Tablet and web-based audiometry to screen for hearing loss in adults with cystic fibrosis.

INTRODUCTION: Individuals with chronic lung disease (eg, cystic fibrosis (CF)) often receive antimicrobial therapy including aminoglycosides resulting in ototoxicity. Extended high-frequency audiometry has increased sensitivity for ototoxicity detection, but diagnostic audiometry in a sound-booth is costly, time-consuming and requires a trained audiologist. This cross-sectional study analysed tablet-based audiometry (Shoebox MD) performed by non-audiologists in an outpatient setting, alongside home web-based audiometry (3D Tune-In) to screen for hearing loss in adults with CF. METHODS: Hearing was analysed in 126 CF adults using validated questionnaires, a web self-hearing test (0.5 to 4 kHz), tablet (0.25 to 12 kHz) and sound-booth audiometry (0.25 to 12 kHz). A threshold of ≥25 dB hearing loss at ≥1 audiometric frequency was considered abnormal. Demographics and mitochondrial DNA sequencing were used to analyse risk factors, and accuracy and usability of hearing tests determined. RESULTS: Prevalence of hearing loss within any frequency band tested was 48%. Multivariate analysis showed age (OR 1.127; (95% CI: 1.07 to 1.18; p value<0.0001) per year older) and total intravenous antibiotic days over 10 years (OR 1.006; (95% CI: 1.002 to 1.010; p value=0.004) per further intravenous day) were significantly associated with increased risk of hearing loss. Tablet audiometry had good usability, was 93% sensitive, 88% specific with 94% negative predictive value to screen for hearing loss compared with web self-test audiometry and questionnaires which had poor sensitivity (17% and 13%, respectively). Intraclass correlation (ICC) of tablet versus sound-booth audiometry showed high correlation (ICC >0.9) at all frequencies ≥4 kHz. CONCLUSIONS: Adults with CF have a high prevalence of drug-related hearing loss and tablet-based audiometry can be a practical, accurate screening tool within integrated ototoxicity monitoring programmes for early detection.

A high prevalence of chronic gastrointestinal symptoms in adults with cystic fibrosis is detected using tools already validated in other GI disorders.

Background: People with cystic fibrosis (CF) report a variety of gastrointestinal (GI) symptoms, independent of pancreatic enzyme insufficiency (PEI), reminiscent of other chronic GI disorders. There are currently no accepted or validated assessment tools and neither the range, frequency nor severity of GI symptoms has been systematically described in CF. We present results of a cross-sectional study using established tools and compare them to current measures of quality of life (QOL). Methods: Consecutive patients attending specialist CF appointments were asked to complete questionnaires including the GI Symptom Rating Scale (GSRS); Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS) and Cystic Fibrosis Questionnaire (CFQ-R). Questionnaire terminology was altered to replace references to 'IBS' with 'GI symptoms'. Results: In total, 107 patients were recruited (mean age, 27.8 ± 9.6 years; 60 female), and 94 (88%) had PEI. Body mass index was 22.1 ± 3.6 kg/m2, forced expiratory volume in one second was 59 + 27.7% predicted. Fifty-three (49.5%) were p.Phe508del homozygous. Overall 69/107 (65%) reported significant GI symptoms independent of PEI or adherence to pancreatic enzyme replacement therapy (PERT), with the four most frequent being attributable to the lower GI tract: bloating/distension, flatulence, abdominal pain and borborygmi (gurgling). There was no numerical correlation between any CFQ-R domain (particularly Digestion domain) and GSRS or SSS. Conclusion: This is the first systematic study measuring GI symptoms in CF using validated GI tools. Symptoms are not related to PERT or genotype and appear to be captured well by the GSRS. Further research will study longitudinal changes with treatment, and therapeutic trials in CF may use these tools to demonstrate a positive impact on 'non-respiratory' symptoms and QOL.

Amyloidosis in cystic fibrosis.

