Abstract
Introduction
The North American Cystic Fibrosis Conference (NACFC) is the world's largest international CF conference. It presents a superb opportunity for the CF professional community to join together to hear results of the latest therapeutic studies, the latest advances in basic science and to further their understanding of CF care. The 2008 conference was held in Orlando, Florida, and with over 3500 delegates, it did not disappoint. The majority of those attending the NACFC are naturally from North America, but there is a sizeable minority from Europe and Australasia. Five members of our team (two consultants, two clinical nurse specialists and one specialist physiotherapist) attended, and we willingly took up the invitation to report our highlights on our return to the RSM conference.
DECLARATIONS
None declared
None
Not applicable
TH
All authors contributed equally
Attending an overseas international conference is often not an easy undertaking, not least financially. Including travel, accommodation and conference registration, our attendance cost approximately £5000, a significant sum when there is appropriate limitation of commercial sponsorship. It is therefore a relevant exercise to consider one's reasons to attend an overseas conference, and to regard participation once there with apt seriousness. Although this may be obvious to some, we have listed in Box 1 what we considered our motivation. We tell our patients and their families each year when we are going to the NACFC and they are always interested, and in particular they see this as a way that we can connect with new therapies and keep ourselves up to date. Knowing that we were going to report on the conference provided an extra stimulus, and this is perhaps a good lesson for all CF teams.
Motivation for attending overseas conferences
Presenting our own work
Keeping ourselves up to date with new practice
Allowing our practice to be influenced by others within our field
Hearing about developing therapies
Meeting other teams from our own country and internationally
Refreshing our enthusiasm to provide first-rate care
Team bonding
With three days of presentations and over 700 posters, it was not easy to choose a small number of highlights. The following selection is unapologetically personal, as we gave ourselves free reign to attend those sessions that interested us most, and then describe what we felt might most influence our practice in either the short or long term.
Basic science
Neutrophils are considered responsible for the onset and promotion of the inflammatory response within the CF lung. Neutrophils are recruited to the pulmonary site of inflammation via IL-8 and its two receptors and CXCR2. IL-8 can also mediate neutrophil killing via CXCR1. 1 During a session on inflammation and airway destruction Dominik Hartl described the role of CXCR1 in CF lung disease. 2 Proteases can cleave CXCR1 on neutrophils which can impair their bacterial killing pathways. The released soluble glycosylated CXCR1 fragments stimulate IL-8 production and therefore perpetuate the inflammatory process via further neutrophil recruitment.
There is increasing interest in the protease activity of the matrix metalloproteinases, especially MMP-9 and its natural inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1). Jackson et al. showed an increased ratio of MMP-9/TIMP-1, which correlated with neutrophil elastase (NE), in stable patients with CF. 3 NE also has the capacity to cleave TIMP-1 thus adding to the dysregulation of MMP-9 in CF.
Williams et al. described agmatine, a novel inflammatory agent in CF sputum identified using mass spectroscopy. 4 Although it is a neurotransmitter it also binds to α2-adrenoreceptors. They demonstrated that agmatine stimulated macrophage TNF-α production with or without LPS stimulation, which was blocked by a α2-adrenoreceptor antagonist. Since Pseudomonas aeruginosa is able to synthesize agmatine, they also suggested it may play a role in LPS-independent pathogen recognition.
Jacquot et al. identified amphiregulin as a new biomarker of CF airway inflammation. 5 Comparing CF airway and blood neutrophils to blood neutrophils from healthy subjects, they performed a macro-array analysis of 1050 genes coding for cytokines, their receptors and signalling molecules. They demonstrated an up-regulated expression of 62 genes and a down-regulated expresson of 27 genes in CF blood neutrophils. The mRNA expression of amphiregulin and TNF-α receptor were significantly higher in the CF airway neutrophils. Amphiregulin activates epithelial cells and contributes to TNF-α induced IL-8 release from those cells. They also found significant amounts of amphiregulin in CF sputum samples.
Nutrition
Jadin et al. examined the prevalence of breastfeeding in a cohort of infants enrolled in the Wisconsin Routine CF newborn screening study, and compared growth between those breast-fed (BF) and formula-fed (FF). 6 Twenty-two of the 41 infants investigated had never been breast-fed, whereas 15 had been exclusively breast-fed and four partially breast-fed. Weight between BF and FF infants were similar at 3, 6 and 9 months, but at 12 months weight in those infants exclusively breast-fed was significantly less than those who had received formula feed since birth. They concluded early supplementation of formula milk, once breastfeeding is established, may improve weight gain in CF infants.
