic status, gender and age at death from cystic fibrosis in England and Wales (1959–2008) in a cross sectional study. The authors used national mortality data from the Office for National Statistics between the years 1959 and 2000. During these years socioeconomic status was coded as manual or non-manual. However, from 2001 onwards, a new classification was introduced by the Office for National Statistics which defined three groups: professional and managerial, intermediate, and routine and manual. The authors then derived the median age at death for each of the study years and looked for any effects of gender and socioeconomic status on age of death. They reported the results in terms of odds of death above the median age at death for every study decade. Using logistic regression analysis they showed a statistically significant higher age at death in those from the non-manual group up to the year 2000, and then the professional and managerial group from 2001 to 2008. Between 2001 and 2008 the odds ratio for improved survival was 1.89 (95% confidence intervals 1.20–2.97) for the professional and managerial group compared to the manual group. The authors concluded that both gender and socioeconomic status separately remained strong determinates of survival from cystic fibrosis in England and Wales, and that the magnitude of these effects does not appear to have substantially reduced over the time of the study. Weaknesses of the study include the inadequate data leading to unclassified status in 32% of the 5759 subjects who were coded, and clearly this may have led to a bias. However, it seems unlikely that such a bias would produce such a consistent trend over the long study period. Another relative weakness was the change in socioeconomic classification during the study period.
An editorial in the same issue of the BMJ 3 commented that these findings 2 are consistent with other publications showing socioeconomic and gender health gaps in cystic fibrosis both from the UK and USA data. The authors of the editorial speculate that inequalities may begin in early childhood and persist over time. This may be partly due to better access to best care amongst those of the more affluent socioeconomic group. For instance in the UK journeys to a large regional adult cystic fibrosis centre may be easier and more achievable for those more affluent groups. There is also some evidence that more affluent groups may be earlier recipients of newer cystic fibrosis drugs.
A previous article 4 reported the possible effects of environmental tobacco smoke on lung development in early childhood in cystic fibrosis, and clearly this may be linked to socioeconomic status.
Another paper reported some findings from the North American CF twin and sibling study. 5 The article reported on the relative contribution of environmental and genetic factors on the variation in lung function in cystic fibrosis patients. The study was based upon analysis of lung function data from 134 identical twins, 272 non-identical twins and a separate group of 80 siblings. Analyses carried out included looking at the relative contributions of the environmental influences of living together with their twin or sibling, or living separately. The authors reported that the forced expiratory volume in one second (FEV1) of mono-zygous twins was more similar than in dizygous twins and sibling pairs regardless of the living environment. However, regression modelling revealed that genetic factors accounted for only 50% of the pulmonary function variation and that unique environmental factors contributed 36% and shared environmental factors 14% (P < 0.0001). The authors conclude that genetic and environmental factors contribute equally to the variations seen in cystic fibrosis patients. The influence of environmental factors is also reported in a paper 6 which reported on data from a European database (EuroCareCF). This reported a wide range of childhood cystic fibrosis mortality across Europe with parts of Western Europe now having around 5% mortality for childhood CF, but this is much higher in some Eastern European countries. Conversely the variation in phenotype which may be related to genetic modifiers is the subject of several papers, in particular a paper 7 which reported linkage modifier loci of lung disease severity in cystic fibrosis on chromosomes 11 and 20. It will be intriguing to see further work reported in the future on the relative contributions and interactions of genetic and environmental factors.
Exacerbations in Cystic Fibrosis
A paper 8 reported the results of an analysis of cystic fibrosis exacerbation frequency and clinical outcomes in adult patients. This study had the strength of being a 3-year prospective cohort study looking at 446 adults with cystic fibrosis from Ontario. Patients were included between the years 2005 and 2008, and 3 groups were then derived based upon their exacerbation rates over this 3-year study period. Less than 1 exacerbation per year was found in 140 patients, 1–2 exacerbations per year in 160 patients and more than 2 exacerbations per year in 146 patients. Exacerbations were defined as acute or sub acute deterioration in respiratory symptoms which were significant enough to lead the clinician to prescribe oral or intravenous antibiotics. The authors found that patients with more frequent exacerbations were more likely to be female, diabetic and also to have lower baseline spirometry. The group of patients with the highest number of exacerbations per year had a significantly increased risk of showing a 5% decline from baseline FEV1 compared to patients with less than one exacerbation per year. Also analysis showed an increased 3-year risk of deterioration to death or lung transplantation in those with the most frequent exacerbations.