As the life expectancy of patients with cystic fibrosis has increased, greater attention has been paid towards the diagnosis and management of the longer term consequences of the condition. A recognised but rare complication of the disease is the development of secondary amyloidosis. Whilst deposition of amyloid protein has been reported in a high proportion of patients with cystic fibrosis at post-mortem [1] and Serum Amyloid A protein has been shown to correlate with disease activity and response to antibiotics [2], the manifestation of clinical disease remains extremely uncommon. The prognosis for patients with amyloid secondary to cystic fibrosis in published reports has been historically bleak [3-6], however there may be novel approaches in the era of biological therapies. The theoretical potential for an increase in the incidence of secondary amyloid amongst the population of cystic fibrosis patients who are experiencing much longer lifespans means that it is worthwhile to consider the condition and its possible treatments in more detail. We report a case and a review of the literature.

Anorexia nervosa in cystic fibrosis.

This article explores the challenges associated with diagnosing and managing eating disorders such as anorexia nervosa amongst adolescents and adults with cystic fibrosis. It reviews the known risk factors, generic verses disease specific eating disorder risk screening tools and considers the ethical dilemmas associated with critically low body mass indices. A case review is included to illustrate the complexities of managing both conditions in the context of declining respiratory function.

The Objective Assessment of Cough Frequency in Bronchiectasis.

INTRODUCTION: Cough in bronchiectasis is associated with significant impairment in health status. This study aimed to quantify cough frequency objectively with a cough monitor and investigate its relationship with health status. A secondary aim was to identify clinical predictors of cough frequency. METHODS: Fifty-four patients with bronchiectasis were compared with thirty-five healthy controls. Objective 24-h cough, health status (cough-specific: Leicester Cough Questionnaire LCQ and bronchiectasis specific: Bronchiectasis Health Questionnaire BHQ), cough severity and lung function were measured. The clinical predictors of cough frequency in bronchiectasis were determined in a multivariate analysis. RESULTS: Objective cough frequency was significantly raised in patients with bronchiectasis compared to healthy controls [geometric mean (standard deviation)] 184.5 (4.0) vs. 20.6 (3.2) coughs/24-h; mean fold-difference (95% confidence interval) 8.9 (5.2, 15.2); p < 0.001 and they had impaired health status. There was a significant correlation between objective cough frequency and subjective measures; LCQ r = -0.52 and BHQ r = -0.62, both p < 0.001. Sputum production, exacerbations (between past 2 weeks to 12 months) and age were significantly associated with objective cough frequency in multivariate analysis, explaining 52% of the variance (p < 0.001). There was no statistically significant association between cough frequency and lung function. CONCLUSIONS: Cough is a common and significant symptom in patients with bronchiectasis. Sputum production, exacerbations and age, but not lung function, were independent predictors of cough frequency. Ambulatory objective cough monitoring provides novel insights and should be further investigated as an outcome measure in bronchiectasis.

The development and validation of the Bronchiectasis Health Questionnaire.

Health-related quality of life or health status is significantly impaired in bronchiectasis. There is a paucity of brief, simple-to-use, disease-specific health status measures. The aim of this study was to develop and validate the Bronchiectasis Health Questionnaire (BHQ), a new health status measure that is brief and generates a single overall score.Patients with bronchiectasis were recruited from two outpatient clinics, during a clinically stable stage. The development of the questionnaire followed three phases: item generation and item reduction using Rasch analysis, validation, and repeatability testing. The BHQ was translated into 11 languages using standardised methodology.206 patients with bronchiectasis completed a preliminary 65-item questionnaire. 55 items were removed due to redundancy or poor fit to the Rasch model. The final version of the BHQ consisted of 10 items. Internal consistency was good (Cronbach's α=0.85). Convergent validity of the BHQ with the St George's Respiratory Questionnaire was high (r= -0.82; p<0.001) and moderate with lung function (forced expiratory volume in 1 s % predicted r= -0.27; p=0.001). There was a significant association between BHQ scores and number of exacerbations of bronchiectasis in the last 12 months (p<0.001), hospital admissions (p=0.001) and computed tomography scan bronchiectasis pulmonary lobe counts (p<0.001). BHQ scores were significantly worse in patients with sputum bacterial colonisation versus no colonisation (p=0.048). The BHQ was highly repeatable after 2 weeks (intraclass correlation coefficient 0.89).The BHQ is a brief, valid and repeatable, self-completed health status questionnaire for bronchiectasis that generates a single total score. It can be used in the clinic to assess bronchiectasis from the patient's perspective.