Alfredo Guarino suggested that the intestine is an important target for therapy in CF using pro-biotics. 7 His group has previously investigated intestinal inflammation in CF, and found that children with CF had increased faecal calprotectin concentrations and rectal nitric oxide compared to controls. 8 Some of these children were given Lactobacillus rhamnosus GG (LGG) in a non-controlled fashion and had a reduction of faecal calprotectin and rectal nitric oxide. They have since published a pilot randomized controlled cross-over study of six months of LGG or oral rehydration solution in 38 children with CF and chronic Pseudomonas aeruginosa infection. 9 When treated with LGG, patients had fewer pulmonary exacerbations, hospital admissions and an increase in lung function. They have suggested that restoring the intestinal microflora in CF patients may have benefits that are outside the intestine.
Exercise
Exercise therapy in CF had a high profile at the conference. Boas et al. looked at the relationships between peak work capacity and maximal oxygen consumption (VO2) with lung function as measured by spirometry. 10 Within patients who had normal spirometry, almost 60% had abnormal VO2, particularly those who had bronchiectasis on CT imaging. They suggested that exercise testing might be helpful as an early indicator of lung disease.
Gruber et al. looked at the effects of an exercise programme of 45 minutes performed five days a week in patients with differing disease severity, with exercise testing before and at the end of the six-week programme. 11 Patients across all groups of disease severity showed benefit from the exercise programme, with similar relative increases from baseline parameters. This highlights that all patients with CF may benefit from exercise, regardless of their disease severity.
Brenda Button highlighted the very high prevalence of urinary incontinence in CF. 12 This has been estimated to be between 33% to 47% of adolescent girls with CF, up to 68% of adult women with CF and just under 8% of men with CF. Patients with chronic lung disease have been shown to have pelvic floor muscles that have normal strength but decreased endurance. She advocated teaching pelvic floor exercise to girls over 12 years old and prompt referral to women's health specialists when necessary.
Adherence and quality of life
Branagan et al. presented a study which tried to identify if there was a link between compliance and lifestyle factors such as waking time, smoking, alcohol and illicit drug use in a group of 75 adult CF patients, through anonymized question-naires. 13 The 32 respondents were split into early (before 10:00) and late risers (after 10:00). Self-reported overall compliance was significantly greater in early risers (83%) than late risers (38%), with similar significant differences in individual types of therapy, and also reported intake of three meals per day (72% vs 29%). The authors suggested that we should ask our patients about waking time and that this might identify those who may need closer monitoring and support regarding their compliance.
DeMore et al. explored the barriers and motivators to adherence within a group of older adolescents and adults with CF. 14 They performed a one-hour semi-structured interview with 19 patients, and identified several common themes. The most frequently mentioned barrier to treatment was time management (100%), whereas physical symptoms (69%) and emotional symptoms (44%) could act as both barriers and motivators. An example of the latter was ‘if I've had a bad day breathing, I'll do my treatments’. Clinic visits (25%) were seen by many as a motivator, while the transition period (19%) was seen as a barrier to adherence. Some themes were specific to adults and some to teenagers. The authors suggested investigating these factors further, and specifically tailoring interventions to increase adherence.
The relationship between illness experience and adherence for young adult patients was explored further by Seitz et al. 15 They performed semi-structured interviews in 12 patients aged 17 to 24 years, and identified interesting individual theories of treatment and health. Some patients’ behaviours were partially based on faulty premises, e.g. ‘to do therapy means to be ill. Not to do therapy means not to be ill.’ Other patients knew when they were feeling ill, but didn't want to realize it, avoiding the increased psychic burden. Their findings suggested that barriers are individual to each patient and professionals need to examine the implications that therapies have from the patient's point of view. They suggested that their results support approaches such as motivational interviewing.
Results of an online survey of pain, quality of life and sleep sent to adult patients in the Johns Hopkins adult program were reported by Lechtzin et al. 16 They found that reports of pain were startlingly high, with chronic pain reported by 27% of patients, and that 82% had pain in the previous four weeks. Despite pain being so common, only 44% had spoken to their physician about it. Chronic pain was associated with anxiety, poor sleep and a worse quality of life. We should ask our patients more about their pain symptoms.
