S.P. Conway

Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: A European consensus ☆

In cystic fibrosis inhalation of drugs for the treatment of CF related lung disease has been proven to be highly effective. Consequently, an increasing number of drugs and devices have been developed for CF lung disease or are currently under development. In this European consensus document we review the current status of inhaled medication in CF, including the mechanisms of action of the various drugs, their modes of administration and indications, their effects on lung function, exacerbation rates, survival and quality of life, as well as side effects. Specifically we address antibiotics, mucolytics/mucous mobilizers, anti-inflammatory drugs, bronchodilators and combinations of solutions. Additionally, we review the current knowledge on devices for inhalation therapy with regard to optimal particle sizes and characteristics of wet nebulisers, dry powder and metered dose inhalers. Finally, we address the subject of testing new devices before market introduction.

Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors

BACKGROUND Patients with cystic fibrosis (CF) have many risk factors for reduced bone mineral density (BMD). The aim of this study was to determine the prevalence of osteoporosis and osteopenia in a large cross section of patients and to identify risk factors. METHODS All patients attending the regional centre were invited to participate in the study. Bone mineral density was measured at the lumbar spine, femoral neck, and for total body with a Lunar DPX-L densitometer. Multiple indices of disease severity were investigated, and liver and thyroid function, blood calcium, phosphate, 25-OH vitamin D, follicle stimulating and luteinising hormone, oestradiol, and testosterone levels were measured. Patients completed a four day prospective dietary diary. Exercise was assessed by a seven day activity recall questionnaire. Sexual development and treatment histories were obtained. The relationship between all these variables and BMD measurements was analysed. RESULTS Sixty six percent of 114 patients assessed had osteopenia or osteoporosis. The Shwachman-Kulczycki (SK) clinical score (higher score = less severe disease) correlated significantly with BMD at the lumbar spine and femoral neck, and with total body BMD (p<0.001). There was a predicted increase of 0.0032 g/cm2 in lumbar spine BMD for every unit increase in the SK score. Oral steroid use was significantly associated with reduced BMD at the lumbar spine (p = 0.017) and femoral neck (p = 0.027). CONCLUSIONS Osteopenia and osteoporosis are common findings in a heterogeneous population of adults with CF. Patients at most risk are those with severe disease and those who have used corticosteroids.

Development of a disease specific health related quality of life measure for adults and adolescents with cystic fibrosis

BACKGROUND Health related quality of life (HRQoL) measurement is important in determining the impact of disease on daily functioning and subsequently informing interventions. In cystic fibrosis (CF) generic HRQoL measures have been employed but these may not be sufficiently specific. The aim of the current work was to develop and validate a disease specific HRQoL measure for adults and adolescents with cystic fibrosis. METHODS Areas of concern to adults and adolescents with CF were identified by unstructured interviews, self-administered questionnaires, consultation with multidisciplinary specialist staff, a review of the relevant literature, and examination of other HRQoL measures. Items for the questionnaire were generated on the basis of this process. Continued evaluation and development of the Cystic Fibrosis Quality of Life (CFQoL) questionnaire was undertaken by a process of statistical analysis and continued feedback from patients. The full testing and validation of the CFQoL questionnaire took place over four phases: (1) initial item generation and testing of a preliminary questionnaire, (2) testing and validation of the second version of the questionnaire, (3) test-retest reliability of a third and final version of the questionnaire, and (4) sensitivity testing of the final version of the questionnaire. RESULTS Nine domains of functioning were identified using principal components analysis with varimax rotation. Internal reliability of the identified domains was demonstrated using Cronbach alpha coefficients (range 0.72–0.92) and item to total domain score correlations. Concurrent validity (ranger = 0.64–0.74), discriminatory ability between different levels of disease severity, sensitivity across transient changes in health (effect size range, moderate d = 0.56 to large d = 1.95), and test-retest reliability (r = 0.74–0.96) were also found to be robust. CONCLUSIONS The CFQoL questionnaire is a fully validated disease specific measure consisting of 52 items across nine domains of functioning which have been identified by, and are of importance to, adolescents and adults with cystic fibrosis. This measure will be useful in clinical trials and longitudinal studies.