Physiological markers of exercise capacity and lung disease severity in cystic fibrosis.

BACKGROUND AND OBJECTIVE: Peak aerobic capacity (VO2 peak) is an important outcome measure in cystic fibrosis (CF), but measurement is not widely available and can be influenced by patient motivation, pain and fatigue. Alternative markers of disease severity would be helpful. Neural respiratory drive, measured using parasternal intercostal muscle electromyography (EMGpara), reflects the load to capacity balance of the respiratory system and provides a composite measure of pulmonary function impairment in CF. The aim of the study was to investigate the relationship between exercise capacity, EMGpara and established measures of pulmonary function in clinically stable adult CF patients. METHODS: Twenty CF patients (12 males, median (range) age: 22.3 (17.0-43.1) years) performed the 10-m incremental shuttle walk test (ISWT) maximally with contemporaneous measures of aerobic metabolism. EMGpara was recorded from second intercostal space at rest and normalized using peak electromyogram activity obtained during maximum respiratory manoeuvres and expressed as EMGpara%max (EMGpara expressed as a percentage of maximum). RESULTS: VO2 peak was strongly correlated with ISWT distance (r = 0.864, P < 0.0001). Lung gas transfer (TL CO) % predicted was best correlated with VO2 peak (r = 0.842, P < 0.0001) and ISWT distance (r = 0.788, P < 0.0001). EMGpara%max also correlated with VO2 peak (-0.757, P < 0.0001), while the relationships between exercise outcome measures and forced expiratory volume in 1 s (FEV1 ) % predicted and forced vital capacity (FVC) % predicted were less strong. A TL CO% predicted of <70.5% was the strongest predictor of VO2 peak <32 mL/min/kg (area under the curve (AUC): 0.96, 100% sensitivity, 83.3% specificity). ISWT distance and EMGpara%max also performed well, with other pulmonary function variables demonstrating poorer predictive ability. CONCLUSION: TL CO% predicted and EMGpara%max relate strongly to exercise performance markers in CF and may provide alternative predictors of lung disease progression.

Blunted perception of neural respiratory drive and breathlessness in patients with cystic fibrosis.

The electromyogram recorded from the diaphragm (EMGdi) and parasternal intercostal muscle using surface electrodes (sEMGpara) provides a measure of neural respiratory drive (NRD), the magnitude of which reflects lung disease severity in stable cystic fibrosis. The aim of this study was to explore perception of NRD and breathlessness in both healthy individuals and patients with cystic fibrosis. Given chronic respiratory loading and increased NRD in cystic fibrosis, often in the absence of breathlessness at rest, we hypothesised that patients with cystic fibrosis would be able to tolerate higher levels of NRD for a given level of breathlessness compared to healthy individuals during exercise. 15 cystic fibrosis patients (mean forced expiratory volume in 1 s (FEV1) 53.5% predicted) and 15 age-matched, healthy controls were studied. Spirometry was measured in all subjects and lung volumes measured in the cystic fibrosis patients. EMGdi and sEMGpara were recorded at rest and during incremental cycle exercise to exhaustion and expressed as a percentage of maximum (% max) obtained from maximum respiratory manoeuvres. Borg breathlessness scores were recorded at rest and during each minute of exercise. EMGdi % max and sEMGpara % max and associated Borg breathlessness scores differed significantly between healthy subjects and cystic fibrosis patients at rest and during exercise. The relationship between EMGdi % max and sEMGpara % max and Borg score was shifted to the right in the cystic fibrosis patients, such that at comparable levels of EMGdi % max and sEMGpara % max the cystic fibrosis patients reported significantly lower Borg breathlessness scores compared to the healthy individuals. At Borg score 1 (clinically significant increase in breathlessness from baseline) corresponding levels of EMGdi % max (20.2±12% versus 32.15±15%, p=0.02) and sEMGpara % max (18.9±8% versus 29.2±15%, p=0.04) were lower in the healthy individuals compared to the cystic fibrosis patients. In the cystic fibrosis patients EMGdi % max at Borg score 1 was related to the degree of airways obstruction (FEV1) (r=-0.664, p=0.007) and hyperinflation (residual volume/total lung capacity) (r=0.710, p=0.03). This relationship was not observed for sEMGpara % max. These data suggest that compared to healthy individuals, patients with cystic fibrosis can tolerate much higher levels of NRD before increases in breathlessness from baseline become clinically significant. EMGdi % max and sEMGpara % max provide physiological tools with which to elucidate factors underlying inter-individual differences in breathlessness perception.