New therapies
The Cystic Fibrosis Foundation has an impressive Drug Development Pipeline (www.cff.org/treatments/Pipeline), however within the area of gene therapy, the UK Cystic Fibrosis Gene Therapy Consortium is running the most important clinical trial. Eric Alton, always a superb speaker, reported on his group's recent progress, highlighting with utmost clarity their recent advances as well as the difficulties in running such a complex study. The 200-patient run-in study has already started, with the 100-patient multidose randomized controlled study to start in early 2010.
Kerem et al. presented further results on PTC124, an oral drug with potential benefit for patients with nonsense mutations. 17 This agent induces ribosomes to read through premature stop codons in the gene, thereby allowing production of full length, functional CFTR. The phase 2a study has already been published, showing significant improvements in nasal potential difference (PD). 18 In the phase 2 extension study, patients who had responded to low dose therapy had a further three months of the same dose, whereas non-responders had three months of higher dose therapy. There were consistent improvements in nasal PD, with changes at three months in some patients who had not improved at one month. Therapy was well tolerated, and although there was some reduction in objectively measured cough, there was no significant change in lung function. The next phase of this study will be an interventional randomized controlled study with FEV1 as the primary outcome measure.
High-throughput screening, in which a large number of compounds are tested and modified in a screening assay, has identified novel agents that may increase the presence and/or function of CFTR at the cell membrane. Two classes of these potential agents have been described, with correctors increasing CFTR trafficking to the cell surface, whereas potentiators alter the opening (or gating) of the chloride channel within defective CFTR and thereby restoring chloride flux. VX-770 has been identified as a potentiator, and has been shown to restore chloride flux in vitro. Accurso et al. described its first use in patients with G551D mutations (a Class III mutation with a gating defect). 19 Patients aged over 18 years took part in a phase 2a dose ranging randomized controlled cross-over study with safety and tolerability as the primary outcome measures. Twenty patients had oral VX-770 at different doses twice per day or placebo for two 14-day periods in the first part of the study, and then for two 28-day periods in the second part. VX-770 was well tolerated with no obvious serious adverse events attributable to the study drug. However there were striking changes in secondary outcome measures. There was an approximate 5mV improvement towards normal in nasal PD, and an extremely impressive reduction in sweat chloride concentration (with changes of between 30 to 50 mmol/L). FEV1 also increased by between 7% and 11% over 28 days, depending on dose. For many clinicians these results were the most important of the conference, with an almost palpable feeling of excitement during their presentation. Investigation of VX-770 is to be extended into patients with other mutations.
VX-809 has been indentified as a potential corrector therapy. In a CF cell line model, VX-809 has been shown in vitro to increase CFTR activity to over 20% of normal. However the combination of VX-809 and the potentiator VX-770 increased CFTR activity to almost 40% of normal. Aphase 2a safety study of VX-809 is planned for 2009.
A novel therapy using an alternative strategy is denufosol. This is a P2Y2 agonist, which is an alternative chloride channel within the cell membrane. Restoring chloride flux in this way may improve mucosal hydration. Frank Accurso reported the results of TIGER-1, a phase 3 randomized controlled trial in 352 patients aged over 5 years at 62 centres in North America. 20 Subjects received either inhaled denufosol or placebo three times per day over a 24-week period, followed by a further 24-week open label extension period. Patients had a mean age of 14 years and a mean FEV1 of 93%. There was a significant improvement in FEV1 over the study period, with an absolute mean change of 45 mLs. In the extension period, FEV1 appeared to continue to increase, as did the lung function of those patients who had previously been in the placebo arm. There was no difference in the rate of exacerbations, but for those patients who did exacerbate during the study period, FEV1 appeared to be more stable in those receiving denufosol than placebo. Interestingly there also appeared to be less nasal or sinus-related symptoms in those on denufosol. TIGER-2 has already started, with the study duration extended to 48 weeks.
With the results of trials of new therapies starting to come through and many more studies already underway, this NACFC had an extremely strong positive atmosphere. There was a clear feeling that a real change in clinical therapy was not far away. We returned home enthused and have already updated our families at a subsequent parents’ evening. We'll see you in Minneapolis in 2009!
Footnotes
Acknowledgements
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