A paper 9 reported on data from the CF Foundation Registry. This study was retrospective in nature and reported results for both adults and children with cystic fibrosis. Data were derived from 8490 patients. The authors looked at the number of exacerbations in the year 2003 and then looked at the decline in lung function between the years 2004 and 2006 in the same patients. They found highly significant association between subsequent decline in FEV1 and the frequency of exacerbations. In adults who had 3 or more exacerbations per year and in children having any exacerbations per year there was a significant association with a faster decline in FEV1 over the 3-year period. The authors noted that this is an association and not necessary causation; for instance certain cystic fibrosis patients could have an intrinsically faster rate of FEV1 decline and then be at higher risk of being labelled as having exacerbations by the clinicians.
However, the same group 10 had also published work which showed that around a quarter of patients who had had an acute exacerbation had not shown a recovery of their lung function back to their baseline level within 3 months of the exacerbation being treated with intravenous antibiotics. Overall these results suggest that in some, if not all CF patients, exacerbations lead to a faster rate of FEV1 decline. This clearly has implications in terms of assessing suitability and timing of individual patients for lung transplantation.
Physiotherapy topics
A comparison of postural drainage with percussion and autogenic drainage in the treatment of cystic fibrosis was reported from the Vancouver Paediatric Group. 11 Their hypothesis was that autogenic drainage is as effective as postural drainage with percussion. They undertook a 2-year prospective crossover study of 36 CF adolescences who were allocated to one of the two types of physiotherapy technique in year 1 and then crossed over to the second type in year 2. At the start of the study the mean FEV1 of the whole group was around 74%. Every 3 months, clinical status and spirometry were recorded. Unfortunately, only the results from the first 12 months were reported as 10 out of the 17 patients who had been allocated in their first year to autogenic drainage, refused to revert back to postural drainage with percussion for year 2. Analysis of this first year showed improved lung function in both groups without any significant difference between them. There was no difference in rates of hospitalization or intravenous usage. There was a “massive” stated preference for autogenic drainage by the patients. Clearly the weaknesses of this study include its incomplete nature, small numbers and problems related to its unblinded design. A Cochrane review by the Cochrane Cystic Fibrosis and Genetic Disorders Group 12 reported on an investigation of the timing of Dornase Alfa (Dnase) inhalation for cystic fibrosis. They identified 47 studies of which 5 met their inclusion criteria. These 5 studies provided data on 122 patients. All 5 studies used a crossover design with intervention periods ranging from 2 – 8 weeks. Four of these trials compared Dnase inhalation before versus after airway clearance techniques. The authors reported that there was no significant difference in FEV1, FVC or quality of life measurements when inhalation was carried out after instead of before airway clearance. However, the small airway measurement FEF 25 was significantly worse when Dnase inhalation was carried out after airway clearance compared to before airway clearance based on the pooled data from 2 small studies in children with well preserved lung function. All other secondary outcomes were statistically non-significant.
Nutrition and Diabetes
There is increasing evidence about the deleterious effects caused by cystic fibrosis-related diabetes (CFRD) and also those with impaired glucose tolerance. It is already known that CFRD is associated with increased decline of pulmonary function and increased mortality compared to non-diabetic cystic fibrosis patients. A study 13 looked at the 1-hour plasma glucose level following a standard oral glucose tolerance test. Oral glucose tolerance test results were available in 101 CF patients with an age range of 5–22 years who had a mean FEV1 % predicted of 94.5%. Using the standard 2-hour plasma glucose level, 91 out of 101 were normal, 8 had impaired glucose tolerance and 2 were frankly diabetic. Using the plasma glucose level at 1 hour, 39 glucose tolerance tests were normal, 36 showed a level of 140–199 mg/dL and 14 were 200 mg/dL or greater. Overall, the plasma glucose level at 1 hour was negatively correlated with FEV1 % predicted (P = 0.009). FEV1 % predicted of the overall group was not associated with baseline or 2-hour plasma glucose levels, age, sex or lung bacterial colonization. The authors concluded that there was an association between increasing plasma glucose level at 1 hour with worsening lung function. This could be due to the adverse effects caused by the raised plasma glucose levels or alternatively, raised plasma glucose levels may be an early marker for worsening disease. It is suggested that the 1-hour plasma glucose level should be recorded as well as the 2-hour one during routine glucose tolerance testing.
In another study, 14 2-year overnight oxygen saturation was measured in children together with measurement of serum inflammatory markers and oral glucose tolerance testing. They found a strong mean negative correlation between the mean nocturnal oxygen saturation and the area under the curve of the glucose tolerance test. They suggest that further studies are needed to investigate whether lower overnight oxygen saturations affect glucose regulation or perhaps whether abnormalities in glucose regulation may be an early sign of pulmonary dysfunction.