The validity of health-related quality of life questionnaires in bronchiectasis: a systematic review and meta-analysis.

BACKGROUND: A range of questionnaires have been used to assess health-related quality of life (HRQOL) in bronchiectasis. A systematic review was conducted to evaluate their psychometric properties and assess associations between HRQOL and clinical measures. METHODS: Five electronic databases were searched. Studies eligible for inclusion were those that investigated the validity of HRQOL questionnaires and/or their association with other outcomes in adults with bronchiectasis. Patients with cystic fibrosis were excluded. The identified questionnaires were assessed for convergent, discriminant and cross-cultural translation validity; missing data, floor and ceiling effects, internal consistency, responsiveness and test-retest reliability. A meta-analysis was conducted to estimate the strength of associations between HRQOL and clinical measures. RESULTS: From 1918 studies identified, 43 studies were included in the systematic review, of which 38 were suitable for the meta-analysis. Nine HRQOL questionnaires were identified, with the most widely used being: St George's Respiratory Questionnaire, Leicester Cough Questionnaire, Quality of Life-Bronchiectasis and Short Form-36. HRQOL questionnaires had moderate to good internal consistency and good test-retest reliability. Only 8 of 18 studies that used translated HRQOL questionnaires reported or referred to the validity of the translated questionnaire. There was a stronger correlation (mean r (95% CI)) between HRQOL and subjective outcome measures, such as dyspnoea (0.55 (0.41 to 0.68)) and fatigue (0.42 (0.23 to 0.58)) compared with objective measures; exercise capacity (-0.41 (-0.54 to -0.24)), FEV1% predicted (-0.31 (-0.40 to -0.23)) and extent of bronchiectasis on CT scan (0.35 (0.03 to 0.61)); all p<0.001. CONCLUSIONS: This review supports most HRQOL questionnaires used in bronchiectasis have good psychometric properties. There was a weak to moderate association between HRQOL and objective outcome measures. This suggests that HRQOL questionnaires assess a unique aspect of health not captured by objective measures.

Prevalence of nontuberculous mycobacteria in cystic fibrosis clinics, United Kingdom, 2009.

Incidence of pulmonary infection with nontuberculous mycobacteria (NTM) is increasing among persons with cystic fibrosis (CF). We assessed prevalence and management in CF centers in the United Kingdom and found 5.0% of 3,805 adults and 3.3% of 3,317 children had recently been diagnosed with NTM. Of those, 44% of adults and 47% of children received treatment.

Chronic lung disease in adolescents with delayed diagnosis of vertically acquired HIV infection.

BACKGROUND: Long-term survivors of vertically acquired human immunodeficiency virus (HIV) infection are reaching adolescence in large numbers in Africa and are at high risk of delayed diagnosis and chronic complications of untreated HIV infection. Chronic respiratory symptoms are more common than would be anticipated based on the HIV literature. METHODS: Consecutive adolescents with presumed vertically acquired HIV attending 2 HIV care clinics in Harare, Zimbabwe, were recruited and assessed with clinical history and examination, CD4 count, pulmonary function tests, Doppler echocardiography, and chest radiography (CXR). Those with suspected nontuberculous chronic lung disease (CLD) were scanned using high-resolution computed tomography (HRCT). RESULTS: Of 116 participants (43% male; mean age, 14 ± 2.6 years, mean age at HIV diagnosis, 12 years), 69% were receiving antiretroviral therapy. Chronic cough and reduced exercise tolerance were reported by 66% and 21% of participants, respectively; 41% reported multiple respiratory tract infections in the previous year, and 10% were clubbed. More than 40% had hypoxemia at rest (13%) or on exercise (29%), with pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg) in 7%. Forced expiratory volume in 1 second (FEV(1)) was <80% predicted in 45%, and 47% had subtle CXR abnormalities. The predominant HRCT pattern was decreased attenuation as part of a mosaic attenuation pattern (31 of 56 [55%]), consistent with small airway disease and associated with bronchiectasis (Spearman correlation coefficient (r(2) = 0.8) and reduced FEV(1) (r(2) = -0.26). CONCLUSIONS: Long-term survivors of vertically acquired HIV in Africa are at high risk of a previously undescribed small airway disease, with >40% of unselected adolescent clinic attendees meeting criteria for severe hypoxic CLD. This condition is not obvious at rest. Etiology, prognosis, and response to treatment are currently unknown.