Antibiotic Treatment of Multidrug-Resistant Organisms in Cystic Fibrosis

Respiratory tract infection with eventual respiratory failure is the major cause of morbidity and mortality in cystic fibrosis (CF). Infective exacerbations need to be treated promptly and effectively to minimize potentially accelerated attrition of lung function. The choice of antibiotic depends on in vitro sensitivity patterns. However, physicians treating patients with CF are increasingly faced with infection with multidrug-resistant isolates of Pseudomonas aeruginosa. In addition, innately resistant organisms such as Burkholderia cepacia complex, Stenotrophomonas maltophilia and Achromobacter (Alcaligenes) xylosoxidans are becoming more prevalent. Infection with methicillin-resistant Staphylococcus aureus (MRSA) is also a problem. These changing patterns probably result from greater patient longevity and increased antibiotic use for acute exacerbations and maintenance care.Multidrug-resistant P. aeruginosa infection may be treated successfully by using two antibiotics with different mechanisms of action. In practice antibiotic choices have usually been made on a best-guess basis, but recent research suggests that more directed therapy can be achieved through the application of multiple-combination bactericidal testing (MCBT). Aerosol delivery of tobramycin for inhalation solution achieves high endobronchial concentrations that may overcome bacterial resistance as defined by standard laboratory protocols. Resistance to colistin is rare and this antibiotic should be seen as a valuable second-line drug to be reserved for multidrug-resistant P. aeruginosa. The efficacy of new antibiotic groups such as the macrolides needs to be evaluated.CF units should adopt strict segregation policies to interrupt person-to-person spread of B. cepacia complex. Treatment of panresistant strains is difficult and often arbitrary. Combination antibiotic therapy is recommended, usually tobramycin and high-dose meropenem and/or ceftazidime, but the choice of treatment regimen should always be guided by the clinical response.The clinical significance of S. maltophilia, A. xylosoxidans and MRSA infection in CF lung disease remains uncertain. If patients show clinical decline and are chronically colonized/infected with either of the former two pathogens, treatment is recommended but efficacy data are lacking. There are defined microbiological reasons for attempting eradication of MRSA but there are no proven deleterious effects of this infection on lung function in patients with CF. Various treatment protocols exist but none has been subject to a randomized, controlled trial.Multidrug-resistant microorganisms are an important and growing issue in the care of patients with CF. Each patient infected with such strains should be assessed individually and antibiotic treatment planned according to in vitro sensitivity, patient drug tolerance, and results of in vitro studies which may direct the physician to antibiotic combinations most likely to succeed.

Accurate Assessment of Adherence: Self-Report and Clinician Report vs Electronic Monitoring of Nebulizers

BACKGROUND People with cystic fibrosis have a high treatment burden. While uncertainty remains about individual patient level of adherence to medication, treatment regimens are difficult to tailor, and interventions are difficult to evaluate. Self- and clinician-reported measures are routinely used despite criticism that they overestimate adherence. This study assessed agreement between rates of adherence to prescribed nebulizer treatments when measured by self-report, clinician report, and electronic monitoring suitable for long-term use. METHODS Seventy-eight adults with cystic fibrosis were questioned about their adherence to prescribed nebulizer treatments over the previous 3 months. Self-report was compared with clinician report and stored adherence data downloaded from the I-Neb nebulizer system. Adherence measures were expressed as a percentage of the prescribed regimen, bias was estimated by the paired difference in mean (95% CI) patient and clinician reported and actual adherence. Agreement between adherence measures was calculated using intraclass correlation coefficients (95% CI), and disagreements for individuals were displayed using Bland-Altman plots. RESULTS Patient-identified prescriptions matched the medical record prescription. Median self-reported adherence was 80% (interquartile range, 60%-95%), whereas median adherence measured by nebulizer download was 36% (interquartile range, 5%-84.5%). Nine participants overmedicated and underreported adherence. Median clinician report ranged from 50% to 60%, depending on profession. Extensive discrepancies between self-report and clinician report compared with nebulizer download were identified for individuals. CONCLUSIONS Self- and clinician-reporting of adherence does not provide accurate measurement of adherence when compared with electronic monitoring. Using inaccurate measures has implications for treatment burden, clinician prescribing practices, cost, and accuracy of trial data.

Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials.