Another study 15 looked at a group of 48 patients who were a mixture of children and adults. This was a cross-sectional study and patients had clinical and nutritional evaluation, oral glucose tolerance test, lung function tests, chest X-ray and a 6-minute walk exercise test. Patients were divided into 3 groups; having normal glucose tolerance, impaired glucose tolerance or CFRD. In the glucose intolerance group there was an association with poor clinical score, lower resting of oxygen saturation, a bigger difference between pre and post oxygen saturation after the exercise test, poor lung function and lower chest X-ray score. The results were significantly worse in females with impaired glucose tolerance than males.
Terminal care
Not many studies have been published regarding terminal care in cystic fibrosis, and a qualitative study 16 reported carers views on discussions about the use of intensive treatments in cystic fibrosis patients nearing the end of their lives. Thirty-six carers of 36 patients who had died of CF took part in a semistructured interview. Twenty of the patients had received intensive treatment during their last week of life, 61% of carers reported having had discussions regarding intensive treatment preferences with a physician and only 77% of these discussions were started during the acute illness. Furthermore, only 14 of the patients participated in these discussions. The vast majority of care-givers endorsed the concept of first discussing treatment preferences during a period of medical stability, when patients would be far more likely to be able to participate so that patient preferences were documented and unwanted treatments minimized.
Paper of the Year
My paper of the year is the exciting paper 17 reporting the effects of a cystic fibrosis transmembrane conductance regulator potentiator, VX-770. This paper together with another very recent one on the same topic, 18 were discussed in detail by another speaker at the symposium. The key points were that in 39 adults with CF and at least one G551D CFTR, allele oral treatment was given with either active drug at 1 of 4 doses or placebo for 28 days. At day-28, subjects who received 150 mg bd of VX-770 showed a median change in nasal potential difference of -3.5 mV, median change in sweat chloride of -59.5 mmols/L and median improvement from baseline in FEV1 % predicted of 8.7%. This study shows that CFTR potentiators could have enormous benefit in cystic fibrosis patients with specific mutations.
Microbiology papers
There has been a rapid increase in knowledge regarding CF microbiology, partly through the use of non culture molecular techniques which are becoming increasingly more sophisticated. A study 19 reported the relative contributions of the anaerobe Prevotella intermedia and Pseudomonas aeruginosa to lung pathology in the airways of patients with CF. There is increasing interest in anaerobic infections in CF and a realization that they may be far more important than previously thought. The authors compared the virulence of Prevotella intermedia and Pseudomonas aeruginosa in vitro and also in mice using a novel molecular probe. Prevotella intermedia was found to be much commoner using this technique compared to routine culture. The results from this in vitro and mouse model study suggest that Prevotella intermedia may play a critical role in the complex patho-physiology of CF lung disease.
The diversity and turnover of Pseudomonas aeruginosa in cystic fibrosis patients’ lungs were reported in a study from Liverpool. 20 Ten patients with an epidemic strain of Pseudomonas aeruginosa had a series of sputum samples collected and were analysed for phenotypic and genotypic characteristics. The results were analysed in terms of differences between patients, between samples within patients and also between isolates within individual samples. Molecular techniques enabled an analysis of the bacterial population dynamics to be assessed. Very high levels of diversity were found within individual patient sputum samples, and a correlation was found between the virulence related phenotype (over production of pyocya-nin) and acute pulmonary symptoms. Of the 43 sputum samples analysed, there were 398 variations (haplotypes) identified. There was much phenotypic diversity regarding antibiotic resistances. In an editorial in the same journal 21 it was commented that the conventional view has been that Pseudomonas aeruginosa chronic infection in cystic fibrosis involves the evolution over time of a single clone which becomes dominant and then undergoes clonal expansion in the airways leading to the emergence of a population dominated by a single chronic phenotype that, although may be less virulent than the initial strains, tends to become more resistant to antibiotic treatment. However, the Liverpool study suggests that rather than having a single dominant clone, the Pseudomonas aeruginosa population in the airways of CF patients are very heterogeneous. This raises further questions about their contribution to disease progression and also antibiotic choices.
A further study 22 looked at traditional culture and also molecular analysis of sputum samples to determine the effects of antibiotic treatment on the microbial population during exacerbations of cystic fibrosis. Sputum was collected at the start and end of treatment for exacerbations and also during a period of clinical stability. Anaerobic bacteria were detected in all patients at the start of treatment and in stable samples, and in most of those at the completion of treatment. Molecular analysis showed much greater diversity within sputum samples than traditional culture techniques and in particular poor agreement between the two techniques for the presence of anaerobes. Both methods show the spectrum of the bacterial community to vary between patients but to remain relatively stable in most individuals despite treatment. With the advent of increasingly sophisticated molecular techniques, we should be entering an era of increasing knowledge about the nature and diversity of the bacterial population in CF lungs, and the hope is that this will be translated into improved antibiotic therapy.
The author regrets that it has not been possible due to time constraints to include many other interesting papers published over the last 12 months.
Footnotes
Acknowledgements
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