Effect of endurance exercise on respiratory muscle function in patients with cystic fibrosis.

During exercise, patients with cystic fibrosis (CF) dynamically hyperinflate, which imposes both elastic and threshold loads on the inspiratory muscles and places them at a mechanical disadvantage due to muscle shortening. Conversely, dynamic hyperinflation imposes a progressively resistive load and lengthens the expiratory muscles potentially increasing their susceptibility to develop low frequency fatigue (LFF). The aim of the study was to determine whether high intensity endurance exercise leads to the development of LFF in either the diaphragm or expiratory abdominal wall muscles in patients with CF. Ten patients and ten healthy individuals were studied. Twitch transdiaphragmatic pressure (TwP(di)) and twitch abdominal pressure (TwT(10)) were measured before and after exhaustive endurance cycle exercise at 80% of their previously determined maximum work rate. There was no difference in TwP(di) or TwT(10) at 20, 40 or 60 min post exercise compared to pre-exercise resting values in any of the participants, indicating that overt LFF of the respiratory muscles did not develop.

Measurement of parasternal intercostal electromyogram during an infective exacerbation in patients with cystic fibrosis.

The parasternal intercostal muscle electromyogram (sEMGpara) is a measure of neural respiratory drive and reflects lung disease severity in stable cystic fibrosis (CF). The aim of the study was to measure sEMGpara in acute infective exacerbations of CF and compare changes in sEMGpara with those in conventional lung function measures. 12 patients with CF admitted to hospital with an acute chest infection were studied. There was a significant reduction in mean ± SD sEMGpara (ΔsEMGpara -38 ± 19%, p<0.001) between admission and discharge. Spirometery also improved significantly from admission to discharge; Δforced expiratory volume in 1 s % predicted 39 ± 30%, p<0.001 and Δvital capacity % pred 22 ± 18%, p<0.001. sEMGpara has potential value as a nonvolitional measure of change in respiratory function in CF.

Improving outcomes in patients with cystic fibrosis.

Cystic fibrosis (CF) is the most common fatal inherited disease in Caucasian people. Inheritance follows an autosomal recessive pattern. Recent data indicate that there are more than 9,000 patients with CF in the UK. At a cellular level there is an abnormal CF transmembrane conductance regulator (CFTR), a protein essential for chloride and sodium homoeostasis, caused by a mutation in the CF gene. The consequence of this abnormal protein is thick, viscous secretions in the lungs and GI tract, which lead to recurrent lung infections and pancreatic insufficiency with intestinal malabsorption. Most patients present in early childhood with classic CF. They show one or more of the typical CF phenotypic characteristics (chronic pulmonary disease, GI symptoms and malabsorption, nutritional abnormalities and sinus disease). A minority of patients have atypical CF. They tend to present at an older age, often in adulthood, are mainly pancreatic sufficient, have milder disease and a better prognosis. When CF is suspected the diagnosis can be confirmed by measuring sweat chloride concentration and by looking for CFTR mutations. Immunoreactive trypsinogen is measured in blood taken from a heel prick in all neonates, and is a marker of pancreatic injury consistent with (but not specific for) CF.

Neural respiratory drive, pulmonary mechanics and breathlessness in patients with cystic fibrosis.