Pulmonary exacerbations represent a key outcome variable in clinical trials of cystic fibrosis (CF). As there is variation in the trigger for use of intravenous antibiotics compared to the use of oral antibiotics or new nebulised therapy for treatment of exacerbations, the consensus view is that use of intravenous antibiotics cannot be regarded as the key defining character for an exacerbation on its own. The consensus view is that the clinical need for additional treatment as indicated by a recent change in clinical parameters provides the best definition of an exacerbation. Which parameters to include as well as the problems associated with the use of scoring systems and symptom clusters are being discussed.

PmrB mutations promote polymyxin resistance of Pseudomonas aeruginosa isolated from colistin-treated cystic fibrosis patients

ABSTRACT Pseudomonas aeruginosa can develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of colistin (polymyxin E) resistance in laboratory strains and clinical isolates of this organism (MICs of 8 to 64 mg/liter). To explore the role of PmrAB in high-level clinical polymyxin resistance, P. aeruginosa isolates from chronically colistin-treated cystic fibrosis patients, most with colistin MICs of >512 mg/liter, were analyzed. These cystic fibrosis isolates contained probable gain-of-function pmrB alleles that conferred polymyxin resistance to strains with a wild-type or pmrAB deletion background. Double mutant pmrB alleles that contained mutations in both the periplasmic and dimerization-phosphotransferase domains markedly augmented polymyxin resistance. Expression of mutant pmrB alleles induced transcription from the promoter of the arnB operon and stimulated addition of 4-amino-l-arabinose to lipid A, consistent with the known role of this lipid A modification in polymyxin resistance. For some highly polymyxin-resistant clinical isolates, repeated passage without antibiotic selection pressure resulted in loss of resistance, suggesting that secondary suppressors occur at a relatively high frequency and account for the instability of this phenotype. These results indicate that pmrB gain-of-function mutations can contribute to high-level polymyxin resistance in clinical strains of P. aeruginosa.

Measuring and improving respiratory outcomes in cystic fibrosis lung disease: Opportunities and challenges to therapy ☆

Cystic fibrosis (CF) is a life-shortening disease with significant morbidity. Despite overall improvements in survival, patients with CF experience frequent pulmonary exacerbations and declining lung function, which often accelerates during adolescence. New treatments target steps in the pathogenesis of lung disease, such as the basic defect in CF (CF Transmembrane Conductance Regulator [CFTR]), pulmonary infections, inflammation, and mucociliary clearance. These treatments offer hope but also present challenges to patients, clinicians, and researchers. Comprehensive assessment of efficacy is critical to identify potentially beneficial treatments. Lung function and pulmonary exacerbation are the most commonly used outcome measures in CF clinical research. Other outcome measures under investigation include measures of CFTR function; biomarkers of infection, inflammation, lung injury and repair; and patient-reported outcomes. Molecular diagnostics may help elucidate the complex CF airway microbiome. As new treatments are developed for patients with CF, efforts should be made to balance treatment burden with quality of life. This review highlights emerging treatments, obstacles to optimizing outcomes, and key future directions for research.

European cystic fibrosis bone mineralisation guidelines

Patients with cystic fibrosis (CF) are at risk of developing low bone mineral density (BMD) and fragility fractures. This paper presents consensus statements that summarise current knowledge of the epidemiology and pathophysiology of CF-related skeletal deficits and provides guidance on its assessment, prevention and treatment. The statements were validated using a modified Delphi methodology.

Chronic Pseudomonas aeruginosa infection definition: EuroCareCF Working Group report

Chronic pulmonary infection with P. aeruginosa develops in most patients with cystic fibrosis (CF); by adulthood 80% of patients are infected and chronic P. aeruginosa infection is the primary cause of increased morbidity and mortality in CF. Chronic infection is preceded by an intermittent stage of infection. The initial stage is characteristically followed by the gradual emergence of mucoid variants of the colonizing strains and a rise in anti-Pseudomonas antibodies. In addition to optimizing existing therapeutic strategies, effective new agents need to be identified. Studies in patients with CF are particularly challenging: the progressive nature of the disease and the wide variation in severity influence considerably the outcome of drug testing. A validated, universally accepted, and clinically useful classification of patients infected with P. aeruginosa, particularly those chronically infected, is needed that can be used as both a criterion for patient selection for clinical trials and as a study endpoint.