BACKGROUND: Neural respiratory drive (NRD) measured from the diaphragm electromyogram (EMGdi) reflects the load/capacity balance of the respiratory muscle pump and is a marker of lung disease severity. EMGdi measurement is invasive, but recording the EMG from the parasternal intercostal muscles using surface electrodes (sEMGpara) could provide a non-invasive method of assessing NRD and disease severity. Objectives To test the hypothesis that NRD measured by sEMGpara correlates with EMGdi, to provide an index of disease severity in cystic fibrosis (CF) and to relate to exercise-induced breathlessness. METHODS: 15 patients with CF (mean forced expiratory volume in 1 s (FEV(1)) 53.5% predicted) and 15 age-matched healthy controls were studied. sEMGpara and EMGdi were recorded at rest and during exercise. sEMGpara was recorded using surface electrodes and EMGdi using a multipair oesophageal electrode catheter. Signals were normalised using the peak EMG recorded during maximum respiratory manoeuvres and expressed as EMG%max. The respiratory pattern, metabolic data, oesophageal and gastric pressures and Borg scores were also recorded. RESULTS: Mean (SD) resting sEMGpara%max and EMGdi%max were higher in patients with CF than in controls (13.1 (7)% and 18.5 (7.5)% vs 5.8 (3)% and 7.5 (2)%, respectively, p<0.001). In the patients with CF, resting sEMGpara%max and EMGdi%max were related to the degree of airways obstruction (FEV(1)) (r = -0.91 and r = -0.82, both p<0.001), hyperinflation (r = 0.63 and r = 0.56, both p<0.001) and dynamic lung compliance (r = -0.53 and r = -0.59, both p<0.001). During exercise, sEMGpara%max and EMGdi%max were strongly correlated with breathlessness in the patients with CF before (r = 0.906, p<0.001) and after (r = 0.975, p<0.001) the onset of neuromechanical dissociation. CONCLUSION: sEMGpara%max provides a non-invasive marker of neural drive, which reflects disease severity and exercise-induced breathlessness in CF.

Inflammation in cystic fibrosis--when and why? Friend or foe?

Pulmonary infection and an excessive neutrophil-driven inflammatory response are responsible for most of the morbidity and mortality associated with cystic fibrosis. Although inflammation is first and foremost a protective response to injury or infection it has the potential to cause considerable harm when it is excessive. Whereas most published reports emphasize the damaging effects of the chronic inflammatory response in cystic fibrosis, the beneficial effects are more difficult to quantify. Low levels of inflammation may assist in clearing infection, particularly early in the disease process, and surges of acute inflammation may be beneficial during exacerbations. Anti-inflammatory therapies are used to modify the inflammatory response but there is clearly a need to preserve the protective aspects of the inflammatory response because host defense and a fine balance exist between benefit and harm. The underlying processes involved in the inflammatory response are reviewed along with current and future anti-inflammatory therapies.

New continuous and specific fluorometric assays for Pseudomonas aeruginosa elastase and LasA protease.

A highly sensitive assay based on new internally quenched fluorogenic peptide substrates has been developed for monitoring protease activities. These novel substrates comprise an Edans (5-(2-aminoethylamino)-1-naphthalenesulfonic acid) group at the C terminus and a Dabsyl (4-(dimethylamino)azobenzene-4'-sulfonyl chloride) fluorophore at the N terminus of the peptide chains. The Edans fluorescence increases upon peptide hydrolysis by Pseudomonas aeruginosa proteases, and this increase is directly proportional to the amount of substrate cleaved, i.e., protease activity. The substrates Dabsyl-Ala-Ala-Phe-Ala-Edans and Dabsyl-Leu-Gly-Gly-Gly-Ala-Edans were used for testing the peptidasic activities of P. aeruginosa elastase and LasA protease, respectively. Elastase and LasA kinetic parameters were calculated and a sensitive assay was designed for the detection of P. aeruginosa proteases in bacterial supernatants. The sensitivity and the small sample requirements make the assay suitable for high-throughput screening of biological samples. Furthermore, this P. aeruginosa protease assay improves upon existing assays because it is simple, it requires only one step, and even more significantly it is enzyme specific.